Traumatic Brain Injury

A history of concussion can have serious long-term mental health implications for women, even years after giving birth, according to a new study.

Researchers looked at all people who delivered babies in Ontario, Canada, and found that those with a predelivery history of concussion were 25% more likely to have a serious mental illness up to 14 years after giving birth than those with no history of concussion.

The findings indicate the need for early identification and screening of women with a history of concussion, as well as ongoing, long-term supports to prevent adverse psychiatric outcomes, wrote the authors.

“I played a lot of sports growing up, and I definitely would not have thought about how a concussion could affect childbearing or parenting,” author Samantha Krueger, RM, MSc, told this news organization. She completed the research as part of her studies at the University of Toronto, Ontario.

The data were published on November 4 in The Journal of Clinical Psychiatry.
 

Implications for Prevention

“Birthing people, and women in general, are an often-overlooked population in the scientific literature on traumatic brain injury, including concussion. There is a potential interplay between concussion history and the challenges of being a new parent (such as labor and birth, lack of sleep, and increased noise) that make this an important population to study,” said Krueger.

The researchers conducted a population-based cohort study of all women who gave birth in Ontario between 2007 and 2017. Follow-up continued until 2021. The primary outcome was severe maternal mental illness, which was defined as a psychiatric emergency department visit, psychiatric hospital admission, or self-harm or suicide in the 14 years after delivery.

The researchers identified 18,064 women with a predelivery history of concussion and 736,689 women without a history of concussion during the study period. Women with a predelivery history of concussion were more likely than those without such a history to live in a rural area and have a history of assault or mental illness.

Overall, 11.3% (n = 2033) of the women with a predelivery history of concussion developed severe maternal mental illness (14.7 per 1000 person-years), compared with 6.8% (n = 49,928) of the women without a predelivery history of concussion (7.9 per 1000 person-years).

The adjusted hazard ratio (aHR) was 1.25. The association was strongest in women who had a predelivery history of concussion but no history of mental illness (aHR, 1.33).

“We hope to increase awareness of the seriousness of having a concussion, even when it is considered a mild head injury,” Krueger said. “The results have important implications for concussion prevention measures for young people and for the provision of postpartum supports (such as mental health and other social supports like sleep relief) to mitigate the risk of serious mental illness outcomes in birthing people with a history of concussion.”

Healthcare providers, including maternity care providers, should be asking about concussion history and providing mental health screening and supports to clients and their families to detect mental illness before a serious outcome occurs, Krueger added.

“Maternity care providers can help birthing people and their families set up supports for after the baby is born and teach families about mental health symptoms to look out for. It’s also important that providers be certain that their care is trauma informed to avoid triggering a trauma response when providing care,” she said.
 

Area of Concern

“This research is novel and highlights an area of major concern,” Simon Sherry, PhD, professor of psychology and neuroscience at Dalhousie University in Halifax, Nova Scotia, Canada, told this news organization. Sherry did not participate in the study.

“Postpartum depression occurs in approximately 10%-25% of mothers, but it is likely that many more cases go undiagnosed. It is attributed to hormonal changes, genetic predisposition, and environmental factors, and while previous depression or mental illness is frequently considered a risk factor, traumatic brain injuries or concussions usually are not,” Sherry said.

“Mothers are already an at-risk population for mental illness, as illustrated by the high rates of postpartum depression, and so are people with a history of concussion or traumatic brain injury. What sets this study apart is that it shows the heightened risk for women with the combination of those two distinct risk factors. Identifying these risk factors is essential to providing preventive care. If care providers know a patient is at increased risk when starting a pregnancy, then they will likely catch warning signs earlier,” he said.

“Additionally, as the article suggests, maternal mental health often is not studied beyond the first postpartum year,” Sherry said.

“Mental health struggles during the first postpartum year have largely been normalized as part of the transition into parenthood, but mental health issues among parents later in life are less accepted. After birth, so much emphasis is moved from the parent to the child. Parents rightly prioritize their children, but our job as care providers is to ensure we are also prioritizing them. The prolonged period of this study helps illustrate how important the practice of prioritizing mothers’ mental health is,” he added.

The study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The Canadian Institutes of Health Research also supported the study. Krueger is supported by a Canadian Institutes of Health Research Canada Graduate Scholarship Masters Award. Sherry reported no relevant financial relationships.

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

A history of concussion can have serious long-term mental health implications for women, even years after giving birth, according to a new study.

Researchers looked at all people who delivered babies in Ontario, Canada, and found that those with a predelivery history of concussion were 25% more likely to have a serious mental illness up to 14 years after giving birth than those with no history of concussion.

The findings indicate the need for early identification and screening of women with a history of concussion, as well as ongoing, long-term supports to prevent adverse psychiatric outcomes, wrote the authors.

“I played a lot of sports growing up, and I definitely would not have thought about how a concussion could affect childbearing or parenting,” author Samantha Krueger, RM, MSc, told this news organization. She completed the research as part of her studies at the University of Toronto, Ontario.

The data were published on November 4 in The Journal of Clinical Psychiatry.
 

Implications for Prevention

“Birthing people, and women in general, are an often-overlooked population in the scientific literature on traumatic brain injury, including concussion. There is a potential interplay between concussion history and the challenges of being a new parent (such as labor and birth, lack of sleep, and increased noise) that make this an important population to study,” said Krueger.

The researchers conducted a population-based cohort study of all women who gave birth in Ontario between 2007 and 2017. Follow-up continued until 2021. The primary outcome was severe maternal mental illness, which was defined as a psychiatric emergency department visit, psychiatric hospital admission, or self-harm or suicide in the 14 years after delivery.

The researchers identified 18,064 women with a predelivery history of concussion and 736,689 women without a history of concussion during the study period. Women with a predelivery history of concussion were more likely than those without such a history to live in a rural area and have a history of assault or mental illness.

Overall, 11.3% (n = 2033) of the women with a predelivery history of concussion developed severe maternal mental illness (14.7 per 1000 person-years), compared with 6.8% (n = 49,928) of the women without a predelivery history of concussion (7.9 per 1000 person-years).

The adjusted hazard ratio (aHR) was 1.25. The association was strongest in women who had a predelivery history of concussion but no history of mental illness (aHR, 1.33).

“We hope to increase awareness of the seriousness of having a concussion, even when it is considered a mild head injury,” Krueger said. “The results have important implications for concussion prevention measures for young people and for the provision of postpartum supports (such as mental health and other social supports like sleep relief) to mitigate the risk of serious mental illness outcomes in birthing people with a history of concussion.”

Healthcare providers, including maternity care providers, should be asking about concussion history and providing mental health screening and supports to clients and their families to detect mental illness before a serious outcome occurs, Krueger added.

