Traumatic Brain Injury

Posttraumatic headache (PTH) is associated with an increase in iron accumulation in certain brain regions , notably those involved in the pain network, early research shows.

Investigators found positive correlations between iron accumulation and headache frequency, number of lifetime mild traumatic brain injuries (mTBIs), and time since last mTBI.

The findings come on the heels of previous research showing patients with iron accumulation in certain brain regions don’t respond as well to treatment, study investigator, Simona Nikolova, PhD, assistant professor of neurology, Mayo Clinic, Phoenix, Arizona, told this news organization.

“This is really important, and doctors need to be aware of it. If you have a patient who is not responding to treatment, then you know what to look at,” she said. 

The findings (Abstract #3379) will be presented on April 15 at the American Academy of Neurology (AAN) 2024 Annual Meeting. 
 

Dose Effect

The study included 60 people with acute PTH due to mTBI. Most were White, and almost half had sustained a concussion due to a fall, with about 30% injured in a vehicle accident and a smaller number injured during a fight.

The mean number of lifetime mTBIs was 2.4, although participants had sustained as many as five or six and as few as one. The mean time from the most recent mTBI was 25 days, and the mean score on the Sport Concussion Assessment Tool (SCAT), which measures postconcussion symptom severity, was 29.

Most in the mTBI group (43) had migraine or probable migraine, and 14 had tension-type headaches. Mean headache frequency was 81%.

Researchers matched these patients with 60 controls without concussion or headache. Because iron accumulation is age-related, they tried to eliminate this covariant by pairing each participant with mTBI with an age- and sex-matched control.

All participants underwent a type of brain MRI known as T2* weighted sequence that can identify brain iron accumulation, a marker of neural injury. 

Investigators found that the PTH group had significantly higher levels of iron accumulation in several areas of the brain, most of which are part of a “pain network” that includes about 63 areas of the brain, Dr. Nikolova said.

The study wasn’t designed to determine how much more iron accumulation mTBI patients had vs controls. 

“We can’t say it was twice as much or three times as much; we can only say it was significant. Measuring concentrations in PTH patients and comparing that with controls is something we haven’t don’t yet,” said Dr. Nikolova.

Areas of the brain with increased iron accumulation, included the periaqueductal gray (PAG), anterior cingulated cortex, and supramarginal gyrus. 

Research suggests patients with migraine who have elevated levels of iron in the PAG have a poorer response to botulinum toxin treatment. An earlier study by the same team showed a poorer response to the calcitonin gene-related peptide inhibitor erenumab in migraine patients with elevated iron in the PAG.

Researchers discovered that those with more lifetime TBIs had higher iron accumulation in the right gyrus rectus and right putamen vs those with fewer injuries and that headache frequency was associated with iron accumulation in the posterior corona radiata, bilateral temporal, right frontal, bilateral supplemental motor area, left fusiform, right hippocampus, sagittal striatum, and left cerebellum.
 

Surprising Result

The investigators also found a link between time since the most recent mTBI and iron accumulation in the bilateral temporal, right hippocampus, posterior and superior corona radiata, bilateral thalamus, right precuneus and cuneus, right lingual, and right cerebellum. 

“The more time that passed since the concussion occurred, the more likely that people had higher iron levels,” said Dr. Nikolova.

It’s perhaps to be expected that the length of time since injury is linked to iron accumulation in the brain as iron accumulates over time. But even those whose injury was relatively recent had higher amounts of iron, which Dr. Nikolova said was “surprising.”

“We thought iron accumulates over time so we were thinking maybe we should be doing a longitudinal study to see what happens, but we see definite iron accumulation due to injury shortly after the injury,” she said.

There was no association between iron accumulation and symptom severity as measured by SCAT scores.
 

Questions Remain

It’s unclear why iron accumulates after an injury or what the ramifications are of this accumulation, Dr. Nikolova noted. 

The imaging used in the study doesn’t distinguish between “bound” iron found after a hemorrhage and “free” iron in the brain. The free iron type has been shown to be increased after TBI and is “the stuff you should be afraid of,” Dr. Nikolova said.

