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Cutting-edge nasal tech could usher in a new era of medicine
Noses are like caverns – twisting, turning, no two exactly the same. But if you nose past anyone’s nostrils, you’ll discover a surprisingly sprawling space.
“The size of the nasal cavity is about the same as a large handkerchief,” said Hugh Smyth, PhD, a professor of molecular pharmaceutics and drug delivery at the University of Texas at Austin.
“It’s very accessible tissue, and it has a lot of blood flow,” said Dr. Smyth. “The speed of onset can often be as fast as injections, sometimes even faster.”
It’s nothing new to get medicines via your nose. For decades, we’ve squirted various sprays into our nostrils to treat local maladies like allergies or infections. Even the ancients saw wisdom in the nasal route.
But recently, the nose has gained scientific attention as a gateway to the rest of the body – even the brain, a notoriously difficult target.
The upshot: Someday, inhaling therapies could be as routine as swallowing pills.
The nasal route is quick, needle free, and user friendly, and it often requires a smaller dose than other methods, since the drug doesn’t have to pass through the digestive tract, losing potency during digestion.
But there are challenges.
How hard can it be?
Old-school nasal sprayers, mostly unchanged since the 1800s, aren’t cut out for deep-nose delivery. “The technology is relatively limited because you’ve just got a single spray nozzle,” said Michael Hindle, PhD, a professor of pharmaceutics at Virginia Commonwealth University, Richmond.
These traditional devices (similar to perfume sprayers) don’t consistently push meds past the lower to middle sections inside the nose, called the nasal valve – if they do so at all: In a 2020 Rhinology study (doi: 10.4193/Rhin18.304) conventional nasal sprays only reached this first segment of the nose, a less-than-ideal spot to land.
Inside the nasal valve, the surface is skin-like and doesn’t absorb very well. Its narrow design slows airflow, preventing particles from moving to deeper regions, where tissue is vascular and porous like the lungs. And even if this structural roadblock is surpassed, other hurdles remain.
The nose is designed to keep stuff out. Nose hair, cilia, mucus, sneezing, coughing – all make “distributing drugs evenly across the nasal cavity difficult,” said Dr. Smyth. “The spray gets filtered out before it reaches those deeper zones,” potentially dripping out of the nostrils instead of being absorbed.
Complicating matters is how every person’s nose is different. In a 2018 study, Dr. Smyth and a research team created three dimensional–printed models of people’s nasal cavities. They varied widely. “Nasal cavities are very different in size, length, and internal geometry,” he said. “This makes it challenging to target specific areas.”
Although carefully positioning the spray nozzle can help, even something as minor as sniffing too hard (constricting the nostrils) can keep sprays from reaching the absorptive deeper regions.
Still, the benefits are enough to compel researchers to find a way in.
“This really is a drug delivery challenge we’ve been wrestling with,” said Dr. Hindle. “It’s not new formulations we hear about. It’s new devices and delivery methods trying to target the different nasal regions.”
Delivering the goods
In the late aughts, John Hoekman was a graduate student in the University of Washington’s pharmaceutics program, studying nasal drug delivery. In his experiments, he noticed that drugs distributed differently, depending on the region targeted – aiming for the upper nasal cavity led to a spike in absorption.
The results convinced Mr. Hoekman to stake his future on nasal drug delivery.
In 2008, while still in graduate school, he started his own company, now known as Impel Pharmaceuticals. In 2021, Impel released its first product: Trudhesa, a nasal spray for migraines. Although the drug itself – dihydroergotamine mesylate – was hardly novel, used for migraine relief since 1946 (Headache. 2020 Jan;60[1]:40-57), it was usually delivered through an intravenous line, often in the ED.
But with Mr. Hoekman’s POD device – short for precision olfactory delivery – the drug can be given by the patient, via the nose. This generally means faster, more reliable relief, with fewer side effects. “We were able to lower the dose and improve the overall absorption,” said Mr. Hoekman.
The POD’s nozzle is engineered to spray a soft, narrow plume. It’s gas propelled, so patients don’t have to breathe in any special way to ensure delivery. The drug can zip right through the nasal valve into the upper nasal cavity.
Another company – OptiNose – has a “bidirectional” delivery method that propels drugs, either liquid or dry powder, deep into the nose.