“Maternity care providers can help birthing people and their families set up supports for after the baby is born and teach families about mental health symptoms to look out for. It’s also important that providers be certain that their care is trauma informed to avoid triggering a trauma response when providing care,” she said.
 

Area of Concern

“This research is novel and highlights an area of major concern,” Simon Sherry, PhD, professor of psychology and neuroscience at Dalhousie University in Halifax, Nova Scotia, Canada, told this news organization. Sherry did not participate in the study.

“Postpartum depression occurs in approximately 10%-25% of mothers, but it is likely that many more cases go undiagnosed. It is attributed to hormonal changes, genetic predisposition, and environmental factors, and while previous depression or mental illness is frequently considered a risk factor, traumatic brain injuries or concussions usually are not,” Sherry said.

“Mothers are already an at-risk population for mental illness, as illustrated by the high rates of postpartum depression, and so are people with a history of concussion or traumatic brain injury. What sets this study apart is that it shows the heightened risk for women with the combination of those two distinct risk factors. Identifying these risk factors is essential to providing preventive care. If care providers know a patient is at increased risk when starting a pregnancy, then they will likely catch warning signs earlier,” he said.

“Additionally, as the article suggests, maternal mental health often is not studied beyond the first postpartum year,” Sherry said.

“Mental health struggles during the first postpartum year have largely been normalized as part of the transition into parenthood, but mental health issues among parents later in life are less accepted. After birth, so much emphasis is moved from the parent to the child. Parents rightly prioritize their children, but our job as care providers is to ensure we are also prioritizing them. The prolonged period of this study helps illustrate how important the practice of prioritizing mothers’ mental health is,” he added.

The study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The Canadian Institutes of Health Research also supported the study. Krueger is supported by a Canadian Institutes of Health Research Canada Graduate Scholarship Masters Award. Sherry reported no relevant financial relationships.

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

A history of concussion can have serious long-term mental health implications for women, even years after giving birth, according to a new study.

Researchers looked at all people who delivered babies in Ontario, Canada, and found that those with a predelivery history of concussion were 25% more likely to have a serious mental illness up to 14 years after giving birth than those with no history of concussion.

The findings indicate the need for early identification and screening of women with a history of concussion, as well as ongoing, long-term supports to prevent adverse psychiatric outcomes, wrote the authors.

“I played a lot of sports growing up, and I definitely would not have thought about how a concussion could affect childbearing or parenting,” author Samantha Krueger, RM, MSc, told this news organization. She completed the research as part of her studies at the University of Toronto, Ontario.

The data were published on November 4 in The Journal of Clinical Psychiatry.
 

Implications for Prevention

“Birthing people, and women in general, are an often-overlooked population in the scientific literature on traumatic brain injury, including concussion. There is a potential interplay between concussion history and the challenges of being a new parent (such as labor and birth, lack of sleep, and increased noise) that make this an important population to study,” said Krueger.

The researchers conducted a population-based cohort study of all women who gave birth in Ontario between 2007 and 2017. Follow-up continued until 2021. The primary outcome was severe maternal mental illness, which was defined as a psychiatric emergency department visit, psychiatric hospital admission, or self-harm or suicide in the 14 years after delivery.

The researchers identified 18,064 women with a predelivery history of concussion and 736,689 women without a history of concussion during the study period. Women with a predelivery history of concussion were more likely than those without such a history to live in a rural area and have a history of assault or mental illness.

Overall, 11.3% (n = 2033) of the women with a predelivery history of concussion developed severe maternal mental illness (14.7 per 1000 person-years), compared with 6.8% (n = 49,928) of the women without a predelivery history of concussion (7.9 per 1000 person-years).

The adjusted hazard ratio (aHR) was 1.25. The association was strongest in women who had a predelivery history of concussion but no history of mental illness (aHR, 1.33).

“We hope to increase awareness of the seriousness of having a concussion, even when it is considered a mild head injury,” Krueger said. “The results have important implications for concussion prevention measures for young people and for the provision of postpartum supports (such as mental health and other social supports like sleep relief) to mitigate the risk of serious mental illness outcomes in birthing people with a history of concussion.”

Healthcare providers, including maternity care providers, should be asking about concussion history and providing mental health screening and supports to clients and their families to detect mental illness before a serious outcome occurs, Krueger added.

“Maternity care providers can help birthing people and their families set up supports for after the baby is born and teach families about mental health symptoms to look out for. It’s also important that providers be certain that their care is trauma informed to avoid triggering a trauma response when providing care,” she said.
 

Area of Concern

“This research is novel and highlights an area of major concern,” Simon Sherry, PhD, professor of psychology and neuroscience at Dalhousie University in Halifax, Nova Scotia, Canada, told this news organization. Sherry did not participate in the study.

“Postpartum depression occurs in approximately 10%-25% of mothers, but it is likely that many more cases go undiagnosed. It is attributed to hormonal changes, genetic predisposition, and environmental factors, and while previous depression or mental illness is frequently considered a risk factor, traumatic brain injuries or concussions usually are not,” Sherry said.

“Mothers are already an at-risk population for mental illness, as illustrated by the high rates of postpartum depression, and so are people with a history of concussion or traumatic brain injury. What sets this study apart is that it shows the heightened risk for women with the combination of those two distinct risk factors. Identifying these risk factors is essential to providing preventive care. If care providers know a patient is at increased risk when starting a pregnancy, then they will likely catch warning signs earlier,” he said.

“Additionally, as the article suggests, maternal mental health often is not studied beyond the first postpartum year,” Sherry said.

“Mental health struggles during the first postpartum year have largely been normalized as part of the transition into parenthood, but mental health issues among parents later in life are less accepted. After birth, so much emphasis is moved from the parent to the child. Parents rightly prioritize their children, but our job as care providers is to ensure we are also prioritizing them. The prolonged period of this study helps illustrate how important the practice of prioritizing mothers’ mental health is,” he added.

The study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The Canadian Institutes of Health Research also supported the study. Krueger is supported by a Canadian Institutes of Health Research Canada Graduate Scholarship Masters Award. Sherry reported no relevant financial relationships.

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

Researchers have identified a potential new sign of concussion in athletes, particularly football players, that can easily be spotted on the field, indicating the need for immediate removal from the game and evaluation for potential traumatic brain injury (TBI).

Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.

In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.

The results were published online in Diagnostics.
 

Call to Action

“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.

Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.

Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.

“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
 

The Case of Miami Dolphins QB Tua Tagovailoa

Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.

After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.

If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.

For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.

Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.

Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).

Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.

Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.

The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
 

Instant Replay for Brain Injury?

Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.

The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.

“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.

“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.

Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”

“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.

In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.

This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Researchers have identified a potential new sign of concussion in athletes, particularly football players, that can easily be spotted on the field, indicating the need for immediate removal from the game and evaluation for potential traumatic brain injury (TBI).

Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.

In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.

The results were published online in Diagnostics.
 

Call to Action

“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.

Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.

Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.

“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
 

The Case of Miami Dolphins QB Tua Tagovailoa

Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.

After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.

If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.

For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.

Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.

Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).

Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.

Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.

The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
 

Instant Replay for Brain Injury?

Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.

The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.

“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.

“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.

Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”

“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.

In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.

This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Researchers have identified a potential new sign of concussion in athletes, particularly football players, that can easily be spotted on the field, indicating the need for immediate removal from the game and evaluation for potential traumatic brain injury (TBI).

Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.

In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.

The results were published online in Diagnostics.
 

Call to Action

“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.

Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.

Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.

“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
 

The Case of Miami Dolphins QB Tua Tagovailoa

Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.

After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.

If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.

For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.

Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.

Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).

Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.

Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.

The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
 

Instant Replay for Brain Injury?

Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.

The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.

“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.

“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.

Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”

“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.

In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.

This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

At least 25% of unresponsive patients with a disorder of consciousness show signs of brain activity, an estimate that is higher than previous studies suggest.

“We found that at least 1 in 4 patients who are unresponsive to commands might actually be quite present and highly cognitive,” said study investigator Nicholas D. Schiff, MD, Feil Family Brain & Mind Research Institute and Department of Neurology, Weill Cornell Medicine, Rockefeller University Hospital, New York.

“In other words, if you go to the bedside and carefully examine someone with a severe brain injury and find no evidence of responsiveness, no one has been able to give you an a priori number to say how likely you are to be wrong in thinking this person is actually unaware, not processing language, and not capable of high-level cognitive work. And the answer to that now is at least 1 in 4 times.”

The findings were published online in The New England Journal of Medicine.
 

Clinical Implications? 

Cognitive motor dissociation (CMD) is a condition whereby patients with a severe brain injury who are unresponsive to commands at the bedside show brain activity on functional MRI (fMRI) or electroencephalography (EEG) when presented with selective motor imagery commands, such as “imagine playing tennis,” or “ imagine opening and closing your hand.”

Previous research shows that CMD is present in 10%-20% of people with a disorder of consciousness, a rate similar to that in patients with acute or chronic brain injury.

Understanding that a patient who appears unconscious has signs of cognitive processing could change the way clinicians and family interact with such individuals. Unresponsive patients who are aware may eventually be able to harness emerging communication technologies such as brain-computer interfaces.

In addition, knowing an individual’s CMD status could aid in prognosis. “We know from one study that there’s a four times increased likelihood that patients will be independent in a year in their function if they have cognitive motor dissociation,” said Dr. Schiff.

Unlike most previous studies of CMD, which were conducted at single sites and had relatively small cohorts, this new study included 353 adults with a disorder of consciousness (mean age, 37.9 years; 64% male) at six multinational sites.

Participants were recruited using a variety of methods, including consecutive enrollment of critically ill patients in the intensive care unit and enrollment of those with chronic illness or injury who were in the postacute phase of brain injury.
 

Response to Commands

Study participants were at different stages of recovery from an acute brain injury that had occurred an average of 8 months before the study started.

To determine the presence or absence of an observable response to commands among participants, trained staff used the Coma Recovery Scale–Revised (CRS-R); scores on this instrument range from 0 to 23, and higher scores indicate better neurobehavioral function.

About 40% of individuals were diagnosed with coma or vegetative state, 29% with minimally conscious state–minus, and 22% with minimally conscious state–plus. In all, 10% had emerged from a minimally conscious state.

Researchers assessed response to timed and repeated commands using fMRI or EEG in participants without an observable response to verbal commands, including those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state–minus, and in participants with an observable response to verbal commands.

Of the 353 study participants, 61% underwent at least one fMRI assessment and 74% at least one EEG assessment. Both fMRI and EEG were performed in 35% of participants.

Dr. Schiff explained the two assessment types provide slightly different information, in that they measuring different types of brain signals. He also noted that although “every medical center in the world” has EEG, many do not have fMRI.

The brain imaging assessments captured brain activity within the motor area of the frontal cortex when tasked with motor imagery.

Of the 241 participants deemed to be in a coma or vegetative state or minimally conscious state–minus on the basis of CRS-R score, 60 (25%) had a response to commands on task-based fMRI, task-based EEG, or both.

The percentage of participants with CMD varied across study sites, from 2% to 45%, but Dr. Schiff said the reason for this is unclear. 

The proportion of participants with CMD may have been even higher if all individuals had been assessed with both imaging techniques, he said.
 

Higher Rate of Awareness Than in Previous Research

The investigators noted that the percentage of participants with CMD in their study was up to 10 percentage points higher than in previous studies. This may be due to the multimodal approach that classified participants undergoing assessment with both fMRI and EEG on the basis of responses on either technique, they said. 

The median age was lower among participants with CMD than those without CMD (30.5 years vs 45.3 years).

Compared with participants without CMD, a higher percentage of those with such dissociation had brain trauma as an etiologic factor (65% vs 38%) and a diagnosis of minimally conscious state–minus on the CRS-R (53% vs 38%).

Among people with CMD, 18% were assessed with fMRI only, 22% with EEG only, and 60% with both fMRI and EEG.

Dr. Schiff noted that the use of both fMRI and EEG appears to be more sensitive in detecting brain activity during tasks compared with use of one of these techniques alone.

Of the 112 participants with a diagnosis of minimally conscious state–plus or who had emerged from the minimally conscious state, 38% had a response to commands on task-based fMRI, task-based EEG, or both. Among these participants, 23% were assessed with fMRI only, 19% with EEG only, and 58% with both fMRI and EEG.

Research shows “it’s very clear that people with severe brain injury continue to get better over time,” noted Dr. Schiff. “Every month and week matters, and so it probably is the case that a lot of these patients are picking up the level of recovery, and the later we go out to measure them, the more likely we are to find people who are CMD than not.”

These new results should prompt further study to explore whether detection of CMD can lead to improved outcomes, the investigators noted. “In addition, the standardization, validation, and simplification of task-based fMRI and EEG methods that are used to detect cognitive motor dissociation are needed to prompt widespread clinical integration of these techniques and investigation of the bioethical implications of the findings.”

All study participants with chronic brain injury had survived their initial illness or injury and had access to a research facility with advanced fMRI and EEG capabilities. “This survival bias may reflect greater cognitive reserve and resilience over time among the participants. As such, the results of our study may not be generalizable to the overall population of patients with cognitive motor dissociation,” the investigators wrote.