Iron’s role in the metabolic process is important, but must be closely regulated, she said. Even a small accumulation can lead to oxidative stress.

Researchers are investigating whether the findings would be similar in mTBI but no headache and want to increase the number of study participants. A larger, more diverse sample would allow them to probe other questions, including whether iron accumulation is different in men and women. More data could also eventually lead to iron accumulation becoming a biomarker for concussion and PTH, Dr. Nikolova said.

“If you know a certain person has that biomarker, you might be able to administer a drug or some therapeutic procedure to prevent that iron from continuing to accumulate in the brain.”

Chelation drugs and other therapies may clear iron from the body but not necessarily from the brain. 

Commenting on the study for this news organization, Frank Conidi, MD, director, Florida Center for Headache and Sports Neurology, Port St. Lucie , said that the study supports the hypothesis that concussion “is not a benign process for the brain, and the cumulative effect of repetitive head injury can result in permanent brain injury.”

He said that he found the accumulation of iron in cortical structures particularly interesting. This, he said, differs from most current research that suggests head trauma mainly results in damage to white matter tracts.

He prefers the term “concussion” over “mild traumatic brain injury” which was used in the study. “Recent guidelines, including some that I’ve been involved with, have defined mild traumatic brain injury as a more permanent process,” he said.

The study was supported by the US Department of Defense and National Institutes of Health. No relevant conflicts of interest were disclosed. 

A version of this article appeared on Medscape.com.

Posttraumatic headache (PTH) is associated with an increase in iron accumulation in certain brain regions , notably those involved in the pain network, early research shows.

Investigators found positive correlations between iron accumulation and headache frequency, number of lifetime mild traumatic brain injuries (mTBIs), and time since last mTBI.

The findings come on the heels of previous research showing patients with iron accumulation in certain brain regions don’t respond as well to treatment, study investigator, Simona Nikolova, PhD, assistant professor of neurology, Mayo Clinic, Phoenix, Arizona, told this news organization.

“This is really important, and doctors need to be aware of it. If you have a patient who is not responding to treatment, then you know what to look at,” she said. 

The findings (Abstract #3379) will be presented on April 15 at the American Academy of Neurology (AAN) 2024 Annual Meeting. 
 

Dose Effect

The study included 60 people with acute PTH due to mTBI. Most were White, and almost half had sustained a concussion due to a fall, with about 30% injured in a vehicle accident and a smaller number injured during a fight.

The mean number of lifetime mTBIs was 2.4, although participants had sustained as many as five or six and as few as one. The mean time from the most recent mTBI was 25 days, and the mean score on the Sport Concussion Assessment Tool (SCAT), which measures postconcussion symptom severity, was 29.

Most in the mTBI group (43) had migraine or probable migraine, and 14 had tension-type headaches. Mean headache frequency was 81%.

Researchers matched these patients with 60 controls without concussion or headache. Because iron accumulation is age-related, they tried to eliminate this covariant by pairing each participant with mTBI with an age- and sex-matched control.

All participants underwent a type of brain MRI known as T2* weighted sequence that can identify brain iron accumulation, a marker of neural injury. 

Investigators found that the PTH group had significantly higher levels of iron accumulation in several areas of the brain, most of which are part of a “pain network” that includes about 63 areas of the brain, Dr. Nikolova said.

The study wasn’t designed to determine how much more iron accumulation mTBI patients had vs controls. 

“We can’t say it was twice as much or three times as much; we can only say it was significant. Measuring concentrations in PTH patients and comparing that with controls is something we haven’t don’t yet,” said Dr. Nikolova.

Areas of the brain with increased iron accumulation, included the periaqueductal gray (PAG), anterior cingulated cortex, and supramarginal gyrus. 

Research suggests patients with migraine who have elevated levels of iron in the PAG have a poorer response to botulinum toxin treatment. An earlier study by the same team showed a poorer response to the calcitonin gene-related peptide inhibitor erenumab in migraine patients with elevated iron in the PAG.

