Scientists have recently harnessed artificial intelligence (AI) to build "aging clocks" that aim to estimate a person's true biological age.

While a person's chronological age reflects the number of years they've been alive, their biological age is intended to capture how well their bodily systems are functioning. The idea is that people with older biological ages have a higher risk of age-related diseases ‪—‬ such as cancer, heart disease or dementia ‪—‬ while younger biological ages come with less risk. Some aging clocks even aim to predict people's impending risk of death.

Many aging clocks look at epigenetic markers, meaning chemical tags that bind DNA and change how genes activate, while others measure features such as the pace and pitch of people's voices. But some scientists say we don't know how to use these aging clocks yet, arguing that the tools are useful for studying aging at a population level but not for guiding individual health decisions.

Others posit that the data the clocks are based on is too noisy, and thus, there's potential for drawing faulty conclusions about what they're measuring. They say, for example, that we don't know if the clocks are measuring the downstream effects of aging or its underlying causes. And in any case, we don't currently have any treatments to "wind back" the clocks.

What do you think? Would you use these AI tools to measure your biological age? Let us know in the poll below, and explain your reasoning and additional thoughts about the technology in the comments.

Mpox is an infectious disease caused by a poxvirus, meaning a virus in the same family as smallpox. The infection was formerly known as monkeypox.

Historically, mpox was endemic to Africa, and the virus consistently spread in the continent's central, eastern and western regions. In 2022, an unprecedented global outbreak spurred the widespread transmission of mpox in places that had seen only sporadic cases in the past.

Today, many countries affected by that outbreak — including Germany, Portugal and the United States — are still contending with local mpox transmission. Here's what to know about the virus, how it spreads and how to prevent infection.

What to know about mpox in the U.S.

Mpox is still spreading at low levels in the United States and may soon be considered endemic to the country. While case counts have fallen dramatically since the peak of the global outbreak in summer 2022, some people are still advised to get vaccinated against the virus.

Who should get vaccinated for mpox?

The mpox vaccine currently used in the U.S. is called JYNNEOS. One dose is about 35% to 86% effective, while the complete two-dose series is 66% to 90% effective. (The effectiveness varies, in part, because some studies include people with HIV and people without HIV, and inadequately treated HIV can undermine the body's response to vaccines.)

The JYNNEOS vaccine is not currently recommended for routine use in the general population because, beyond vulnerable groups, the risk is not high enough to warrant a universal vaccination strategy. The current outbreak is primarily affecting men who have sex with men, and those sexual networks are the primary targets for JYNNEOS vaccination.

However, not all men who have sex with men need to be vaccinated, according to the Centers for Disease Control and Prevention (CDC). Instead, vaccination is recommended for a specific subset of the group, including those who, in the last six months, have had more than one sex partner, have had sex at commercial sex venues, or have been diagnosed with other sexually transmitted diseases.

Nonbinary and transgender people with these risk factors are also recommended to get two doses of JYNNEOS, as are any sexual partners of anyone in the above groups.

Vaccines are also recommended after a suspected exposure to mpox, as they can help prevent or reduce the severity of the infection.

"For those who are eligible and have not yet completed vaccination, now is a good time to talk with a healthcare provider about getting protected," Dr. Demetre Daskalakis, chief medical officer of Callen-Lorde, an LGBTQ+ community health center in New York City, told Live Science in an email.

With the exception of laboratory researchers who work with mpox, people who have received two doses of JYNNEOS are fully vaccinated and do not need a booster, he said. And if a person has caught mpox in the past and recovered, they do not need to get a vaccine, he added.

About the virus

The poxvirus family also includes smallpox, which has been eradicated worldwide. Mpox and smallpox cause some similar symptoms, but mpox tends to be far milder than smallpox. However, the viruses are closely related enough that vaccines designed to prevent smallpox can also protect against mpox.

Mpox was initially named monkeypox because the virus behind the disease was discovered in captive monkeys in Denmark. But monkeys are not the main hosts of the virus in the wild; rodents and small mammals mostly found in West and Central Africa likely are. Health officials changed the name to mpox in 2022.

There are two major branches of the mpox family tree, called clade I and clade II. These clades were historically thought to have very different death rates, with clade I being the deadlier of the two. The case-fatality rate (CFR) of clade I has been estimated to range from 1.4% to over 10%, depending on the outbreak, while the CFR for clade II has been estimated at between 0.1% and 3.6%.

However, as both clades have spread beyond Africa, data suggests that the CFR for clade I may be lower than once thought, said Joel Wertheim, a professor of medicine in the Division of Infectious Diseases and Global Public Health at the University of California, San Diego.

The features of a given outbreak — such as the surrounding health infrastructure, patients' access to timely medical care, and the population's underlying risk factors for severe disease — likely play a big role in determining the virus's death toll, Wertheim told Live Science. In short, rather than being an immutable feature of the virus itself, the CFR is dependent on the underlying health of and resources available to a given population.

How mpox spreads

Mpox can spread from infected animals to humans through the animals' bites or scratches. Additionally, people can get the virus when they come into close contact with animals and/or their bodily fluids during hunting, skinning, trapping, cooking, eating animals or handling carcasses, the World Health Organization (WHO) notes.

The virus also spreads from person to person, primarily through very close contact, including intimate contact during sex. The virus typically enters the body through broken skin, the respiratory tract or mucous membranes (thin tissues found in the eyes, nose, mouth, anus and genitals), spreading via bodily fluids such as spit, mucus or blood. People can also pick up the virus via objects, such as clothing or linen, that are contaminated with the bodily fluids of an infected person.

The virus can spread through small respiratory droplets expelled during speaking or breathing. However, this is thought to be a less-common transmission route than close contact. There is also evidence that asymptomatic spread sometimes occurs, though it's unclear how frequently that happens.

Mpox can spread from mother to baby during pregnancy or birth. This route of infection can result in pregnancy loss, stillbirth, death of the newborn, or complications for the mother.

Symptoms of mpox

Symptoms of mpox typically appear within a week of a person being exposed to the virus, but they can sometimes take up to 21 days to develop. Once they emerge, symptoms last about two to four weeks, although the illness can linger longer in people with weakened immune systems.

Common symptoms include rash (see images), fever, sore throat, headache, muscle aches, back pain, swollen lymph nodes and low energy. Often, mpox rashes first appear on the face and then spread to other parts of the body; however, if a person becomes infected during sex, the rash may instead start around their genitals. The rashes begin as flat, discolored patches of skin and then progress into raised bumps, blisters, and large, pus-filled pimples that eventually scab over and fall off.

Some people with mpox develop painful swelling of the rectum (proctitis), while others have pain and difficulty when peeing (dysuria) or when swallowing.

Mpox rashes can make people vulnerable to bacterial skin infections, which can cause abscesses or other serious skin damage. Additional complications of the illness include pneumonia, infection of the cornea that can cause vision loss, and vomiting and diarrhea that causes dehydration or malnutrition. Mpox can also lead to blood infections, the intense immune reaction sepsis and, rarely, brain infections (encephalitis) or heart inflammation (myocarditis).

Children, pregnant people, and people with weakened immune systems, including from HIV infection, have a higher risk of serious illness and death from mpox.

Mpox prevention measures

Beyond vaccination, other strategies to decrease the risk of mpox infection include washing hands frequently, avoiding contact with contaminated objects and materials used by people with mpox, avoiding contact with other people's scabs or rashes, and using condoms, although they may only reduce, not eliminate, the risk of mpox exposure during sex.

Mpox treatment

Mpox treatment aims to manage a person's rashes and pain while also preventing complications. "Early and supportive care is important to help manage symptoms and avoid further problems," according to the WHO.

There is no antiviral drug approved for use in mpox, although some are available for emergency use in various countries. For example, the U.S. allows the use of certain smallpox medicines for mpox.

Severe mpox infections also may be treated with vaccinia immune globulin intravenous, which contains antibodies taken from the blood of people who were immunized against smallpox.