Another study limitation was that participating sites used heterogeneous strategies to acquire, analyze, and interpret data, which led to differences in the number, type, and ordering of the cognitive tasks assessed on fMRI and EEG.

“These differences, along with variations in recruitment strategies and participant characteristics, may have contributed to the unequal percentage of participants with cognitive motor dissociation observed at each site. Our findings may therefore not be generalizable across all centers,” the researchers wrote. 

Only a few academic medical centers have the specially trained personnel and techniques needed to assess patients for CMD — which, the researchers noted, limits the feasibility of performing these assessments in general practice.
 

Challenging Research

Commenting on the research, Aarti Sarwal, MD, professor of neurology and section chief, Neurocritical Care, Virginia Commonwealth University, Richmond, Virginia, noted that this was a “very challenging” study to perform, given that only a few academic centers are equipped to perform both fMRI and quantitative EEG analysis.

“In general, finding patients this far out, who have access to clinical, radiological, and electrophysiological testing and were provided good care enough to receive these, is a mammoth task in itself.” 

Dr. Sarwal said the study builds on efforts of the Curing Coma campaign , a clinical, scientific, and public health effort of the Neurocritical Care Society to tackle the concept of coma as a treatable medical entity.

“It continues to highlight the challenges of prognostication in acute brain injured patients by showing a higher presence of cognitive function than previously perceived,” she said.

Dr. Sarwal believes that the study’s largest impact is underscoring the need for more research into understanding the degree and quality of cognitive processing in patients with a disorder of consciousness. But it also underlines the need for a “healthy debate” on the cost/benefit analysis of pursuing such research, given the limited number of patients with access to resources. 

“This debate needs to include the caregivers and families outside the traditional realms of stakeholders overseeing the science.” 

Although communication with comatose patients is still “a ways away,” this research is “a step in the right direction,” said Dr. Sarwal. 

The study was funded by the James S. McDonnell Foundation and others. Dr. Schiff and Dr. Sarwal report no relevant financial disclosures.
 

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

At least 25% of unresponsive patients with a disorder of consciousness show signs of brain activity, an estimate that is higher than previous studies suggest.

“We found that at least 1 in 4 patients who are unresponsive to commands might actually be quite present and highly cognitive,” said study investigator Nicholas D. Schiff, MD, Feil Family Brain & Mind Research Institute and Department of Neurology, Weill Cornell Medicine, Rockefeller University Hospital, New York.

“In other words, if you go to the bedside and carefully examine someone with a severe brain injury and find no evidence of responsiveness, no one has been able to give you an a priori number to say how likely you are to be wrong in thinking this person is actually unaware, not processing language, and not capable of high-level cognitive work. And the answer to that now is at least 1 in 4 times.”

The findings were published online in The New England Journal of Medicine.
 

Clinical Implications? 

Cognitive motor dissociation (CMD) is a condition whereby patients with a severe brain injury who are unresponsive to commands at the bedside show brain activity on functional MRI (fMRI) or electroencephalography (EEG) when presented with selective motor imagery commands, such as “imagine playing tennis,” or “ imagine opening and closing your hand.”

Previous research shows that CMD is present in 10%-20% of people with a disorder of consciousness, a rate similar to that in patients with acute or chronic brain injury.

Understanding that a patient who appears unconscious has signs of cognitive processing could change the way clinicians and family interact with such individuals. Unresponsive patients who are aware may eventually be able to harness emerging communication technologies such as brain-computer interfaces.

In addition, knowing an individual’s CMD status could aid in prognosis. “We know from one study that there’s a four times increased likelihood that patients will be independent in a year in their function if they have cognitive motor dissociation,” said Dr. Schiff.

Unlike most previous studies of CMD, which were conducted at single sites and had relatively small cohorts, this new study included 353 adults with a disorder of consciousness (mean age, 37.9 years; 64% male) at six multinational sites.

Participants were recruited using a variety of methods, including consecutive enrollment of critically ill patients in the intensive care unit and enrollment of those with chronic illness or injury who were in the postacute phase of brain injury.
 

Response to Commands

Study participants were at different stages of recovery from an acute brain injury that had occurred an average of 8 months before the study started.

To determine the presence or absence of an observable response to commands among participants, trained staff used the Coma Recovery Scale–Revised (CRS-R); scores on this instrument range from 0 to 23, and higher scores indicate better neurobehavioral function.

About 40% of individuals were diagnosed with coma or vegetative state, 29% with minimally conscious state–minus, and 22% with minimally conscious state–plus. In all, 10% had emerged from a minimally conscious state.

Researchers assessed response to timed and repeated commands using fMRI or EEG in participants without an observable response to verbal commands, including those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state–minus, and in participants with an observable response to verbal commands.

Of the 353 study participants, 61% underwent at least one fMRI assessment and 74% at least one EEG assessment. Both fMRI and EEG were performed in 35% of participants.

Dr. Schiff explained the two assessment types provide slightly different information, in that they measuring different types of brain signals. He also noted that although “every medical center in the world” has EEG, many do not have fMRI.

The brain imaging assessments captured brain activity within the motor area of the frontal cortex when tasked with motor imagery.

Of the 241 participants deemed to be in a coma or vegetative state or minimally conscious state–minus on the basis of CRS-R score, 60 (25%) had a response to commands on task-based fMRI, task-based EEG, or both.

The percentage of participants with CMD varied across study sites, from 2% to 45%, but Dr. Schiff said the reason for this is unclear. 

The proportion of participants with CMD may have been even higher if all individuals had been assessed with both imaging techniques, he said.
 

Higher Rate of Awareness Than in Previous Research

The investigators noted that the percentage of participants with CMD in their study was up to 10 percentage points higher than in previous studies. This may be due to the multimodal approach that classified participants undergoing assessment with both fMRI and EEG on the basis of responses on either technique, they said. 

The median age was lower among participants with CMD than those without CMD (30.5 years vs 45.3 years).

Compared with participants without CMD, a higher percentage of those with such dissociation had brain trauma as an etiologic factor (65% vs 38%) and a diagnosis of minimally conscious state–minus on the CRS-R (53% vs 38%).

Among people with CMD, 18% were assessed with fMRI only, 22% with EEG only, and 60% with both fMRI and EEG.

Dr. Schiff noted that the use of both fMRI and EEG appears to be more sensitive in detecting brain activity during tasks compared with use of one of these techniques alone.

Of the 112 participants with a diagnosis of minimally conscious state–plus or who had emerged from the minimally conscious state, 38% had a response to commands on task-based fMRI, task-based EEG, or both. Among these participants, 23% were assessed with fMRI only, 19% with EEG only, and 58% with both fMRI and EEG.