Researchers discovered that those with more lifetime TBIs had higher iron accumulation in the right gyrus rectus and right putamen vs those with fewer injuries and that headache frequency was associated with iron accumulation in the posterior corona radiata, bilateral temporal, right frontal, bilateral supplemental motor area, left fusiform, right hippocampus, sagittal striatum, and left cerebellum.
 

Surprising Result

The investigators also found a link between time since the most recent mTBI and iron accumulation in the bilateral temporal, right hippocampus, posterior and superior corona radiata, bilateral thalamus, right precuneus and cuneus, right lingual, and right cerebellum. 

“The more time that passed since the concussion occurred, the more likely that people had higher iron levels,” said Dr. Nikolova.

It’s perhaps to be expected that the length of time since injury is linked to iron accumulation in the brain as iron accumulates over time. But even those whose injury was relatively recent had higher amounts of iron, which Dr. Nikolova said was “surprising.”

“We thought iron accumulates over time so we were thinking maybe we should be doing a longitudinal study to see what happens, but we see definite iron accumulation due to injury shortly after the injury,” she said.

There was no association between iron accumulation and symptom severity as measured by SCAT scores.
 

Questions Remain

It’s unclear why iron accumulates after an injury or what the ramifications are of this accumulation, Dr. Nikolova noted. 

The imaging used in the study doesn’t distinguish between “bound” iron found after a hemorrhage and “free” iron in the brain. The free iron type has been shown to be increased after TBI and is “the stuff you should be afraid of,” Dr. Nikolova said.

Iron’s role in the metabolic process is important, but must be closely regulated, she said. Even a small accumulation can lead to oxidative stress.

Researchers are investigating whether the findings would be similar in mTBI but no headache and want to increase the number of study participants. A larger, more diverse sample would allow them to probe other questions, including whether iron accumulation is different in men and women. More data could also eventually lead to iron accumulation becoming a biomarker for concussion and PTH, Dr. Nikolova said.

“If you know a certain person has that biomarker, you might be able to administer a drug or some therapeutic procedure to prevent that iron from continuing to accumulate in the brain.”

Chelation drugs and other therapies may clear iron from the body but not necessarily from the brain. 

Commenting on the study for this news organization, Frank Conidi, MD, director, Florida Center for Headache and Sports Neurology, Port St. Lucie , said that the study supports the hypothesis that concussion “is not a benign process for the brain, and the cumulative effect of repetitive head injury can result in permanent brain injury.”

He said that he found the accumulation of iron in cortical structures particularly interesting. This, he said, differs from most current research that suggests head trauma mainly results in damage to white matter tracts.

He prefers the term “concussion” over “mild traumatic brain injury” which was used in the study. “Recent guidelines, including some that I’ve been involved with, have defined mild traumatic brain injury as a more permanent process,” he said.

The study was supported by the US Department of Defense and National Institutes of Health. No relevant conflicts of interest were disclosed. 

A version of this article appeared on Medscape.com.

Posttraumatic headache (PTH) is associated with an increase in iron accumulation in certain brain regions , notably those involved in the pain network, early research shows.

Investigators found positive correlations between iron accumulation and headache frequency, number of lifetime mild traumatic brain injuries (mTBIs), and time since last mTBI.

The findings come on the heels of previous research showing patients with iron accumulation in certain brain regions don’t respond as well to treatment, study investigator, Simona Nikolova, PhD, assistant professor of neurology, Mayo Clinic, Phoenix, Arizona, told this news organization.

“This is really important, and doctors need to be aware of it. If you have a patient who is not responding to treatment, then you know what to look at,” she said. 

The findings (Abstract #3379) will be presented on April 15 at the American Academy of Neurology (AAN) 2024 Annual Meeting. 
 

Dose Effect

The study included 60 people with acute PTH due to mTBI. Most were White, and almost half had sustained a concussion due to a fall, with about 30% injured in a vehicle accident and a smaller number injured during a fight.