People who have recently been exposed to mpox can be given an mpox vaccine to reduce the severity of their symptoms or to prevent the illness altogether. This approach is known as post-exposure prophylaxis, or PEP.

"Post-exposure vaccine should be given as soon as possible, ideally within 4 days of exposure; administration 4 through 14 days after exposure may still provide some protection against monkeypox," the CDC states.

Mpox spread across the world in 2022, triggering tens of thousands of cases in countries where the infection was once rarely seen. Although the disease has since fallen out of news headlines, mpox (formerly called monkeypox) continues to circulate. Now, recent data suggests that the viral illness may soon be endemic to the United States, meaning it will circulate in the country consistently.

Previously, mpox cropped up sporadically in the U.S. via travelers who had visited African countries where the disease is endemic, as well as imported, infected animals that spread the virus to people. Cases have fallen substantially since the peak of the outbreak in 2022, but they haven't disappeared. A report published in August found that there were 2,800 cases in 2024 and over 2,500 in 2025, with only a small fraction being tied to travel. Nearly all of the viral samples analyzed were descendants of the strain that sparked the 2022 outbreak. In short, once the virus arrived, it never went away.

"There's no set threshold for what constitutes endemicity of monkeypox virus (MPXV) in the United States," Ryan Standford, an epidemiologist in the Centers for Disease Control and Prevention's (CDC) Poxvirus and Rabies Branch and co-author of the report, told Live Science in an email. "But each year provides further evidence of this transition."

Why is mpox still spreading in the U.S., and what can be done to snuff it out? It's likely that too few people have received two doses of the mpox vaccine JYNNEOS, which together are 66% to 90% effective. But beyond low vaccination, there may be other, less-understood factors that are contributing to the continued spread, experts told Live Science.

"We don't quite know how it's able to persist at such low numbers across the entire country," said Joel Wertheim, a professor of medicine in the Division of Infectious Diseases and Global Public Health at the University of California, San Diego.

At the same time, public health efforts around mpox have dwindled. Without a sustained effort on that front, it's unlikely the disease will be eliminated from the U.S.

"We have vaccines, testing, and a much stronger understanding of the disease than we did in 2022," Dr. Demetre Daskalakis, chief medical officer of Callen-Lorde, a LGBTQ+ community health center in New York City, told Live Science in an email. "Our focus now should be making sure those tools remain accessible, especially for communities that continue to face ongoing risk," said Daskalakis, who coordinated the nation's mpox response during the previous presidential administration.

"People at increased risk should know that mpox has not disappeared."

Who is at risk of mpox in the U.S.?

In the U.S., mpox is predominantly affecting men who have sex with men, and current vaccine recommendations are aimed at this group and their sexual partners. Mpox mostly spreads from person to person through close contact, and transmission during sex is playing a major role in the ongoing spread in the U.S.

Men who have sex with men are not more prone to mpox infection than anyone else. Rather, this transmission pattern stems from the outbreak beginning within a specific sexual network and then continuing to persist within the same network. "The mpox virus rediscovered the same transmission network that HIV had explored decades earlier," Wertheim said.

In a paper published in 2025, Wertheim and colleagues described the transmission dynamics of mpox in New York City during the 2022 outbreak. Similar to how HIV previously spread, mpox triggered "densely connected" clusters of infection. Then, as people in the network gained immunity via infection and vaccination, the cases petered out, decreasing to the persistent trickle we see now.

Wertheim noted that he's not surprised that mpox has remained largely confined to the same network, rather than leaping into new groups.

"From an evolutionary, ecological perspective, it's not hugely successful," Wertheim said. "It's sort of barely hanging on as an STI."

Why is mpox still circulating?

So if mpox is not hugely successful and we have a vaccine, how has the virus continued to circulate? One big factor is that too few at-risk people have been vaccinated, experts said.

The CDC's Center for Forecasting and Outbreak Analytics has crunched the numbers to see what percentage of that at-risk group needs to have immunity to stop mpox transmission, Daskalakis said. The at-risk group is estimated by counting the men who have sex with men who are either taking HIV-preventing medicines or have HIV, and then adding 25% to that total to account for additional people in the same sexual network. That estimate comes out to about 2 million people.

To prevent an outbreak bigger than the one in 2022, between 21% and 35% would have to have immunity through vaccination or a past infection. If over 50% of the group had immunity, that would mean there's a "very small probability" of sustained local transmission, the CDC's modeling suggested.

The current case counts suggest we haven't hit the 50% mark, or a total of roughly 1 million complete vaccinations or past infections.

Data from the August report on mpox seems to support the idea that too few people are vaccinated. That said, information about vaccination status was missing for about 62% of the reported cases. Among the remaining cases, 76% were unvaccinated, while 10% had gotten one dose and 14% had gotten two.

In a subset of 860 cases, the effect of vaccination was striking: Unvaccinated people had nearly 10 times higher odds of hospitalization due to mpox than fully vaccinated people did.

Waning public health attention

It's difficult to pin down exactly how many at-risk people are vaccinated, given that that data is no longer tracked at the national level. "My understanding is that there's no mandatory reporting on mpox vaccination data," Wertheim said.

The CDC previously monitored national vaccination trends, comparing the number of people vaccinated to the overall at-risk population. But that tracking stopped in early 2024, when about 23% of the at-risk population had been fully vaccinated.

Some states, such as New York, previously mandated that clinicians provide their state health department data on the number of people given mpox vaccines. But that reporting is now voluntary, a spokesperson for the New York State Department of Health told Live Science in an email.

Meanwhile, "as the emergency phase faded from public attention, awareness and risk perception may have declined," Daskalakis said. Public health messaging about the virus and vaccination has also waned.

"In recent weeks, HHS [the Department of Health and Human Services] has pulled down some of the plain-language guidance, which is not helpful in supporting messaging," Daskalakis noted. This decision to remove online resources about mpox reflects the federal government's current stance against addressing issues that affect LGBTQ+ health, he told Live Science.

Complicating factors

Although JYNNEOS substantially lowers the risk of severe mpox infection, the vaccine is not perfect, said Rachel Roper, a professor of microbiology and immunology at East Carolina University.

The virus typically enters the body through broken skin, the respiratory tract or mucous membranes (thin tissues found in the eyes, nose, mouth, anus and genitals). The mpox vaccine is good at generating systemic immunity, but it's not as good at guarding against the virus's immediate effects at those mucous membranes, said Roper, who studies poxviruses and vaccines against them.

Because mpox is largely spreading through sexual contact that involves those membranes, that slight gap in protection may also help to explain some of the ongoing spread, she suggested.

Plus, "there are also some data supporting asymptomatic infection as a possible route of transmission, making it more difficult to eliminate local transmission of mpox," Daskalakis said.

What can be done?

Given that mpox is already well established within some sexual networks in the U.S., "preventing endemicity entirely may be increasingly difficult," Standford told Live Science.

And notably, some federal funding cuts could undermine efforts to address mpox, Daskalakis said. These include cuts to Medicaid, mental-health services, housing programs, and HIV services such as the Ryan White HIV/AIDS Program.

Thankfully, looking at current mpox trends, "there's no indication we're returning back to 2022 levels," Wertheim told Live Science. So far in 2026, just under 1,000 mpox cases have been reported, according to the CDC. Month over month, the number of cases is generally trending downward. So, at a glance, the current situation seems better than it was in 2025, he said.

"We sort of seem to be on this razor's edge between endemicity and extinction," he said. "And it's not really clear which way it'll go."

Tipping the virus toward extinction will require healthcare providers to be informed and equipped to spot and manage cases, Daskalakis said. And communicating the importance of vaccination is key.

"One lesson from 2022 was that trusted messengers matter," he said. "We [at Callen-Lorde] work closely with LGBTQ+ communities and make information and vaccination opportunities available in settings where people already receive care." The clinic integrates conversations about mpox vaccination into routine health visits, sexual health services, HIV prevention programs and community outreach activities.