“You insert the nozzle into your nose, and as you blow through the mouthpiece, your soft palate closes,” said Dr. Hindle. With the throat sealed off, “the only place for the drug to go is into one nostril and out the other, coating both sides of the nasal passageways.”
The device is only available for Onzetra Xsail, a powder for migraines. But another application is on its way.
In May, OptiNose announced that the FDA is reviewing Xhance, which uses the system to direct a steroid to the sinuses. In a clinical trial, patients with chronic sinusitis who tried the drug-device combo saw a decline in congestion, facial pain, and inflammation.
Targeting the brain
Both of those migraine drugs – Trudhesa and Onzetra Xsail – are thought to penetrate the upper nasal cavity. That’s where you’ll find the olfactory zone, a sheet of neurons that connects to the olfactory bulb. Located behind the eyes, these two nerve bundles detect odors.
“The olfactory region is almost like a back door to the brain,” said Mr. Hoekman.
By bypassing the blood-brain barrier, it offers a direct pathway – the only direct pathway, actually – between an exposed area of the body and the brain. Meaning it can ferry drugs straight from the nasal cavity to the central nervous system.
Nose-to-brain treatments could be game-changing for central nervous system disorders, such as Parkinson’s disease, Alzheimer’s, or anxiety.
But reaching the olfactory zone is notoriously hard. “The vasculature in your nose is like a big freeway, and the olfactory tract is like a side alley,” explained Mr. Hoekman. “It’s very limiting in what it will allow through.” The region is also small, occupying only 3%-10% of the nasal cavity’s surface area.
Again, POD means “precision olfactory delivery.” But the device isn’t quite as laser focused on the region as its name implies. “We’re not at the stage where we’re able to exclusively deliver to one target site in the nose,” said Dr. Hindle.
While wending its way toward the olfactory zone, some of the drug will be absorbed by other regions, then circulate throughout the body.
“About 59% of the drug that we put into the upper nasal space gets absorbed into the bloodstream,” said Mr. Hoekman.
Janssen Pharmaceuticals’ Spravato – a nasal spray for drug-resistant depression – is thought to work similarly: Some goes straight to the brain via the olfactory nerves, while the rest takes a more roundabout route, passing through the blood vessels to circulate in your system.
A needle-free option
Sometimes, the bloodstream is the main target. Because the nose’s middle and upper stretches are so vascular, drugs can be rapidly absorbed.
This is especially valuable for time-sensitive conditions. “If you give something nasally, you can have peak uptake in 15-30 minutes,” said Mr. Hoekman.
Take Narcan nasal spray, which delivers a burst of naloxone to quickly reverse the effects of opioid an overdose. Or Noctiva nasal spray. Taken just half an hour before bed, it can prevent frequent nighttime urination.
There’s also a group of seizure-stopping sprays, known as “rescue treatments.” One works by temporarily loosening the space between nasal cells, allowing the seizure drug to be quickly absorbed through the vessels.
This systemic access also has potential for drugs that would otherwise have to be injected, such as biologics.
The same goes for vaccines. Mucosal tissue inside the nasal cavity offers direct access to the infection-fighting lymphatic system, making the nose a prime target for inoculation against certain viruses.
Inhaling protection against viruses
Despite the recent surge of interest, nasal vaccines faced a rocky start. After the first nasal flu vaccine hit the market in 2001, it was pulled due to potential toxicity and reports of Bell’s palsy, a type of facial paralysis.
FluMist came in 2003 and has been plagued by problems ever since. Because it contains a weakened live virus, flu-like side effects can occur. And it doesn’t always work. During the 2016-2017 flu season, FluMist protected only 3% of kids, prompting the Centers for Disease Control and Prevention to advise against the nasal route that year.
Why FluMist can be so hit-or-miss is poorly understood. But generally, the nose can pose an effectiveness challenge. “The nose is highly cycling,” said Dr. Hindle. “Anything we deposit usually gets transported out within 15-20 minutes.”
For kids – big fans of not using needles – chronically runny noses can be an issue. “You squirt it in the nose, and it will probably just come back out in their snot,” said Jay Kolls, MD, a professor of medicine and pediatrics at Tulane University, New Orleans, who is developing an intranasal pneumonia vaccine.