The mean number of lifetime mTBIs was 2.4, although participants had sustained as many as five or six and as few as one. The mean time from the most recent mTBI was 25 days, and the mean score on the Sport Concussion Assessment Tool (SCAT), which measures postconcussion symptom severity, was 29.

Most in the mTBI group (43) had migraine or probable migraine, and 14 had tension-type headaches. Mean headache frequency was 81%.

Researchers matched these patients with 60 controls without concussion or headache. Because iron accumulation is age-related, they tried to eliminate this covariant by pairing each participant with mTBI with an age- and sex-matched control.

All participants underwent a type of brain MRI known as T2* weighted sequence that can identify brain iron accumulation, a marker of neural injury. 

Investigators found that the PTH group had significantly higher levels of iron accumulation in several areas of the brain, most of which are part of a “pain network” that includes about 63 areas of the brain, Dr. Nikolova said.

The study wasn’t designed to determine how much more iron accumulation mTBI patients had vs controls. 

“We can’t say it was twice as much or three times as much; we can only say it was significant. Measuring concentrations in PTH patients and comparing that with controls is something we haven’t don’t yet,” said Dr. Nikolova.

Areas of the brain with increased iron accumulation, included the periaqueductal gray (PAG), anterior cingulated cortex, and supramarginal gyrus. 

Research suggests patients with migraine who have elevated levels of iron in the PAG have a poorer response to botulinum toxin treatment. An earlier study by the same team showed a poorer response to the calcitonin gene-related peptide inhibitor erenumab in migraine patients with elevated iron in the PAG.

Researchers discovered that those with more lifetime TBIs had higher iron accumulation in the right gyrus rectus and right putamen vs those with fewer injuries and that headache frequency was associated with iron accumulation in the posterior corona radiata, bilateral temporal, right frontal, bilateral supplemental motor area, left fusiform, right hippocampus, sagittal striatum, and left cerebellum.
 

Surprising Result

The investigators also found a link between time since the most recent mTBI and iron accumulation in the bilateral temporal, right hippocampus, posterior and superior corona radiata, bilateral thalamus, right precuneus and cuneus, right lingual, and right cerebellum. 

“The more time that passed since the concussion occurred, the more likely that people had higher iron levels,” said Dr. Nikolova.

It’s perhaps to be expected that the length of time since injury is linked to iron accumulation in the brain as iron accumulates over time. But even those whose injury was relatively recent had higher amounts of iron, which Dr. Nikolova said was “surprising.”

“We thought iron accumulates over time so we were thinking maybe we should be doing a longitudinal study to see what happens, but we see definite iron accumulation due to injury shortly after the injury,” she said.

There was no association between iron accumulation and symptom severity as measured by SCAT scores.
 

Questions Remain

It’s unclear why iron accumulates after an injury or what the ramifications are of this accumulation, Dr. Nikolova noted. 

The imaging used in the study doesn’t distinguish between “bound” iron found after a hemorrhage and “free” iron in the brain. The free iron type has been shown to be increased after TBI and is “the stuff you should be afraid of,” Dr. Nikolova said.

Iron’s role in the metabolic process is important, but must be closely regulated, she said. Even a small accumulation can lead to oxidative stress.

Researchers are investigating whether the findings would be similar in mTBI but no headache and want to increase the number of study participants. A larger, more diverse sample would allow them to probe other questions, including whether iron accumulation is different in men and women. More data could also eventually lead to iron accumulation becoming a biomarker for concussion and PTH, Dr. Nikolova said.

“If you know a certain person has that biomarker, you might be able to administer a drug or some therapeutic procedure to prevent that iron from continuing to accumulate in the brain.”

Chelation drugs and other therapies may clear iron from the body but not necessarily from the brain. 

Commenting on the study for this news organization, Frank Conidi, MD, director, Florida Center for Headache and Sports Neurology, Port St. Lucie , said that the study supports the hypothesis that concussion “is not a benign process for the brain, and the cumulative effect of repetitive head injury can result in permanent brain injury.”