Beyond vaccinating at-risk populations, educating patients about how mpox spreads and how to reduce their risk is also key, Standford noted. "Vaccination coverage is a very important factor, but it is not the only one," he said.

Tipping mpox toward extinction will also require enough investment to maintain the disease surveillance, vaccination, testing and treatment capacity that the federal government helped to expand in 2022, Daskalakis said. The vaccine itself is now commercially available to clinics and in adequate supply, he emphasized.

"The fact that we're seeing ongoing circulation underscores the need for sustained prevention efforts rather than viewing mpox as a resolved public health issue," he said. "Infectious diseases don't disappear simply because public attention shifts."

This article is for informational purposes only and is not meant to offer medical advice.

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Could a psychedelic drug help the brain recover from mild injuries? New research suggests that psilocybin, the mind-bending ingredient in magic mushrooms, might protect the brain from the damage caused by minor head impacts.

Even mild head impacts that don't count as concussions can raise the risk of neurodegenerative disorders such as chronic traumatic encephalopathy (CTE), so finding an effective treatment for these blows could be useful for warding off debilitating conditions down the line.

The new research, published in the journal Communications Biology, included only lab rats, so there's more work to be done to translate the findings to humans. But the early results hint at a new application for psilocybin — a drug that's already been explored for a range of other conditions, including depression, PTSD and anorexia.

Live Science spoke with study co-author Argel Aguilar-Valles, an associate professor of neuroscience at Carleton University in Ontario, about the new study and how the research might eventually translate to treatments for repetitive head injuries.

Nicoletta Lanese: In this new study you focus on mild head trauma. Why does that minor level of injury still raise concern?

Argel Aguilar-Valles: This work was spearheaded by our collaborator, Dr. Craig Ferris at Northeastern University in Boston. The idea was to focus on the cumulative effect of those milder head hits, or injuries, that happen quite commonly; a lot of children and older adults can have repeated instances of these events of head trauma, and it doesn't necessarily lead to any immediate treatment or hospitalizations because they are considered fairly mild.

But over time, there's evidence that this can lead to cumulative and long-term effects that can affect the health outcomes of these individuals, particularly as we age. It's a risk factor for several forms of dementia. So the idea was to try to model this with a milder version of head injury [in lab rats].

So it's repeated — it's three hits — they're controlled, they're fairly mild. And they produce some alterations in the brain networks that are evident in using either MRI [which looks at the brain's structure] or functional MRI [which analyzes brain activity] analysis.

NL: So these are head impacts that don't come with the symptoms associated with concussions?

AAV: It's always difficult to compare [what a rat is experiencing] to what a human might experience, especially here. One good way to put it is that there's no loss of consciousness ‪—‬ so in those instances where the hits happen but you don't black out.

NL: Is there anything available now to manage and treat these mild impacts?

AAV: Well, as far as I'm aware, there's not really an intervention. I've experienced this secondhand with my children. Sometimes, they will come back from school and then they [the teachers] say, "OK, they had a hit on the head; there's a bump, but they didn't lose consciousness or anything."

Then sometimes, you go to the doctor concerned and typically you're told, "OK, just keep them under observation." If there's no vomiting, nausea, if there was no loss of consciousness, typically they just send you home and say keep an eye. Put some ice on it. Maybe don't overexert yourself in the next few days — and that's about it.

There is no intervention — for instance, if we do this [treatment], it's going to prevent you from developing dementia 50 years down the line. There's obviously nothing like that, particularly when you have repeated instances and the effects are cumulative.

NL: What made psilocybin seem like a potentially promising treatment for head trauma?

AAV: My group specifically has had an interest in testing the ability of molecules collectively known as psychoplastogens. We didn't coin the term, but it basically refers to all of these drugs that produce these brain-plasticity effects [changes in the brain's structure and activity]. These include serotonergic psychedelics [such as psilocybin and LSD, which affect serotonin receptors], and also things like ketamine or even MDMA.

We observe changes in cultured neurons in response to these drugs, in terms of dendritic complexity and increased synaptic spine density [changes in neurons' incoming and outgoing wires]. And in vivo [in live animals], you also observe functional reorganization of networks. All of these drugs have the ability to trigger these mechanisms. They do it through different pharmacological targets, but they all converge on some of these plasticity effects.

There are deficits in this plasticity in psychiatric illnesses, but also, obviously, in neurological disorders and even neurodegenerative disorders, where these plasticity mechanisms are completely nonfunctional.

So, we wanted to test the limit of the ability of these molecules to rescue, or to provide some therapeutic relief, in conditions where you have physical damage or neurodegenerative pathological mechanisms underlying the disorders. We observed — and not only us, but several other labs have also observed — that some of these molecules do seem to provide some level of therapeutic relief. [Editor's note: The current study looked only at physical trauma, but other labs have started to explore psilocybin for neurodegenerative disorders.]

It's still unclear if they're disease-modifying, in the sense they could provide lasting changes that can modify the course of the disorder. But so far, the evidence indicates that they can at least help to ameliorate some of the negative consequences of either neurodegeneration models or physical trauma, like in this case.

NL: Psychedelics have been more thoroughly studied for conditions like depression. In both depression and head trauma, could similar mechanisms explain the drug's potential benefits?

AAV: Some of the cellular effects might be similar. But the underlying condition can look quite different. Even if you think of two cases of depression, they can look very, very different. The drugs are going to be engaging similar mechanisms, but also the context in which these mechanisms are occurring will probably affect the outcome. What is remarkable about these drugs is that they seem to be working in both cases, so they're certainly tackling something that might be common in both situations.

We don't know the limits of these drugs yet. I'm not trying to imply that they don't have limits; what I'm trying to say is that our knowledge is incomplete. We don't know when they will work better than other potential treatment options.

I feel that will come when their clinical use is more widespread and we have a better idea of how they work in the heterogeneous populations that clinicians have in real life. In our animal models, conditions are very, very controlled and homogeneous, so they respond in a certain, similar way, whereas in the clinic, you observe huge disparity [in responses].

NL: Is there reason to think that psilocybin would be more promising than other psychoplastogens?

AAV: I think a lot of the focus on psilocybin has been because it's one of the psychedelics that's been more widely tested both in clinic and preclinical settings.

I'm not a clinician, but one of the reasons why psilocybin is favored over others is the length of the psychedelic trip. It's a few hours. If you go with something like LSD, it will last much longer. While the person is under the influence of the drug and undergoing the trip, there needs to be clinical supervision, so it becomes really challenging logistically to arrange sessions with psychedelics that last a long time.

That's also motivated preclinical research, like ours, to focus on this drug, as opposed to others that may have similar effects. From a potential translational perspective, it might be a safer bet to study this drug.

NL: In clinical trials of psychedelics, scientists often use a very small dose to try to avoid triggering strong hallucinogenic effects. Was that a goal with the rats?

AAV: No, they're probably experiencing something — this is a relatively high dose. A lot of people use 1 milligram of psilocybin per kilogram of body weight. In this case, they were using 3 milligram per kilogram, and it was based on previous imaging studies where they looked at the effects of this drug.

One measure we use is the "head twitch response," which is a behavioral measure that we commonly use in rodent work to test the hallucinogenic potential of a drug. This is a very rapid head movement that occurs in response to the serotonergic psychedelics. It's a behavioral response that correlates with hallucinogenic potential, and not perfectly.

For psilocybin, it's been very well characterized in the sense that it's mediated by the serotonin 5-HT2A receptor [in rodents], which is the same receptor that mediates hallucinations and the psychedelic trip in humans.

NL: What notable changes did you see in the rats in this study?

AAV: The measurements were done nearly three weeks after the injury. It's relatively short if you think of a human, but for a mouse, things happen much faster metabolically and physiologically. There was at least evidence of increased phosphorylation of tau [changes in a specific brain protein tied to Alzheimer's], and that was reversed by the treatment with psilocybin. That was certainly one surprising finding, and it's worth following up, I believe.