Research shows “it’s very clear that people with severe brain injury continue to get better over time,” noted Dr. Schiff. “Every month and week matters, and so it probably is the case that a lot of these patients are picking up the level of recovery, and the later we go out to measure them, the more likely we are to find people who are CMD than not.”

These new results should prompt further study to explore whether detection of CMD can lead to improved outcomes, the investigators noted. “In addition, the standardization, validation, and simplification of task-based fMRI and EEG methods that are used to detect cognitive motor dissociation are needed to prompt widespread clinical integration of these techniques and investigation of the bioethical implications of the findings.”

All study participants with chronic brain injury had survived their initial illness or injury and had access to a research facility with advanced fMRI and EEG capabilities. “This survival bias may reflect greater cognitive reserve and resilience over time among the participants. As such, the results of our study may not be generalizable to the overall population of patients with cognitive motor dissociation,” the investigators wrote.

Another study limitation was that participating sites used heterogeneous strategies to acquire, analyze, and interpret data, which led to differences in the number, type, and ordering of the cognitive tasks assessed on fMRI and EEG.

“These differences, along with variations in recruitment strategies and participant characteristics, may have contributed to the unequal percentage of participants with cognitive motor dissociation observed at each site. Our findings may therefore not be generalizable across all centers,” the researchers wrote. 

Only a few academic medical centers have the specially trained personnel and techniques needed to assess patients for CMD — which, the researchers noted, limits the feasibility of performing these assessments in general practice.
 

Challenging Research

Commenting on the research, Aarti Sarwal, MD, professor of neurology and section chief, Neurocritical Care, Virginia Commonwealth University, Richmond, Virginia, noted that this was a “very challenging” study to perform, given that only a few academic centers are equipped to perform both fMRI and quantitative EEG analysis.

“In general, finding patients this far out, who have access to clinical, radiological, and electrophysiological testing and were provided good care enough to receive these, is a mammoth task in itself.” 

Dr. Sarwal said the study builds on efforts of the Curing Coma campaign , a clinical, scientific, and public health effort of the Neurocritical Care Society to tackle the concept of coma as a treatable medical entity.

“It continues to highlight the challenges of prognostication in acute brain injured patients by showing a higher presence of cognitive function than previously perceived,” she said.

Dr. Sarwal believes that the study’s largest impact is underscoring the need for more research into understanding the degree and quality of cognitive processing in patients with a disorder of consciousness. But it also underlines the need for a “healthy debate” on the cost/benefit analysis of pursuing such research, given the limited number of patients with access to resources. 

“This debate needs to include the caregivers and families outside the traditional realms of stakeholders overseeing the science.” 

Although communication with comatose patients is still “a ways away,” this research is “a step in the right direction,” said Dr. Sarwal. 

The study was funded by the James S. McDonnell Foundation and others. Dr. Schiff and Dr. Sarwal report no relevant financial disclosures.
 

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

At least 25% of unresponsive patients with a disorder of consciousness show signs of brain activity, an estimate that is higher than previous studies suggest.

“We found that at least 1 in 4 patients who are unresponsive to commands might actually be quite present and highly cognitive,” said study investigator Nicholas D. Schiff, MD, Feil Family Brain & Mind Research Institute and Department of Neurology, Weill Cornell Medicine, Rockefeller University Hospital, New York.

“In other words, if you go to the bedside and carefully examine someone with a severe brain injury and find no evidence of responsiveness, no one has been able to give you an a priori number to say how likely you are to be wrong in thinking this person is actually unaware, not processing language, and not capable of high-level cognitive work. And the answer to that now is at least 1 in 4 times.”

The findings were published online in The New England Journal of Medicine.
 

Clinical Implications? 

Cognitive motor dissociation (CMD) is a condition whereby patients with a severe brain injury who are unresponsive to commands at the bedside show brain activity on functional MRI (fMRI) or electroencephalography (EEG) when presented with selective motor imagery commands, such as “imagine playing tennis,” or “ imagine opening and closing your hand.”

Previous research shows that CMD is present in 10%-20% of people with a disorder of consciousness, a rate similar to that in patients with acute or chronic brain injury.

Understanding that a patient who appears unconscious has signs of cognitive processing could change the way clinicians and family interact with such individuals. Unresponsive patients who are aware may eventually be able to harness emerging communication technologies such as brain-computer interfaces.

In addition, knowing an individual’s CMD status could aid in prognosis. “We know from one study that there’s a four times increased likelihood that patients will be independent in a year in their function if they have cognitive motor dissociation,” said Dr. Schiff.

Unlike most previous studies of CMD, which were conducted at single sites and had relatively small cohorts, this new study included 353 adults with a disorder of consciousness (mean age, 37.9 years; 64% male) at six multinational sites.

Participants were recruited using a variety of methods, including consecutive enrollment of critically ill patients in the intensive care unit and enrollment of those with chronic illness or injury who were in the postacute phase of brain injury.
 

Response to Commands

Study participants were at different stages of recovery from an acute brain injury that had occurred an average of 8 months before the study started.

To determine the presence or absence of an observable response to commands among participants, trained staff used the Coma Recovery Scale–Revised (CRS-R); scores on this instrument range from 0 to 23, and higher scores indicate better neurobehavioral function.

About 40% of individuals were diagnosed with coma or vegetative state, 29% with minimally conscious state–minus, and 22% with minimally conscious state–plus. In all, 10% had emerged from a minimally conscious state.

Researchers assessed response to timed and repeated commands using fMRI or EEG in participants without an observable response to verbal commands, including those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state–minus, and in participants with an observable response to verbal commands.

Of the 353 study participants, 61% underwent at least one fMRI assessment and 74% at least one EEG assessment. Both fMRI and EEG were performed in 35% of participants.

Dr. Schiff explained the two assessment types provide slightly different information, in that they measuring different types of brain signals. He also noted that although “every medical center in the world” has EEG, many do not have fMRI.

The brain imaging assessments captured brain activity within the motor area of the frontal cortex when tasked with motor imagery.

Of the 241 participants deemed to be in a coma or vegetative state or minimally conscious state–minus on the basis of CRS-R score, 60 (25%) had a response to commands on task-based fMRI, task-based EEG, or both.

The percentage of participants with CMD varied across study sites, from 2% to 45%, but Dr. Schiff said the reason for this is unclear. 

The proportion of participants with CMD may have been even higher if all individuals had been assessed with both imaging techniques, he said.
 