He said that he found the accumulation of iron in cortical structures particularly interesting. This, he said, differs from most current research that suggests head trauma mainly results in damage to white matter tracts.

He prefers the term “concussion” over “mild traumatic brain injury” which was used in the study. “Recent guidelines, including some that I’ve been involved with, have defined mild traumatic brain injury as a more permanent process,” he said.

The study was supported by the US Department of Defense and National Institutes of Health. No relevant conflicts of interest were disclosed. 

A version of this article appeared on Medscape.com.

Moderate, severe, and penetrating traumatic brain injury (TBI) is associated with an elevated risk of developing brain cancer, new research suggested. However, mild TBI appears to confer no increased risk.

In a large cohort of post-9/11 US veterans, those who suffered moderate/severe TBI had a nearly twofold increased risk for a subsequent brain cancer diagnosis, while those with penetrating TBI had a greater than threefold increased risk.

“While the absolute number of brain cancer diagnoses was small, these diagnoses are associated with profoundly poor outcomes. Further research of this rare but devastating condition is needed to better identify those at risk and develop screening protocols,” wrote investigators led by Ian Stewart, MD, with the Uniformed Services University of Health Sciences, Bethesda, Maryland.

The study was published online on February 15 in JAMA Network Open.
 

Common War Wound

TBI is one of the most common battlefield wounds among veterans of the Iraq and Afghanistan wars. But evidence to date on the potential association of TBI with the subsequent risk for brain cancer is conflicting, the authors noted.

To investigate further, they reviewed the records of nearly 2 million mostly male US veterans of the Iraq and Afghanistan wars. A total of 449,880 people experienced TBI, which was mild in 385,848 cases, moderate/severe in 46,859 cases, and penetrating in 17,173 cases.

During a median follow-up of 7.2 years, brain cancer occurred in 318 veterans without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (0.06% or less).

There was a stepwise increase in brain cancer incidence with worse TBI severity. Crude incidence rates per 100,000 person-years were 3.06 for no TBI, 2.85 for mild TBI, 4.88 for moderate/severe TBI, and 10.34 for penetrating TBI.

In the fully adjusted model, moderate/severe TBI showed a near-doubling of brain cancer risk vs no TBI (adjusted hazard ratio [aHR], 1.90; 95% CI, 1.16-3.12), while penetrating TBI was associated with a greater than tripling of risk (aHR, 3.33; 95% CI, 1.71-6.49). There was no significantly increased risk after mild TBI.

There are plausible biological mechanisms linking TBI to brain cancer, the authors noted, including alterations in metabolism, inflammation, astrocyte proliferation, and stem cell migration and differentiation.

They caution that with few female veterans and a predominantly young cohort, the findings may not extend to the general population.
 

Meaningful New Data 

In an accompanying editorial, Elie Massaad, MD, MSc, and Ali Kiapour, PhD, MMSc, Massachusetts General Hospital, Boston, noted that federal data show glioblastoma, the most aggressive malignant brain tumor, is the third leading cause of cancer-related death among active duty personnel.

“Post-9/11 veterans deployed to Iraq, Afghanistan, and elsewhere face a 26% higher glioblastoma rate vs the general public, with an average age of onset decades earlier than in broader populations,” they wrote.

Overall, they noted this new research provides “meaningful data clarifying associations between combat-related TBI severity and subsequent brain cancer risk among post-9/11 veterans.

“Elucidating potential connections between battlefield trauma and longer-term health outcomes is imperative to inform prevention and care approaches for those who have served,” they added.

This study was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military Relevant Brain Injury Consortium. The authors and editorialists had declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Moderate, severe, and penetrating traumatic brain injury (TBI) is associated with an elevated risk of developing brain cancer, new research suggested. However, mild TBI appears to confer no increased risk.

In a large cohort of post-9/11 US veterans, those who suffered moderate/severe TBI had a nearly twofold increased risk for a subsequent brain cancer diagnosis, while those with penetrating TBI had a greater than threefold increased risk.