But also the hyperconnectivity — the brain's functional connectivity was really dramatically affected in the treated rodents with the head hits. They not only recovered but went to higher levels than the control-group animals.

We don't really know what the meaning of that is, but certainly it's quite remarkable how the networks became hyperconnected. And hopefully that means something positive for the animals. But it was certainly surprising, the level of recovery of that particular measure.

NL: And these effects were seen throughout the brain?

AAV: There were effects in a lot of brain regions — the thalamus, the hippocampus, the basal ganglia, and all different parts of the cortex, etc. One of the things that stands out from this study was the connectivity of dopaminergic nuclei [hubs of dopamine production in the middle of the brain]. Their connectivity is really fundamentally changed by the hits and then by the treatment with psilocybin.

These modulatory regions, the dopaminergic regions, are concentrated in one part of the brain, but they affect overall brain function because they have these widespread connections. So they're really crucial for a lot of functions, and we're seeing effects in these regions — that's really intriguing.

NL: Is it known whether the strength of the psychedelic trip has anything to do with the degree of benefit?

AAV: It is currently a hotly debated topic in the psychedelic field, whether the intensity of the psychedelic experience has anything to do with the beneficial effects or not. You can envision situations like psychological trauma, as opposed to physical trauma, where that trip might be part of the therapeutic mechanisms. It becomes evident in the debriefing sessions after psychedelic treatment, where it seems like in some cases, the psychedelic experience is fundamental.

But these are fairly correlative measures — if the two happen at the same time, it doesn't mean that they are linked together causally. So that's something that is being tested actively. One of the ways is the development of these non-hallucinogenic analogues that seemingly trigger similar plasticity mechanisms as their psychedelic counterparts do [without causing a trip].

I don't think we've had the first clinical trial with these drugs yet. Some of them may have undergone Phase I clinical trials just for safety, but I believe none of them have been tested in Phase II trials yet [in which their effectiveness is explored for specific conditions].

NL: Given this work is in rats, what are the next steps to translate this into a treatment for people?

AAV: Extending the observations, like other groups have done — looking at what happens if you do give this treatment months after the events. It's still unclear to me if, with this model we have, you will have effects months later.

We have some correlative measures that potentially BDNF expression [a gene for brain-derived neurotrophic factor, which helps neurons grow connections] is increased, and also the levels of its receptor, called TrkB. That is a possibility that needs to be further investigated, trying to find out whether these neurotrophic factors are crucial for the effects that we're seeing.

And obviously, the psychedelic trip is still a potential issue. But testing whether these non-hallucinogenic derivatives have the same lasting effects as their hallucinogenic counterparts do — that will be crucial and that can, in some cases, potentially facilitate the translation [into treatments]. Because not every person reacts the same way to these hallucinogenic compounds, and not everybody has the same risks.

NL: I assume the non-psychedelic options might be better for children, for instance?

AAV: We don't know what the consequences [of psychedelic use] are in a developing brain. There's not enough data. That will be obviously a big thing to sort out before recommending the use of these drugs, and maybe some of those non-hallucinogenic derivatives may hold the answer for that — for those cases where you really don't want to induce a full-on psychedelic experience.

There's also schizophrenia and a bunch of other psychiatric diagnoses with psychosis associated with them — from bipolar or psychosis-like events or episodes — where you might not want to apply a serotonergic psychedelic.

NL: Looking ahead to the next five to 10 years, what do you hope to see in the field?

AAV: There's a lot of enthusiasm in the field and a lot of push to try to characterize and understand better these drugs, from a basic perspective or a cellular level up to a brain wave level and then also the psychological effects. So there are a lot of different disciplines implicated in studying these drugs, and I think that's really exciting. That will hopefully lead to a wealth of knowledge about these drugs — not only their effects but also their limitations and their potential risks.

Hopefully we will have a balanced approach as scientists, to be able to really tease apart in which cases it [psychedelic treatment] will be really useful and in which cases the risks outweigh the benefits. That will be crucial to understand.

There's a lot of potential there, but we should proceed with caution.

This interview has been condensed and edited lightly for clarity. This article is for informational purposes only and is not meant to offer medical advice.

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Many people are familiar with melatonin, a hormone that helps ready the body for sleep. But there's another, lesser-known chemical in the brain, called orexin, that tips the scale in the other direction: waking the body up.

In 1999, two scientists independently uncovered the function of orexin and published papers about it. Dr. Masashi Yanagisawa, a molecular biologist and physician now at the University of Tsukuba in Japan, came across orexin while studying the interaction of receptors and chemicals in the brain. Dr. Emmanuel Mignot, now the director of the Stanford Center for Narcolepsy, homed in on orexin while studying narcoleptic dogs. (His Chihuahua, named Watson, has narcolepsy, and he previously had another dog with the condition, named Bear.)

This year, the pair of researchers won the coveted Albert Lasker Basic Medical Research Award for this fundamental finding that helped reshape our understanding of sleep. Their work has since led to the development of drugs for insomnia and narcolepsy.

Yanagisawa told Live Science that, at the start of his research career, he didn't expect to end up studying sleep. Mignot, on the other hand, had an early interest in understanding narcolepsy so that better treatments for the neurological disorder could be developed. Live Science spoke with Mignot about the discovery of orexin and how the field might progress in the future.

Nicoletta Lanese: What initially drew you to studying narcolepsy?

Dr. Emmanuel Mignot: There were three things that attracted me to narcolepsy: Number one, it was a human problem. It was already known [at the time] that it was not super rare. I'm not saying it's super common, but 1 person per 3,000, 0.03% ‪—‬ it's reasonably common. And nobody cared about it. I would talk to neurologists and they'd say, "Oh, I've never seen one case in my entire life." So I would say, "Yes, of course; you miss them all." That was the state of the play at the time.

Number two, was what this was a quintessential sleep disorder [in which sleep itself is disrupted]. I thought that if we found the cause of this disease, we could potentially discover something totally new about sleep — a fantastic entry point to a mystery.

The third thing that made me ready to go there was that it was tractable. A lot of problems are not tractable.

NL: Why did you start working with the dogs with narcolepsy?

EM: I studied the pharmacological basis because I was trained in pharmacology, and as a psychiatrist, and I discovered how this drug modafinil [a stimulant-based narcolepsy treatment] was working. But quickly, I realized I'm not going to find the cause by doing pharmacology. I'm only going to explore what's known.

That's when I started to fall in love with genetics, even though I was not trained as a geneticist. I said, "We have to find this gene in the dogs." It looks like they have all the symptoms. It was a huge bet, and it took me 10 years because I was definitely … overoptimistic. But it was worth the price at the end.

NL: And scientists already knew about narcolepsy in dogs at that time?

EM: The guy at Stanford that started the sleep program was called Dr. [William] Dement. He was a graduate student in Chicago in the 1950s, when [Eugene] Aserinsky and [Nathaniel] Kleitman discovered REM sleep. He had the foresight to understand that this was an important discovery.

[Later], he discovered that narcolepsy was really a disorder where people go into REM sleep and have this very abnormal dreaming. He came in 1970 to Stanford, and the first thing he did after his medical school was to start a clinic to see patients with narcolepsy. Around then, he spoke at an American Medical Association conference in San Francisco, and he discussed different sleep disorders, including narcolepsy. And then there was someone in the audience that said, "Oh my god; I have a dog with your disease. Every time it gets excited — boom — it collapses. And it sleeps all the time."

That dog had already been euthanized, but it still gave him the idea that these dogs have narcolepsy — maybe we should try to get some. So he went to a lot of veterinarians to talk to them about it, and they identified a whole series of dogs, including the first poodle, Monique, who had narcolepsy. And they started this little colony of dogs. Initially, they tried to breed them, but most cases of narcolepsy are actually not genetic. Then, in 1977, they got a whole litter of Dobermans, and then Labradors, that had some form that was genetic.