Even so, nasal vaccines became a hot topic among researchers after the world was shut down by a virus that invades through the nose.
“We realized that intramuscular vaccines were effective at preventing severe disease, but they weren’t that effective at preventing transmission,” said Michael Diamond, MD, PhD, an immunologist at Washington University in St. Louis.
Nasal vaccines could solve that problem by putting an immune barrier at the point of entry, denying access to the rest of the body. “You squash the infection early enough that it not only prevents disease,” said Dr. Kolls, “but potentially prevents transmission.”
And yes, a nasal COVID vaccine is on the way
In March 2020, Dr. Diamond’s team began exploring a nasal COVID vaccine. Promising results in animals prompted a vaccine development company to license the technology. The resulting nasal vaccine – the first for COVID – has been approved in India, both as a primary vaccine and a booster.
It works by stimulating an influx of IgA, a type of antibody found in the nasal passages, and production of resident memory T cells, immune cells on standby just beneath the surface tissue in the nose.
By contrast, injected vaccines generate mostly IgG antibodies, which struggle to enter the respiratory tract. Only a tiny fraction – an estimated 1% – typically reach the nose.
Nasal vaccines could also be used along with shots. The latter could prime the whole body to fight back, while a nasal spritz could pull that immune protection to the mucosal surfaces.
Nasal technology could yield more effective vaccines for infections like tuberculosis or malaria, or even safeguard against new – sometimes surprising – conditions.
In a 2021 Nature study, an intranasal vaccine derived from fentanyl was better at preventing overdose than an injected vaccine. “Through some clever chemistry, the drug [in the vaccine] isn’t fentanyl anymore,” said study author Elizabeth Norton, PhD, an assistant professor of microbiology and immunology at Tulane University. “But the immune system still has an antibody response to it.”
Novel applications like this represent the future of nasal drug delivery.
“We’re not going to innovate in asthma or COPD. We’re not going to innovate in local delivery to the nose,” said Dr. Hindle. “Innovation will only come if we look to treat new conditions.”
A version of this article originally appeared on WebMD.com.
Noses are like caverns – twisting, turning, no two exactly the same. But if you nose past anyone’s nostrils, you’ll discover a surprisingly sprawling space.
“The size of the nasal cavity is about the same as a large handkerchief,” said Hugh Smyth, PhD, a professor of molecular pharmaceutics and drug delivery at the University of Texas at Austin.
“It’s very accessible tissue, and it has a lot of blood flow,” said Dr. Smyth. “The speed of onset can often be as fast as injections, sometimes even faster.”
It’s nothing new to get medicines via your nose. For decades, we’ve squirted various sprays into our nostrils to treat local maladies like allergies or infections. Even the ancients saw wisdom in the nasal route.
But recently, the nose has gained scientific attention as a gateway to the rest of the body – even the brain, a notoriously difficult target.
The upshot: Someday, inhaling therapies could be as routine as swallowing pills.
The nasal route is quick, needle free, and user friendly, and it often requires a smaller dose than other methods, since the drug doesn’t have to pass through the digestive tract, losing potency during digestion.
But there are challenges.
How hard can it be?
Old-school nasal sprayers, mostly unchanged since the 1800s, aren’t cut out for deep-nose delivery. “The technology is relatively limited because you’ve just got a single spray nozzle,” said Michael Hindle, PhD, a professor of pharmaceutics at Virginia Commonwealth University, Richmond.
These traditional devices (similar to perfume sprayers) don’t consistently push meds past the lower to middle sections inside the nose, called the nasal valve – if they do so at all: In a 2020 Rhinology study (doi: 10.4193/Rhin18.304) conventional nasal sprays only reached this first segment of the nose, a less-than-ideal spot to land.
Inside the nasal valve, the surface is skin-like and doesn’t absorb very well. Its narrow design slows airflow, preventing particles from moving to deeper regions, where tissue is vascular and porous like the lungs. And even if this structural roadblock is surpassed, other hurdles remain.
The nose is designed to keep stuff out. Nose hair, cilia, mucus, sneezing, coughing – all make “distributing drugs evenly across the nasal cavity difficult,” said Dr. Smyth. “The spray gets filtered out before it reaches those deeper zones,” potentially dripping out of the nostrils instead of being absorbed.