“While the absolute number of brain cancer diagnoses was small, these diagnoses are associated with profoundly poor outcomes. Further research of this rare but devastating condition is needed to better identify those at risk and develop screening protocols,” wrote investigators led by Ian Stewart, MD, with the Uniformed Services University of Health Sciences, Bethesda, Maryland.

The study was published online on February 15 in JAMA Network Open.
 

Common War Wound

TBI is one of the most common battlefield wounds among veterans of the Iraq and Afghanistan wars. But evidence to date on the potential association of TBI with the subsequent risk for brain cancer is conflicting, the authors noted.

To investigate further, they reviewed the records of nearly 2 million mostly male US veterans of the Iraq and Afghanistan wars. A total of 449,880 people experienced TBI, which was mild in 385,848 cases, moderate/severe in 46,859 cases, and penetrating in 17,173 cases.

During a median follow-up of 7.2 years, brain cancer occurred in 318 veterans without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (0.06% or less).

There was a stepwise increase in brain cancer incidence with worse TBI severity. Crude incidence rates per 100,000 person-years were 3.06 for no TBI, 2.85 for mild TBI, 4.88 for moderate/severe TBI, and 10.34 for penetrating TBI.

In the fully adjusted model, moderate/severe TBI showed a near-doubling of brain cancer risk vs no TBI (adjusted hazard ratio [aHR], 1.90; 95% CI, 1.16-3.12), while penetrating TBI was associated with a greater than tripling of risk (aHR, 3.33; 95% CI, 1.71-6.49). There was no significantly increased risk after mild TBI.

There are plausible biological mechanisms linking TBI to brain cancer, the authors noted, including alterations in metabolism, inflammation, astrocyte proliferation, and stem cell migration and differentiation.

They caution that with few female veterans and a predominantly young cohort, the findings may not extend to the general population.
 

Meaningful New Data 

In an accompanying editorial, Elie Massaad, MD, MSc, and Ali Kiapour, PhD, MMSc, Massachusetts General Hospital, Boston, noted that federal data show glioblastoma, the most aggressive malignant brain tumor, is the third leading cause of cancer-related death among active duty personnel.

“Post-9/11 veterans deployed to Iraq, Afghanistan, and elsewhere face a 26% higher glioblastoma rate vs the general public, with an average age of onset decades earlier than in broader populations,” they wrote.

Overall, they noted this new research provides “meaningful data clarifying associations between combat-related TBI severity and subsequent brain cancer risk among post-9/11 veterans.

“Elucidating potential connections between battlefield trauma and longer-term health outcomes is imperative to inform prevention and care approaches for those who have served,” they added.

This study was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military Relevant Brain Injury Consortium. The authors and editorialists had declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Moderate, severe, and penetrating traumatic brain injury (TBI) is associated with an elevated risk of developing brain cancer, new research suggested. However, mild TBI appears to confer no increased risk.

In a large cohort of post-9/11 US veterans, those who suffered moderate/severe TBI had a nearly twofold increased risk for a subsequent brain cancer diagnosis, while those with penetrating TBI had a greater than threefold increased risk.

“While the absolute number of brain cancer diagnoses was small, these diagnoses are associated with profoundly poor outcomes. Further research of this rare but devastating condition is needed to better identify those at risk and develop screening protocols,” wrote investigators led by Ian Stewart, MD, with the Uniformed Services University of Health Sciences, Bethesda, Maryland.

The study was published online on February 15 in JAMA Network Open.
 

Common War Wound

TBI is one of the most common battlefield wounds among veterans of the Iraq and Afghanistan wars. But evidence to date on the potential association of TBI with the subsequent risk for brain cancer is conflicting, the authors noted.

To investigate further, they reviewed the records of nearly 2 million mostly male US veterans of the Iraq and Afghanistan wars. A total of 449,880 people experienced TBI, which was mild in 385,848 cases, moderate/severe in 46,859 cases, and penetrating in 17,173 cases.

During a median follow-up of 7.2 years, brain cancer occurred in 318 veterans without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (0.06% or less).