So when I arrived, it was in 1987. They already had the dog colony. I came to study the pharmacology, to try to find a better treatment for narcolepsy. But I did stand on the shoulders of giants.

NL: At that time, it's not like you had a complete dog genome. Did that make studying their genetics challenging?

EM: It was crazy. A couple of human genes had been isolated, and mouse genes, but it was a handful. We didn't even have the full genome map in humans. And meanwhile, dogs — no pun intended — were in no man's land. Very little was known.

It took me 10 years. I had times where some people didn't believe that the dogs had narcolepsy. There were a few depressing moments, but I was convinced that was the right thing to do.

NL: When you ultimately found the receptor for orexin, did it surprise you? It strikes me as surprising that there would be a discrete "switch" in the brain that controls wakefulness.

EM: I was lucky. Honestly, I had no idea. I got enamored with genetics because what I love [about it] is you can find something without any hypothesis. You just search for it, and what you find tells you what it is. You have no prerequisite for knowing what you would find.

I could have found something much less significant. That was a dream, to find a GPCR [G-protein coupled receptor, a protein on the outside of cells]. Can you imagine? A drug target.

Then, it turned out to be immediately applicable to humans. That, too, was a lot of luck; let's be honest. I was just trying to find the cause of one thing and one step at a time; it could have been something very complicated. It turned out to be simple.

Was I surprised? No, because I was not expecting one or another.

NL: Do you recall what the reception was like when the initial finding was published?

EM: It had an immediate effect, for several reasons. For example, I was seeing a lot of patients with narcolepsy at the time, but they were all old folks that had had narcolepsy forever. A lot of people would tell me, "I think I had it from when I was born, because I don't remember." We were never seeing children.

But after narcolepsy was described — the dog gene — suddenly narcolepsy became much more famous. And what happened is that people started to pay attention to narcolepsy, and we started to see kids. In kids, the picture is so much different. They gain an enormous amount of weight; it's very abrupt. It's a little bit different than what you see in adults, where they have adapted to it.

That was, I think, a practical consequence of the discovery. It really put narcolepsy on the map.

The second thing that happened is, all the drug companies started to develop hypnotics [sleeping pills], trying to block the orexin. They developed hypnotics relatively quickly, and they are very effective. They are probably safer than benzos [benzodiazepines] and so forth.

NL: Is it considered safer because the orexin blockers better replicate natural sleep?

EM: We know that the orexin definitely drops during sleep, so blocking it is definitely a way to recapitulate that drop; that's true. It's an awake-promoting system, so if you remove something that makes you more awake, it's safer than inducing sleep by shutting down the brain.

NL: As you moved to studying narcolepsy in humans, you found evidence that there might be an autoimmune response involved; it's been suggested that such a response may be harming the cells that make orexin in the brain. Was there suspicion that the condition had an autoimmune element previously?

EM: It's not something I 100% discovered. In 1983, before I came to study narcolepsy, there was a guy in Japan who I met, called Yutaka Honda. [Editor's note: Honda's research linked narcolepsy to the human leukocyte antigen (HLA) region of the genome, which helps regulate immune responses.]

The HLA is the way the immune system sees the world. That had just been discovered as very important for transplantation, because it's very polymorphic [takes on different forms] from one person to the next. They [Honda's group] found that all narcoleptics had a particular genetic variant, called HLA-DR2. This was a total surprise.

When I came, that was already known. But then people really looked and tried to see if the disease was autoimmune, but they couldn't find anything — no autoantibody, nothing. It was all negative.

I did a study with African Americans, and in African Americans, I found that this DR2 marker was not the best marker for narcolepsy. It was a gene just next to it that was called DQB1*06:02. [Editor's note: That HLA variant is now recognized as a strong risk factor for narcolepsy, particularly for narcolepsy type 1 (which involves a symptom called cataplexy).]

I'm very proud of that study because I think it's the first time that people used human diversity to actually map down a genetic factor more precisely, which now is used commonly. It's called transethnic mapping.

NL: New treatments that target orexin have just been approved. Do you see those therapies as an extension of your earlier findings?

EM: Of course. I was trained as a pharmacologist originally, so obviously, I do a lot of clinical trials. I see my patients totally transformed by this medication. It's just amazing. I'm so fortunate. How could you get a better reward than seeing your patients totally transformed by this medication?

It's going to have a lot of other applications [beyond narcolepsy]. Some people think it's going to be very helpful for ADHD; some people think it could be very helpful for depressed people with excessive sleepiness. We don't know, really; there's a lot of possibilities.

Another thing I'm excited about is that I have a few patients with [both] narcolepsy and schizophrenia. You cannot give them stimulants. If you give them modafinil or another dopamine stimulant [for narcolepsy], they have even more hallucinations. Often, they are sedated by their medication, and we are very poor at making people more motivated and active. These [orexin-activating] drugs seem to have effects beyond just waking people up. They seem to increase motivation.

You don't know until you try, but I'm sure it's going to have other applications.

This interview has been condensed and edited lightly for clarity. It is for informational purposes only and is not meant to offer medical advice.

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This year's Lasker Awards — coveted prizes for biomedical research that are sometimes called "America's Nobel Prizes" — have gone to scientists behind fundamental discoveries in sleep science and to researchers who developed a groundbreaking treatment for hemophilia.

Additionally, a Lasker Award for public service went to actor Michael J. Fox for his advocacy for patients with Parkinson's disease that has helped advance research into the neurodegenerative condition.

The prizes, each of which comes with an honorarium of $250,000, will be presented in person Sept. 17 in New York City. The awardees were announced Wednesday (Sept. 9) by the Lasker Foundation, which was established in 1942 by the philanthropists and health advocates Albert and Mary Lasker.

A deeper understanding of sleep

The first of the three awards, called the Albert Lasker Basic Medical Research Award, went to two scientists who independently discovered a key substance in the brain that helps control the sleep-wake cycle and is missing in people with some forms of narcolepsy — the neurological disorder marked by excessive daytime sleepiness and, sometimes, cataplexy (sudden episodes of muscle weakness).

The researchers — Dr. Emmanuel Mignot of the Stanford University School of Medicine and Dr. Masashi Yanagisawa of the University of Tsukuba in Japan — arrived at the discovery through different approaches. Mignot wanted to understand the underlying causes of narcolepsy, while Yanagisawa was investigating a curious class of receptors that were known as "orphans" because the chemicals that activated those receptors were unknown.

"We never thought we would end up in sleep," Yanagisawa told Live Science. "This was a kind of biochemical fishing expedition."

In particular, Yanagisawa was interested in proteins at the surface of cells called G protein-coupled receptors (GPCRs). When the right chemicals are plugged into these receptors, they trigger a chain of events within cells. Various compounds that activate GPCRs had already been found to be useful as drugs, but there were many receptors with unknown triggers.

Yanagisawa and colleagues went fishing for those triggering chemicals in rat brains, isolating substances called peptides from the tissue and then exposing GPCRs to those peptides. "We got very lucky, initially," Yanagisawa said. The fifth or sixth receptor they tested had a hit. Through further experiments, they landed on two closely related peptides as the trigger, and they found a second related receptor to match.

They discovered that the peptides came from a part of the brain called the hypothalamus, which was known to be involved in eating behaviors. So they named the peptides "orexins" after the Greek word for appetite, "orexis."

It turned out, though, that orexins' main job wasn't to control appetite; rather, they help promote wakefulness, the opposite of sleepiness. Mice without functional orexin genes would suddenly fall over and remain immobile for a minute or two, the researchers found. Peering into those mice's brains, they found that the animals were suddenly entering REM sleep, a phenomenon also seen in people with narcolepsy with cataplexy.

At the same time, Mignot, the other winner of the Lasker Award, was learning that orexin deficiency is also behind a form of narcolepsy seen in dogs. He then went on to study the mechanism in humans with narcolepsy.