Higher Rate of Awareness Than in Previous Research

The investigators noted that the percentage of participants with CMD in their study was up to 10 percentage points higher than in previous studies. This may be due to the multimodal approach that classified participants undergoing assessment with both fMRI and EEG on the basis of responses on either technique, they said. 

The median age was lower among participants with CMD than those without CMD (30.5 years vs 45.3 years).

Compared with participants without CMD, a higher percentage of those with such dissociation had brain trauma as an etiologic factor (65% vs 38%) and a diagnosis of minimally conscious state–minus on the CRS-R (53% vs 38%).

Among people with CMD, 18% were assessed with fMRI only, 22% with EEG only, and 60% with both fMRI and EEG.

Dr. Schiff noted that the use of both fMRI and EEG appears to be more sensitive in detecting brain activity during tasks compared with use of one of these techniques alone.

Of the 112 participants with a diagnosis of minimally conscious state–plus or who had emerged from the minimally conscious state, 38% had a response to commands on task-based fMRI, task-based EEG, or both. Among these participants, 23% were assessed with fMRI only, 19% with EEG only, and 58% with both fMRI and EEG.

Research shows “it’s very clear that people with severe brain injury continue to get better over time,” noted Dr. Schiff. “Every month and week matters, and so it probably is the case that a lot of these patients are picking up the level of recovery, and the later we go out to measure them, the more likely we are to find people who are CMD than not.”

These new results should prompt further study to explore whether detection of CMD can lead to improved outcomes, the investigators noted. “In addition, the standardization, validation, and simplification of task-based fMRI and EEG methods that are used to detect cognitive motor dissociation are needed to prompt widespread clinical integration of these techniques and investigation of the bioethical implications of the findings.”

All study participants with chronic brain injury had survived their initial illness or injury and had access to a research facility with advanced fMRI and EEG capabilities. “This survival bias may reflect greater cognitive reserve and resilience over time among the participants. As such, the results of our study may not be generalizable to the overall population of patients with cognitive motor dissociation,” the investigators wrote.

Another study limitation was that participating sites used heterogeneous strategies to acquire, analyze, and interpret data, which led to differences in the number, type, and ordering of the cognitive tasks assessed on fMRI and EEG.

“These differences, along with variations in recruitment strategies and participant characteristics, may have contributed to the unequal percentage of participants with cognitive motor dissociation observed at each site. Our findings may therefore not be generalizable across all centers,” the researchers wrote. 

Only a few academic medical centers have the specially trained personnel and techniques needed to assess patients for CMD — which, the researchers noted, limits the feasibility of performing these assessments in general practice.
 

Challenging Research

Commenting on the research, Aarti Sarwal, MD, professor of neurology and section chief, Neurocritical Care, Virginia Commonwealth University, Richmond, Virginia, noted that this was a “very challenging” study to perform, given that only a few academic centers are equipped to perform both fMRI and quantitative EEG analysis.

“In general, finding patients this far out, who have access to clinical, radiological, and electrophysiological testing and were provided good care enough to receive these, is a mammoth task in itself.” 

Dr. Sarwal said the study builds on efforts of the Curing Coma campaign , a clinical, scientific, and public health effort of the Neurocritical Care Society to tackle the concept of coma as a treatable medical entity.

“It continues to highlight the challenges of prognostication in acute brain injured patients by showing a higher presence of cognitive function than previously perceived,” she said.

Dr. Sarwal believes that the study’s largest impact is underscoring the need for more research into understanding the degree and quality of cognitive processing in patients with a disorder of consciousness. But it also underlines the need for a “healthy debate” on the cost/benefit analysis of pursuing such research, given the limited number of patients with access to resources. 

“This debate needs to include the caregivers and families outside the traditional realms of stakeholders overseeing the science.” 

Although communication with comatose patients is still “a ways away,” this research is “a step in the right direction,” said Dr. Sarwal. 

The study was funded by the James S. McDonnell Foundation and others. Dr. Schiff and Dr. Sarwal report no relevant financial disclosures.
 

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

• VA Overview
• Dermatology
• Depression and PTSD
• Diabetes
• Cardiology
• Arthritis
• Traumatic Brain Injury (TBI)
• Women's Health
• Substance Use Disorder
• Transgender and Gender-Diverse Care
• Respiratory Health
• Age-Related Macular Degeneration (AMD)
• Parkinson Disease
• Amyotrophic Lateral Sclerosis (ALS)

• VA Overview
• Dermatology
• Depression and PTSD
• Diabetes
• Cardiology
• Arthritis
• Traumatic Brain Injury (TBI)
• Women's Health
• Substance Use Disorder
• Transgender and Gender-Diverse Care
• Respiratory Health
• Age-Related Macular Degeneration (AMD)
• Parkinson Disease
• Amyotrophic Lateral Sclerosis (ALS)

• VA Overview
• Dermatology
• Depression and PTSD
• Diabetes
• Cardiology
• Arthritis
• Traumatic Brain Injury (TBI)
• Women's Health
• Substance Use Disorder
• Transgender and Gender-Diverse Care
• Respiratory Health
• Age-Related Macular Degeneration (AMD)
• Parkinson Disease
• Amyotrophic Lateral Sclerosis (ALS)

Click to view more from Federal Health Care Data Trends 2024.

Click to view more from Federal Health Care Data Trends 2024.

Click to view more from Federal Health Care Data Trends 2024.

The ability of advanced diffusion MRI (dMRI) techniques to detect microstructural neurological changes in military patients with remote mild traumatic brain injury (mTBI) supports wider adoption of these techniques, according to authors of a recent study. In particular, they said, using neurite orientation dispersion and density imaging (NODDI) to monitor long-term mTBI impact on brain regions related to cognitive and emotional processing can help clinicians assess recovery, predict progression, and optimize treatment.

“Currently,” said co-senior study author Ping-Hong Yeh, PhD, “there is a lack of minimally invasive, quantitative diagnostic biomarkers for monitoring progression or recovery after mild TBI. However, mild TBI can be quite disabling, with many patients reporting symptoms months or even years after injury. This is the most difficult part to diagnose.” Dr. Yeh is a researcher at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center, Bethesda, Maryland.

The NICoE, a Department of Defense organization and the senior member of Defense Intrepid Network for Traumatic Brain Injury and Brain Health, is among several centers charged with improving support for injured service members’ recovery, rehabilitation, and reintegration into their communities. The overarching goal, said Dr. Yeh, is to enable community neurologists to refer service members and veterans to these centers for treatment and advanced imaging when needed.
 

Invisible Wounds

Limitations of conventional MRI and CT make it tough to discern which patients with mTBI will return to baseline functioning, and which will develop long-term complications. Addressing the silent or invisible wounds of mTBI will require improved diagnostic, prognostic, and therapeutic tools, he said.