Complicating matters is how every person’s nose is different. In a 2018 study, Dr. Smyth and a research team created three dimensional–printed models of people’s nasal cavities. They varied widely. “Nasal cavities are very different in size, length, and internal geometry,” he said. “This makes it challenging to target specific areas.”
Although carefully positioning the spray nozzle can help, even something as minor as sniffing too hard (constricting the nostrils) can keep sprays from reaching the absorptive deeper regions.
Still, the benefits are enough to compel researchers to find a way in.
“This really is a drug delivery challenge we’ve been wrestling with,” said Dr. Hindle. “It’s not new formulations we hear about. It’s new devices and delivery methods trying to target the different nasal regions.”
Delivering the goods
In the late aughts, John Hoekman was a graduate student in the University of Washington’s pharmaceutics program, studying nasal drug delivery. In his experiments, he noticed that drugs distributed differently, depending on the region targeted – aiming for the upper nasal cavity led to a spike in absorption.
The results convinced Mr. Hoekman to stake his future on nasal drug delivery.
In 2008, while still in graduate school, he started his own company, now known as Impel Pharmaceuticals. In 2021, Impel released its first product: Trudhesa, a nasal spray for migraines. Although the drug itself – dihydroergotamine mesylate – was hardly novel, used for migraine relief since 1946 (Headache. 2020 Jan;60[1]:40-57), it was usually delivered through an intravenous line, often in the ED.
But with Mr. Hoekman’s POD device – short for precision olfactory delivery – the drug can be given by the patient, via the nose. This generally means faster, more reliable relief, with fewer side effects. “We were able to lower the dose and improve the overall absorption,” said Mr. Hoekman.
The POD’s nozzle is engineered to spray a soft, narrow plume. It’s gas propelled, so patients don’t have to breathe in any special way to ensure delivery. The drug can zip right through the nasal valve into the upper nasal cavity.
Another company – OptiNose – has a “bidirectional” delivery method that propels drugs, either liquid or dry powder, deep into the nose.
“You insert the nozzle into your nose, and as you blow through the mouthpiece, your soft palate closes,” said Dr. Hindle. With the throat sealed off, “the only place for the drug to go is into one nostril and out the other, coating both sides of the nasal passageways.”
The device is only available for Onzetra Xsail, a powder for migraines. But another application is on its way.
In May, OptiNose announced that the FDA is reviewing Xhance, which uses the system to direct a steroid to the sinuses. In a clinical trial, patients with chronic sinusitis who tried the drug-device combo saw a decline in congestion, facial pain, and inflammation.
Targeting the brain
Both of those migraine drugs – Trudhesa and Onzetra Xsail – are thought to penetrate the upper nasal cavity. That’s where you’ll find the olfactory zone, a sheet of neurons that connects to the olfactory bulb. Located behind the eyes, these two nerve bundles detect odors.
“The olfactory region is almost like a back door to the brain,” said Mr. Hoekman.
By bypassing the blood-brain barrier, it offers a direct pathway – the only direct pathway, actually – between an exposed area of the body and the brain. Meaning it can ferry drugs straight from the nasal cavity to the central nervous system.
Nose-to-brain treatments could be game-changing for central nervous system disorders, such as Parkinson’s disease, Alzheimer’s, or anxiety.
But reaching the olfactory zone is notoriously hard. “The vasculature in your nose is like a big freeway, and the olfactory tract is like a side alley,” explained Mr. Hoekman. “It’s very limiting in what it will allow through.” The region is also small, occupying only 3%-10% of the nasal cavity’s surface area.
Again, POD means “precision olfactory delivery.” But the device isn’t quite as laser focused on the region as its name implies. “We’re not at the stage where we’re able to exclusively deliver to one target site in the nose,” said Dr. Hindle.
While wending its way toward the olfactory zone, some of the drug will be absorbed by other regions, then circulate throughout the body.
“About 59% of the drug that we put into the upper nasal space gets absorbed into the bloodstream,” said Mr. Hoekman.