"It became, suddenly, a very, very convincing story," Yanagisawa said of the researchers' converging findings. Previously, the study of sleep involved damaging parts of the brain and then seeing how a lab animal's sleep changed in response.

"There was no molecular level, genetic level, description of sleep regulation mechanisms at all," he said. "So our papers really shed new light on sleep regulation."

Together, the researchers' work paved the way to a new class of insomnia treatments, called orexin receptor antagonists, which promote sleepiness by turning down wakefulness. They have also led to new narcolepsy treatments called orexin receptor agonists, which boost wakefulness by increasing the receptors' activity. The first in the latter class of drugs was just approved in August.

A life-changing hemophilia treatment

The second award, called the Lasker~DeBakey Clinical Medical Research Award, went to three scientists affiliated with the Japanese drug manufacturer Chugai Pharmaceutical. These researchers — Kunihiro Hattori, Takehisa Kitazawa and Tomoyuki Igawa — created an antibody that interacts with key proteins in the blood that produce clots and thus stop bleeding.

This antibody treats hemophilia A, a severe bleeding disorder caused by a genetic mutation. That mutation causes the body to not make enough factor VIII, one of the key blood-clotting proteins. Normally, factor VIII grabs hold of two other clotting factors, and this enables a chain reaction that results in normal blood clotting. Without enough factor VIII, there is abnormal bleeding.

The severity of hemophilia A varies, but people with the disorder frequently experience blood pooling in their joints, which causes chronic pain and impairs mobility; they can also bleed uncontrollably even in the absence of trauma.

The antibody treatment works by binding two other clotting proteins — factors IX and X — to create a structure that fulfills the function of the missing factor VIII. Hattori, who is no longer at Chugai Pharmaceutical, initially launched the effort in 2000 after hatching the idea to use an antibody to bind several clotting factors together. Kitazawa and Igawa then brought the idea to fruition using pharmacology and chemical engineering, respectively.

The antibody, called emicizumab (marketed as Hemlibra), was approved by the U.S. Food and Drug Administration in 2017, and over 100 additional countries have approved the drug since. Over 30,000 people have received the antibody treatment to date, according to the award announcement.

Parkinson's disease advocacy

The third and final award — the Lasker~Bloomberg Public Service Award — went to Fox, actor and founder of The Michael J. Fox Foundation for Parkinson's Research.

Fox began experiencing symptoms of early-onset Parkinson's in 1990 at age 29. He publicly announced the diagnosis in 1998, sparking new discussions around the often-stigmatized disease. Through interactions with existing Parkinson's advocacy groups, Fox realized the field faced a lack of funding that likely hindered the pursuit of better treatments and a cure.

Since its inception in 2000, the foundation has funded more than $3 billion in Parkinson's research, according to the award announcement.

"When we launched the Foundation, our goal was simple, yet ambitious — cure Parkinson's," Fox said in a statement. "I am humbled to be recognized by the Lasker Foundation and jury. I accept this honor on behalf of everyone living with Parkinson's and everyone with us in our shared mission to end the disease."

This article is for informational purposes only and is not meant to offer medical advice.

A fruit fly's brain is roughly the size of a poppy seed — and yet that tiny package contains over 100,000 neurons. A new map charts every single neuron in the male fruit fly brain, as well as the insect's equivalent of a spinal cord, totaling more than 166,000 neurons.

This new map joins a map of a female fruit fly brain that was unveiled in 2024 and covers about 140,000 neurons. These two wiring diagrams, also called "connectomes," can now be compared to see if there are differences between the sexes' brains that help to explain behavioral differences reflected during mating or in aggressive actions, including sex-specific fighting moves.

"It is the first time we can compare both sexes of an animal with complex social behavior," study co-author Gerry Rubin, head of biology and a senior group leader of the Howard Hughes Medical Institute's Janelia Research Campus, said in a statement. "Male and female flies have a lot of differences in their behavior, and neuroscientists want to understand how the brain controls those behaviors. This now allows us to easily home in on the neurons that are causing those differences."

Initially released as a preprint, the new fly brain map was published in the journal Cell and Current Biology Thursday (Sept. 3). The study describing the map was published alongside three other papers, each of which uses the new data to explore a specific aspect of fruit fly neurobiology.

"The fly nervous system performs remarkably sophisticated computations with relatively few neurons and little energy, and its architecture could suggest principles for designing more efficient artificial systems," said Carlos Ribeiro, a principal investigator at the Champalimaud Foundation in Lisbon, Portugal, whose team contributed to the brain map and led one of the related studies.

"This work also provides a technical roadmap for more ambitious connectomics projects in the future, such as those for mice and humans," Ribeiro said in a separate statement from the Champalimaud Foundation.

In the near term, the scientists aim to map the brains of larval zebrafish (Danio rerio) and adult danionin fish (Danionella). In the long run, the goal of this research is to understand how vertebrates' brains enable complex behaviors, and then use that knowledge to help unravel the basis of neurological and psychiatric disorders in humans.

The study led by Ribeiro and other Champalimaud Foundation scientists aimed to map the circuits in the fly brain dedicated to the insect's sense of taste. Fruit flies have taste receptors in many body parts, including their legs, wings, mouthparts and inside of the throat. The researchers identified these taste receptors and traced their connections back to the fly brain. From there, they examined how those circuits interacted with those that govern behaviors such as swallowing or walking. When it comes to eating behaviors, this circuitry helps the fly determine whether a given morsel is safe or harmful and ultimately choose whether to eat it, the researchers concluded.

This diagram of taste processing is a "hypothesis-generation tool," study co-author Inês de Haan Vicente, a research technician in Ribeiro's lab, said in the Champalimaud statement. "Suppose you are interested in how taste controls locomotion. Now you can go to the map and ask: which sensory neurons are connected to the neurons controlling locomotion? Which intermediate neurons should I manipulate? It gives you a place to start."

The other two papers published alongside the map respectively explore the circuits behind vision processing in the fly brain and sex-specific differences in male and female fly brains. The first showed that visual processing extends deep into the brain, involving more than half of the 11,000 or so types of neurons identified in the map. The latter study found a network of cells that's specific to the male brain and appears to coordinate male-specific behaviors, such as specific aspects of fly courtship and physical aggression. (For example, female flies tend to headbutt while males lunge at their targets.)

While there were some networks specific to each sex, the circuits for sensation and movement are largely shared between males and females, the research found. At times, specific switches within those circuits reroute signals to different destinations in the male and female brain; the consequences of that rerouting will be a focus of future investigations.

See how much you know about the most complex organ in the human body with our brain quiz!

Of the former National Football League (NFL) players who died in recent years, at least 25% had brain changes related to chronic traumatic encephalopathy (CTE), a new study suggests.

The study, published Aug. 25 in the journal The BMJ, examined donated brain tissue from 338 former NFL players who died between 2008 and 2021. A total of 1,712 former players died in that time frame, so the analysis included only about 20% of the players' brains that could theoretically have been examined. Then, the researchers used that subset of brains to estimate the likely prevalence of CTE in the overall group.

Among the donated brains, over 93% showed physical signs of CTE, meaning an accumulation of abnormal proteins in specific places within the tissue. About 30% had stage IV CTE, the most severe form that comes with the most extensive brain changes.

These physical signs of CTE aren't always associated with overt symptoms, such as cognitive decline, mood and behavioral changes, or dementia. Only about 60% of the individuals with CTE-related brain changes were also diagnosed with dementia in this study. That said, those with stage IV CTE were more likely to have dementia, with 90% having a diagnosis.

Across the full study time frame, the researchers estimated that between 18.5% and 98.7% of the deceased players likely had CTE. Zooming in on the period with the highest number of brain donations — 2016 to 2021 — they estimated the rate to be between 24.5% and 97.7%. That latter time frame was likely the more representative sample, the researchers determined.