For their study, published in JAMA Network Open, Dr. Yeh and colleagues compared diffusion tensor imaging (DTI) and NODDI data from 65 male service members with remote (more than 2 years old) mTBI against scans of 33 noninjured controls matched for age, sex, and active-duty status.

“Although DTI is very sensitive in detecting microstructural changes in mild TBI,” he said, “it is not specific to the underlying pathophysiological changes.”

Conversely, NODDI uses biophysical modeling of intracellular diffusion, extracellular diffusion, and free water to help physicians to understand subtle pathophysiological changes with greater sensitivity and specificity than does DTI. “This will allow us to correlate symptoms with brain structural changes, making the invisible wound visible.”

In the study, the greatest differences between injured and control patients appeared in the following NODDI metrics (P <.001 in all analyses):

• Intracellular volume fraction (ICVF) of the right corticospinal tract (CST)
• Orientation dispersion index (ODI) of the left posterior thalamic radiation (PTR)
• ODI of the left uncinate fasciculus (UNC)

Regarding patient-reported neurobehavioral symptoms, Neurobehavioral Symptom Inventory cognitive subscores were associated with fractional anisotropy of the left UNC. In addition, PTSD Checklist–Civilian version total scores and avoidance subscores corresponded, respectively, with isotropic volume fraction (ISOVF) of the genu of corpus callosum and with ODI of the left fornix and stria terminalis.
 

Next Steps

Presently, Dr. Yeh said, conventional MRI and CT usually cannot differentiate between axonal injury, axonal inflammation (which develops during the chronic phase of mTBI), and demyelination. “But newer biophysical modeling, such as NODDI, will allow us to tell the difference.” Along with providing prognostic information, he said, such technology can guide appropriate treatment, such as anti-inflammatory agents for chronic inflammation.

Most community neurologists refer patients with persistent mTBI symptoms in the absence of red flags using CT and conventional MRI for advanced neuroimaging, said Dr. Yeh. But because few community neurologists are familiar with NODDI, he said, broadening its reach will require educating these providers. Additional steps that Dr. Yeh said could occur over the next decade or more include boosting advanced dMRI sensitivity levels through improved hardware, software, and diagnostic tools.

“We need to make these techniques clinically feasible,” he added. Currently, protocols that allow advanced dMRI scans in about 10 minutes can be achievable.

The investments required to implement advanced dMRI techniques will be substantial. A state-of-the-art 3T MRI scanner that can support NODDI and DTI can easily cost $1 million, said Dr. Yeh. Factor in additional equipment options and construction costs, he added, and the total price tag can easily exceed $2 million. But rather than replacing all existing MRI systems, said Dr. Yeh, AI one day may help translate high-gradient capability even to widely used lower-field MRI scanners operating at 0.5T.

Streamlining systems that incorporate disparate scanners with different acquisition parameters will require standardized data acquisition and sharing parameters. Along with helping to evaluate new techniques as they become available, data harmonization and sharing can facilitate a shift from research comparisons between large groups to comparing a single patient against many others — a move that Dr. Yeh said must occur for advanced dMRI techniques to achieve clinical relevance.

In addition, experts will need to revise clinical guidelines for use of new technologies as their availability grows. “Improper use of these techniques will not only increase health costs, but also probably result in adverse health results.” Such guidelines could be very useful in evaluating the suitability and quality of referrals for diagnostic images, Dr. Yeh said.

Dr. Yeh reports no relevant financial interests. The project was partially funded by the US Army Medical Research and Materiel Command.

The ability of advanced diffusion MRI (dMRI) techniques to detect microstructural neurological changes in military patients with remote mild traumatic brain injury (mTBI) supports wider adoption of these techniques, according to authors of a recent study. In particular, they said, using neurite orientation dispersion and density imaging (NODDI) to monitor long-term mTBI impact on brain regions related to cognitive and emotional processing can help clinicians assess recovery, predict progression, and optimize treatment.

“Currently,” said co-senior study author Ping-Hong Yeh, PhD, “there is a lack of minimally invasive, quantitative diagnostic biomarkers for monitoring progression or recovery after mild TBI. However, mild TBI can be quite disabling, with many patients reporting symptoms months or even years after injury. This is the most difficult part to diagnose.” Dr. Yeh is a researcher at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center, Bethesda, Maryland.

The NICoE, a Department of Defense organization and the senior member of Defense Intrepid Network for Traumatic Brain Injury and Brain Health, is among several centers charged with improving support for injured service members’ recovery, rehabilitation, and reintegration into their communities. The overarching goal, said Dr. Yeh, is to enable community neurologists to refer service members and veterans to these centers for treatment and advanced imaging when needed.
 

Invisible Wounds

Limitations of conventional MRI and CT make it tough to discern which patients with mTBI will return to baseline functioning, and which will develop long-term complications. Addressing the silent or invisible wounds of mTBI will require improved diagnostic, prognostic, and therapeutic tools, he said.

For their study, published in JAMA Network Open, Dr. Yeh and colleagues compared diffusion tensor imaging (DTI) and NODDI data from 65 male service members with remote (more than 2 years old) mTBI against scans of 33 noninjured controls matched for age, sex, and active-duty status.

“Although DTI is very sensitive in detecting microstructural changes in mild TBI,” he said, “it is not specific to the underlying pathophysiological changes.”

Conversely, NODDI uses biophysical modeling of intracellular diffusion, extracellular diffusion, and free water to help physicians to understand subtle pathophysiological changes with greater sensitivity and specificity than does DTI. “This will allow us to correlate symptoms with brain structural changes, making the invisible wound visible.”

In the study, the greatest differences between injured and control patients appeared in the following NODDI metrics (P <.001 in all analyses):

• Intracellular volume fraction (ICVF) of the right corticospinal tract (CST)
• Orientation dispersion index (ODI) of the left posterior thalamic radiation (PTR)
• ODI of the left uncinate fasciculus (UNC)

Regarding patient-reported neurobehavioral symptoms, Neurobehavioral Symptom Inventory cognitive subscores were associated with fractional anisotropy of the left UNC. In addition, PTSD Checklist–Civilian version total scores and avoidance subscores corresponded, respectively, with isotropic volume fraction (ISOVF) of the genu of corpus callosum and with ODI of the left fornix and stria terminalis.
 

Next Steps

Presently, Dr. Yeh said, conventional MRI and CT usually cannot differentiate between axonal injury, axonal inflammation (which develops during the chronic phase of mTBI), and demyelination. “But newer biophysical modeling, such as NODDI, will allow us to tell the difference.” Along with providing prognostic information, he said, such technology can guide appropriate treatment, such as anti-inflammatory agents for chronic inflammation.