There was a stepwise increase in brain cancer incidence with worse TBI severity. Crude incidence rates per 100,000 person-years were 3.06 for no TBI, 2.85 for mild TBI, 4.88 for moderate/severe TBI, and 10.34 for penetrating TBI.

In the fully adjusted model, moderate/severe TBI showed a near-doubling of brain cancer risk vs no TBI (adjusted hazard ratio [aHR], 1.90; 95% CI, 1.16-3.12), while penetrating TBI was associated with a greater than tripling of risk (aHR, 3.33; 95% CI, 1.71-6.49). There was no significantly increased risk after mild TBI.

There are plausible biological mechanisms linking TBI to brain cancer, the authors noted, including alterations in metabolism, inflammation, astrocyte proliferation, and stem cell migration and differentiation.

They caution that with few female veterans and a predominantly young cohort, the findings may not extend to the general population.
 

Meaningful New Data 

In an accompanying editorial, Elie Massaad, MD, MSc, and Ali Kiapour, PhD, MMSc, Massachusetts General Hospital, Boston, noted that federal data show glioblastoma, the most aggressive malignant brain tumor, is the third leading cause of cancer-related death among active duty personnel.

“Post-9/11 veterans deployed to Iraq, Afghanistan, and elsewhere face a 26% higher glioblastoma rate vs the general public, with an average age of onset decades earlier than in broader populations,” they wrote.

Overall, they noted this new research provides “meaningful data clarifying associations between combat-related TBI severity and subsequent brain cancer risk among post-9/11 veterans.

“Elucidating potential connections between battlefield trauma and longer-term health outcomes is imperative to inform prevention and care approaches for those who have served,” they added.

This study was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military Relevant Brain Injury Consortium. The authors and editorialists had declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

A recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

“This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s disease, Alzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorder, depression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

A recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

“This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s disease, Alzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorder, depression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

A recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

“This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s disease, Alzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorder, depression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

fdp_dt_2023_cover_thumnail.jpg

In this issue: 

• Limb Loss and Prostheses
• Neurology
  • Traumatic Brain Injury
  • Alzheimer's and Dementia
  • Amyotrophic Lateral Sclerosis (ALS)
  • Parkinson's Disease
  • Migraine and Headache
• Cardiology
• Mental Health
  • Depression
  • Opioid Use Disorder
  • PTSD and Psychedelic Treatments
  • Homelessness
  • Eating Disorders
• Diabetes
• Rheumatoid Arthritis
• Respiratory illnesses
• Women's Health
  • Access to Care
  • Infertility
  • Pregnancy
• HPV and Related Cancers

fdp_dt_2023_cover_thumnail.jpg

In this issue: 

• Limb Loss and Prostheses
• Neurology
  • Traumatic Brain Injury
  • Alzheimer's and Dementia
  • Amyotrophic Lateral Sclerosis (ALS)
  • Parkinson's Disease
  • Migraine and Headache
• Cardiology
• Mental Health
  • Depression
  • Opioid Use Disorder
  • PTSD and Psychedelic Treatments
  • Homelessness
  • Eating Disorders
• Diabetes
• Rheumatoid Arthritis
• Respiratory illnesses
• Women's Health
  • Access to Care
  • Infertility
  • Pregnancy
• HPV and Related Cancers

fdp_dt_2023_cover_thumnail.jpg

In this issue: 

• Limb Loss and Prostheses
• Neurology
  • Traumatic Brain Injury
  • Alzheimer's and Dementia
  • Amyotrophic Lateral Sclerosis (ALS)
  • Parkinson's Disease
  • Migraine and Headache
• Cardiology
• Mental Health
  • Depression
  • Opioid Use Disorder
  • PTSD and Psychedelic Treatments
  • Homelessness
  • Eating Disorders
• Diabetes
• Rheumatoid Arthritis
• Respiratory illnesses
• Women's Health
  • Access to Care
  • Infertility
  • Pregnancy
• HPV and Related Cancers

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.