What can this study tell us about the CTE risk that current football players face, from youth sports to the professional level? To put the research into context, Live Science spoke with Thayne Munce, an associate professor and director of the Jayhawk Athletic Performance Laboratory at the University of Kansas, who was not involved in the BMJ study. Munce researches brain health and concussion in contact sports, primarily among young athletes. He cautioned that the BMJ study's findings shouldn't be extrapolated to all levels and ages of play, or even to today's NFL players.

Nicoletta Lanese: This study estimated the rate of CTE among this era of NFL players. Was the prevalence surprising to you, or in line with your expectations?

Thayne Munce: It's not surprising to me. This group and their colleagues have published previous work from donors — so these are former players who have donated their brains for research. They have reported even higher rates than 25% among just their donor sample [in this study]. This really high rate — over 90% of CTE cases in the donor group — is in line with what previous research has shown for these brain banks. So that's not terribly surprising.

What's different in this study is they compared the donors over a certain period of time versus all of the deaths among NFL players during that period of time and estimated the range based on how representative that donor sample was to the overall group of NFL players.

For example, if players just randomly selected to donate their brain to the brain bank and then they found that 98% of all of their samples had CTE — if that's representative of all the players from that era, then that's where you get the higher estimate. But if the majority of players that actually had CTE were the only ones who donated their brains because maybe they were showing outward signs or symptoms of dementia or cognitive decline or behavioral changes while they were living, then it becomes a very highly biased sample.

So that's where you get this big range. [The true prevalence] really depends on how representative that donor sample was to the peer group of players from that era.

NL: Does that broad range of estimates make it difficult to pin down the risk for current players?

TM: I think even more problematic than that big range is to understand that this is a historical study.

So these were players who died between 2008 and 2021, and the average age, I believe, was a little over 70 years of age. So if you extrapolate backwards, they probably played in the NFL starting around age 21 or 22 or 23 — that puts their playing days back in the '60s and '70s. So these were players who played in the NFL predominantly in the '60s and '70s, and would have played college and high school football in the '60s and '50s.

This is a different era of football. So we should not be making any estimations about what current CTE rates are based on this study, because a lot has changed in 50 years. It [the CTE rate] could be the same. It could be greater. It could be less. We really don't know.

I suspect, based on improvements in protective equipment and rules and advances in sports medicine, that the risk is likely lower. I don't have evidence that that's the case, but nobody does. We don't really know how the rates today compare to in the past, since CTE can't be diagnosed in the living. We can't take a sample of current players and look to see how many of them have CTE.

But that is the challenge of this study. It's interesting [in that] it gives us a range of what CTE may be in that group of former players. But it doesn't give us a lot of information about what rates are in current players in the NFL. And even more so, whatever the CTE rate is in professional NFL players does not translate to former collegiate, high school or youth football players, because CTE is an exposure-related disease. For players who have less exposure to these repetitive head impacts, it should follow that they have a considerably lower risk of CTE.

We don't want to confuse a range of CTE prevalence from players who played 50 years ago with contemporary NFL players and definitely don't want to conflate that with what CTE rates may be for current high school and youth players, who have far less levels of exposure.

NL: You mentioned that football has become safer over time. Could you spell out how the game has changed?

TM: We can look at different categories: With the rules back in that era, spearing — hitting with the crown of the head — was allowed, and oftentimes encouraged, as a style of play. That's now penalized and not taught, or shouldn't be taught.

There are changes in equipment, for sure. Modern football helmets — the material, the padding, the way in which these manufacturers are using head impact data to construct position-specific helmets and materials that are designed now to not just prevent catastrophic injuries, like skull fracture, but also to minimize the force from having repetitive head impacts — that's come a long way.

There's the Guardian Caps; you may have seen the NFL has adapted those. So they wear these soft-shell hats on their helmets during the preseason and during practices. That's now required for many of the position groups.

Virginia Tech has a helmet rating system where they test football helmets, and every year, the helmets score better on these tests. They now have star ratings for youth helmets, so manufacturers of youth football helmets are now being held to account, as well.

Maybe the most important thing is just the education around and recognition of concussion and brain injury in the sport. Now, when an athlete has a concussion, they are more likely to be recognized for having a concussion and be pulled from play and have an opportunity to recover before they return to the game. You hear anecdotal stories of former NFL players from that era, like the '60s and '70s, that suffered multiple concussions, oftentimes in the same game, and were not removed from play and continued to practice under those conditions. That medical recognition and treatment management of concussion and brain injury has moved ahead.

You look at the way in which practice was conducted, from full contact, two-a-day practices, which were common even in high school 15, 20 years ago. Now it's really not allowed at any level of play. So the amount of hitting that they do, the amount of contact that players are exposed to in practice and in the preseason is far less.

NL: When players weren't able to recover from concussions, did that likely increase their brain-injury risk?

TM: Theoretically, yes. There's evidence that if the brain is injured and then it's exposed to a second insult or injury before it's properly recovered, that makes the condition even worse.

There's actually a term called "second-impact syndrome," and it's very rare, so I don't want to scare people. But there have been instances where players — it's often, unfortunately, young players, high school players — who have had a concussion which, in retrospect, went undiagnosed and then there was a second concussive blow that led to brain swelling and death. That's the extreme, but there are cases of that [repetitive damage] happening even on a lower scale.

Even if you don't get another concussion, just those nonconcussive repetitive head impacts on top of an injured brain would not be good. It certainly is only going to delay recovery, likely is going to compound your inflammation and all of the downstream consequences of that initial injury.

I suspect that that was fairly common in years past, mainly because concussions generally weren't diagnosed. No one was looking for them, and players certainly weren't encouraged to report if they had the symptoms. So it's very likely that many of these players, including the players that were in the [brain donor] sample, had concussions and played through them and continued to receive additional trauma on top of a brain injury.

Now whether that leads to CTE, we can't really say. But I think it's reasonable to suspect that it probably would increase that risk.

NL: Could you explain whether the physical signs of CTE in the brain tend to come with symptoms, like cognitive decline? Or is the link more nuanced?

TM: So CTE is a neurodegenerative disease that can only be diagnosed by neuropathologists — people that look at slices of the brain and look for particular proteins that are present in certain regions of the brain. [This examination is done after death.] It's a pathological marker. It means that there are changes in the structure of the brain.

The clinical side of that is changes in mood, cognition, behavior, things like dementia or cognitive decline.

Even in the study, they showed that they [the CTE brain changes and symptoms] weren't necessarily linked. Now I believe they showed that for those who had more severe CTE — like the stage IV — that there was a pretty high rate of those individuals who also had subsequently diagnosed dementia. They had these clinicians that looked at the records and diagnosed them. That's a little bit of a limitation of the study: that a lot of the dementia cases were diagnosed after the person had passed away, based on medical records.

To your more immediate point, the presence of CTE: So the presence of these markers in your brain does not necessarily translate into a clinical disease or a clinical diagnosis. There can be signs or symptoms that somebody may have — let's say memory loss or changes in behavior — that may lead someone, like a former football player, to suspect that, "Oh, maybe I have CTE because I played football and I've heard that that's linked with dementia."

That may be true, but it may also be that it's due to old age, or it could be due to genetics or some other condition.

Many of these neurological diseases and conditions can be managed clinically, and there's treatment. There's therapy; there's pharmacological treatments. There's a whole toolbox available for people to seek help. That's, I think, an important message for former athletes or individuals who may be concerned about developing CTE, is to recognize that there is a disconnect between clinical disease and the pathological disease. Just because you have some outward signs or symptoms that doesn't mean that you have CTE.

NL: Since there was a higher likelihood of dementia in the stage IV cases, it seems like there's a stronger link between the pathological and clinical diagnoses at advanced stages. Is that a fair read?

TM: Again, from this study and other studies, just the presence of CTE does not necessarily mean that somebody's mood, behavior, cognition is altered. It seems to be more likely — it seems to be a tighter relationship at the more severe stages, which would kind of speak to what you're talking about. A certain threshold of disease progression seems to be more likely to manifest itself in clinical disease [with overt symptoms].

NL: What should current NFL players take from this study?