Most community neurologists refer patients with persistent mTBI symptoms in the absence of red flags using CT and conventional MRI for advanced neuroimaging, said Dr. Yeh. But because few community neurologists are familiar with NODDI, he said, broadening its reach will require educating these providers. Additional steps that Dr. Yeh said could occur over the next decade or more include boosting advanced dMRI sensitivity levels through improved hardware, software, and diagnostic tools.

“We need to make these techniques clinically feasible,” he added. Currently, protocols that allow advanced dMRI scans in about 10 minutes can be achievable.

The investments required to implement advanced dMRI techniques will be substantial. A state-of-the-art 3T MRI scanner that can support NODDI and DTI can easily cost $1 million, said Dr. Yeh. Factor in additional equipment options and construction costs, he added, and the total price tag can easily exceed $2 million. But rather than replacing all existing MRI systems, said Dr. Yeh, AI one day may help translate high-gradient capability even to widely used lower-field MRI scanners operating at 0.5T.

Streamlining systems that incorporate disparate scanners with different acquisition parameters will require standardized data acquisition and sharing parameters. Along with helping to evaluate new techniques as they become available, data harmonization and sharing can facilitate a shift from research comparisons between large groups to comparing a single patient against many others — a move that Dr. Yeh said must occur for advanced dMRI techniques to achieve clinical relevance.

In addition, experts will need to revise clinical guidelines for use of new technologies as their availability grows. “Improper use of these techniques will not only increase health costs, but also probably result in adverse health results.” Such guidelines could be very useful in evaluating the suitability and quality of referrals for diagnostic images, Dr. Yeh said.

Dr. Yeh reports no relevant financial interests. The project was partially funded by the US Army Medical Research and Materiel Command.

The ability of advanced diffusion MRI (dMRI) techniques to detect microstructural neurological changes in military patients with remote mild traumatic brain injury (mTBI) supports wider adoption of these techniques, according to authors of a recent study. In particular, they said, using neurite orientation dispersion and density imaging (NODDI) to monitor long-term mTBI impact on brain regions related to cognitive and emotional processing can help clinicians assess recovery, predict progression, and optimize treatment.

“Currently,” said co-senior study author Ping-Hong Yeh, PhD, “there is a lack of minimally invasive, quantitative diagnostic biomarkers for monitoring progression or recovery after mild TBI. However, mild TBI can be quite disabling, with many patients reporting symptoms months or even years after injury. This is the most difficult part to diagnose.” Dr. Yeh is a researcher at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center, Bethesda, Maryland.

The NICoE, a Department of Defense organization and the senior member of Defense Intrepid Network for Traumatic Brain Injury and Brain Health, is among several centers charged with improving support for injured service members’ recovery, rehabilitation, and reintegration into their communities. The overarching goal, said Dr. Yeh, is to enable community neurologists to refer service members and veterans to these centers for treatment and advanced imaging when needed.
 

Invisible Wounds

Limitations of conventional MRI and CT make it tough to discern which patients with mTBI will return to baseline functioning, and which will develop long-term complications. Addressing the silent or invisible wounds of mTBI will require improved diagnostic, prognostic, and therapeutic tools, he said.

For their study, published in JAMA Network Open, Dr. Yeh and colleagues compared diffusion tensor imaging (DTI) and NODDI data from 65 male service members with remote (more than 2 years old) mTBI against scans of 33 noninjured controls matched for age, sex, and active-duty status.

“Although DTI is very sensitive in detecting microstructural changes in mild TBI,” he said, “it is not specific to the underlying pathophysiological changes.”

Conversely, NODDI uses biophysical modeling of intracellular diffusion, extracellular diffusion, and free water to help physicians to understand subtle pathophysiological changes with greater sensitivity and specificity than does DTI. “This will allow us to correlate symptoms with brain structural changes, making the invisible wound visible.”

In the study, the greatest differences between injured and control patients appeared in the following NODDI metrics (P <.001 in all analyses):

• Intracellular volume fraction (ICVF) of the right corticospinal tract (CST)
• Orientation dispersion index (ODI) of the left posterior thalamic radiation (PTR)
• ODI of the left uncinate fasciculus (UNC)

Regarding patient-reported neurobehavioral symptoms, Neurobehavioral Symptom Inventory cognitive subscores were associated with fractional anisotropy of the left UNC. In addition, PTSD Checklist–Civilian version total scores and avoidance subscores corresponded, respectively, with isotropic volume fraction (ISOVF) of the genu of corpus callosum and with ODI of the left fornix and stria terminalis.
 

Next Steps

Presently, Dr. Yeh said, conventional MRI and CT usually cannot differentiate between axonal injury, axonal inflammation (which develops during the chronic phase of mTBI), and demyelination. “But newer biophysical modeling, such as NODDI, will allow us to tell the difference.” Along with providing prognostic information, he said, such technology can guide appropriate treatment, such as anti-inflammatory agents for chronic inflammation.

Most community neurologists refer patients with persistent mTBI symptoms in the absence of red flags using CT and conventional MRI for advanced neuroimaging, said Dr. Yeh. But because few community neurologists are familiar with NODDI, he said, broadening its reach will require educating these providers. Additional steps that Dr. Yeh said could occur over the next decade or more include boosting advanced dMRI sensitivity levels through improved hardware, software, and diagnostic tools.

“We need to make these techniques clinically feasible,” he added. Currently, protocols that allow advanced dMRI scans in about 10 minutes can be achievable.

The investments required to implement advanced dMRI techniques will be substantial. A state-of-the-art 3T MRI scanner that can support NODDI and DTI can easily cost $1 million, said Dr. Yeh. Factor in additional equipment options and construction costs, he added, and the total price tag can easily exceed $2 million. But rather than replacing all existing MRI systems, said Dr. Yeh, AI one day may help translate high-gradient capability even to widely used lower-field MRI scanners operating at 0.5T.

Streamlining systems that incorporate disparate scanners with different acquisition parameters will require standardized data acquisition and sharing parameters. Along with helping to evaluate new techniques as they become available, data harmonization and sharing can facilitate a shift from research comparisons between large groups to comparing a single patient against many others — a move that Dr. Yeh said must occur for advanced dMRI techniques to achieve clinical relevance.

In addition, experts will need to revise clinical guidelines for use of new technologies as their availability grows. “Improper use of these techniques will not only increase health costs, but also probably result in adverse health results.” Such guidelines could be very useful in evaluating the suitability and quality of referrals for diagnostic images, Dr. Yeh said.

Dr. Yeh reports no relevant financial interests. The project was partially funded by the US Army Medical Research and Materiel Command.

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.