TM: I would go back to what we discussed earlier: just understanding the time frame in which the study was performed and when those players were in the NFL. I think we need to be cautious about projecting those rates; it's a pretty wide range of estimates, and it has to do with how representative the sample is. We need to use caution if we are trying to interpret those rates for the current players.

If anything, I think it probably validates all of these efforts that we discussed to try to improve brain health and minimize risk of exposure.

Even if the prevalence is on the low end ‪—‬ that 25% of players who played in the '60s and '70s developed CTE ‪—‬ that's pretty alarming. That in and of itself should get the NFL's attention. Players shouldn't have a 1-in-4 chance or greater of developing this disease.

So let's take steps to reduce that risk — and I think it validates all of the changes that have taken place over the last 50 years. I mean, a lot of them have taken place over the last 10 to 15 years. That's probably the biggest message: to say we were right to do these things and we need to continue to see if there are further opportunities to make the game safer.

Hopefully we've made a lot of progress and current-day rates are much lower than they were in the past. We don't know that, but let's not be idle. Let's continue to push forward to reduce as much risk as possible in a game where you can't completely eliminate the risk. That's something that I think everyone acknowledges; every player has to acknowledge that there is some risk.

NL: Looking forward, what further improvements could be made?

TM: There's a couple of areas that are really in the infancy stages right now. If you think about brain health as a continuum where you would have a disease like CTE on one end and then optimal health on the other end — let's say repetitive head impacts take away from your brain health and tip the scale in favor of developing disease, what are things we can do to tip the scale back in favor of improving brain health?

We know that sleep is really powerful and could learn more about that in and of itself. And what about nutrition? What about pharmacological interventions? Wouldn't it be great if we could develop a medicine, a drug at some point that could be taken preventatively to reduce athletes' inflammation? Really looking into ways in which we can optimally improve brain health as a countermeasure to the damage or the trauma that is occurring.

It's not just football where these treatments could be helpful; it's also with soccer, hockey, other sports and occupations where there is exposure to [head] trauma. I think that's a promising area.

And then, certainly, diagnostic techniques. We talked about CTE only being able to be diagnosed at death. It would certainly be a game changer if we could diagnose it convincingly in the living so it could be recognized early. People are going to have different risks, and some of that is probably genetically determined; some people are going to have the same level of exposure and develop CTE while some aren't. If we could identify individuals who are at higher risk or in the earliest stages of the development of the disease, you can then change lifestyle, behavior, exposure — that would be huge as well.

NL: To shift gears slightly, could you describe your own research in youth sports?

TM: Most of my work over the last 15 years has been focused on youth football players. That's been an interest in measuring repetitive head impacts and neurologic function in youth football players and some work in high-school-age players, as well. So a lot of that is focused around subconcussive injury [head trauma that does not trigger overt symptoms of concussion, like nausea, light sensitivity or thinking issues]. We're looking at the effects of these nonconcussive head impacts on brain health.

That ties into the CTE question in the sense that CTE is thought to be due to cumulative exposure to brain trauma — repetitive head impacts — and certainly most of the work, like in this study, has been done in NFL players. The question for a lot of the general population is, "What about youth players, high school players, that make up 90% of all football players?" So from a public health perspective, it's those younger players that I think we really need to be studying and concerned about.

That's not to say this study isn't really important. It certainly is, but my focus has been on that younger population. And then I do have some experience working more in a hospital background [on] clinical concussion management and [developing] objective pictures of concussion.

NL: With recent research, do we better understand how those nonconcussive impacts affect brain health?

TM: Going back maybe 15 to 20 years, people started to recognize that there were some cumulative effects of concussion. Those were some of the earlier studies showing that former NFL players who had multiple diagnosed concussions had worse outcomes later in life — that kind of put the spotlight on concussion. Concussion went to the forefront, in terms of how we thought about brain injury in football.

And then, over time, this recognition of what has been termed subconcussive or nonconcussive brain injury has emerged, as there's been some imaging studies in collegiate athletes, and even high school athletes, that have found that players who don't get concussed sometimes have changes in their brain, even over the course of the season.

That dovetails with some of the CTE research which has shown that history of concussions isn't necessarily predictive of who developed CTE. It's more of a cumulative effect of repetitive brain trauma. So the CTE researchers have essentially concluded that it's history of repetitive brain trauma, rather than history of concussion, per se, that's a leading risk factor for CTE.

With CTE, it's always looking backwards, because it's something that's diagnosed at death. For researchers like myself who study concussion, or study active football players, that has also then been a reaction of saying, "Well, if it is repetitive trauma, if it's repetitive head impacts, that is a risk factor for neurodegenerative disease such as CTE, then that makes it even more important to study it in active players." What does that head impact exposure look like at different ages, and how can we reduce that exposure? How can we reduce the number and severity of head impacts that players are experiencing?

So there's both the CTE angle, which is, again, retrospective — I'm looking at former players. And the contemporary issues of players who are currently playing and what's the risk for concussion, but also what's their exposure to repetitive head impacts? So it's really tied together.

That's why there's so much concern about repetitive head impacts and why there have been rule changes at the collegiate and high school level about the amount of contact and limiting those types of activities, with the idea of reducing that overall head-impact burden.

NL: When you talk about repetitive head impacts broadly, I assume that covers both concussive and nonconcussive impacts?

TM: Yep — so every hit would be considered a head impact, and then certain impacts are strong enough, or hit you in the right spot, to cause a concussion. The vast majority of impacts are nonconcussive.

NL: How do you speak to these athletes' families about the risks of concussion and CTE?

TM: When I do talk to players and coaches and parents, I often like to remind them that, generally, the benefits of playing sports, including tackle football, outweigh the risk. Oftentimes we get so concerned about the risk, which is real, that we forget about the benefits and about the alternatives of not playing. Almost always, the benefits — from the physical, the psychological and social components, the mental health components — are going to outweigh the risks. That's one thing to keep in mind.

Second, the risk of injury — in this case, CTE — is likely going to be far less in those younger players than older players, NFL players because their exposure, the number of impacts, the severity of impacts is far less. With my research, I've measured those head impacts and compared them to high school players and collegiate players, and extrapolated to NFL players because that data isn't available. And you see this big stepwise increase in exposure from the youth, the high school, the collegiate, to the NFL players.

[With parents], I'm reassuring them that the risk is far less for the younger players than what they hear about in this type of study. We're talking about an apples-to-oranges comparison.

I also like to remind them that, in my opinion, the game of football has never been safer. I've got a bit of a personal perspective on this as well, because I played football myself through college.

NL: Who did you play for?

TM: I played for a Division II school in South Dakota called — it's Augustana University now; it was Augustana College when I played there.

So I played 12 years of tackle football, and I can compare what tackle football was like when I was in fifth grade versus now — with the training that coaches have and the type of equipment they have and the way the practices are structured. It's completely night and day.

Even at the collegiate level, the way in which collegiate practices are conducted and the safety measures that are in place for current collegiate players is nothing like what we had when I was playing. So I like to reassure players that this is probably the safest time to be playing the sport of football.

At the same time, I acknowledge that this is an individual decision that parents need to make with their kids and evaluate that risk. One of my goals as a researcher is that I want to provide more empirical evidence so that they can make an informed decision, so that a parent would be able to say, "My son's risk of getting a concussion while playing youth football is 1 in whatever" — you know, 1 in 10, 1 in 5, or 1 in 100, whatever that case may be. And his risk of getting CTE by playing four years of youth football or four years of high school football would be this. Then you make an informed decision. Is that risk worth the benefit of participation?

Unfortunately, we don't know what that risk is [currently]. We can't tell parents, "Here's objectively what your risk of injury is going to be." It makes it tough for parents. So I like to reassure them that a lot of the concerns that are expressed for NFL players are greater than they should have as parents of youth players.

This interview has been condensed and edited lightly for clarity. It is for informational purposes only and is not meant to offer medical advice.

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