Janssen Pharmaceuticals’ Spravato – a nasal spray for drug-resistant depression – is thought to work similarly: Some goes straight to the brain via the olfactory nerves, while the rest takes a more roundabout route, passing through the blood vessels to circulate in your system.
A needle-free option
Sometimes, the bloodstream is the main target. Because the nose’s middle and upper stretches are so vascular, drugs can be rapidly absorbed.
This is especially valuable for time-sensitive conditions. “If you give something nasally, you can have peak uptake in 15-30 minutes,” said Mr. Hoekman.
Take Narcan nasal spray, which delivers a burst of naloxone to quickly reverse the effects of opioid an overdose. Or Noctiva nasal spray. Taken just half an hour before bed, it can prevent frequent nighttime urination.
There’s also a group of seizure-stopping sprays, known as “rescue treatments.” One works by temporarily loosening the space between nasal cells, allowing the seizure drug to be quickly absorbed through the vessels.
This systemic access also has potential for drugs that would otherwise have to be injected, such as biologics.
The same goes for vaccines. Mucosal tissue inside the nasal cavity offers direct access to the infection-fighting lymphatic system, making the nose a prime target for inoculation against certain viruses.
Inhaling protection against viruses
Despite the recent surge of interest, nasal vaccines faced a rocky start. After the first nasal flu vaccine hit the market in 2001, it was pulled due to potential toxicity and reports of Bell’s palsy, a type of facial paralysis.
FluMist came in 2003 and has been plagued by problems ever since. Because it contains a weakened live virus, flu-like side effects can occur. And it doesn’t always work. During the 2016-2017 flu season, FluMist protected only 3% of kids, prompting the Centers for Disease Control and Prevention to advise against the nasal route that year.
Why FluMist can be so hit-or-miss is poorly understood. But generally, the nose can pose an effectiveness challenge. “The nose is highly cycling,” said Dr. Hindle. “Anything we deposit usually gets transported out within 15-20 minutes.”
For kids – big fans of not using needles – chronically runny noses can be an issue. “You squirt it in the nose, and it will probably just come back out in their snot,” said Jay Kolls, MD, a professor of medicine and pediatrics at Tulane University, New Orleans, who is developing an intranasal pneumonia vaccine.
Even so, nasal vaccines became a hot topic among researchers after the world was shut down by a virus that invades through the nose.
“We realized that intramuscular vaccines were effective at preventing severe disease, but they weren’t that effective at preventing transmission,” said Michael Diamond, MD, PhD, an immunologist at Washington University in St. Louis.
Nasal vaccines could solve that problem by putting an immune barrier at the point of entry, denying access to the rest of the body. “You squash the infection early enough that it not only prevents disease,” said Dr. Kolls, “but potentially prevents transmission.”
And yes, a nasal COVID vaccine is on the way
In March 2020, Dr. Diamond’s team began exploring a nasal COVID vaccine. Promising results in animals prompted a vaccine development company to license the technology. The resulting nasal vaccine – the first for COVID – has been approved in India, both as a primary vaccine and a booster.
It works by stimulating an influx of IgA, a type of antibody found in the nasal passages, and production of resident memory T cells, immune cells on standby just beneath the surface tissue in the nose.
By contrast, injected vaccines generate mostly IgG antibodies, which struggle to enter the respiratory tract. Only a tiny fraction – an estimated 1% – typically reach the nose.
Nasal vaccines could also be used along with shots. The latter could prime the whole body to fight back, while a nasal spritz could pull that immune protection to the mucosal surfaces.
Nasal technology could yield more effective vaccines for infections like tuberculosis or malaria, or even safeguard against new – sometimes surprising – conditions.
In a 2021 Nature study, an intranasal vaccine derived from fentanyl was better at preventing overdose than an injected vaccine. “Through some clever chemistry, the drug [in the vaccine] isn’t fentanyl anymore,” said study author Elizabeth Norton, PhD, an assistant professor of microbiology and immunology at Tulane University. “But the immune system still has an antibody response to it.”
Novel applications like this represent the future of nasal drug delivery.
“We’re not going to innovate in asthma or COPD. We’re not going to innovate in local delivery to the nose,” said Dr. Hindle. “Innovation will only come if we look to treat new conditions.”
A version of this article originally appeared on WebMD.com.
Noses are like caverns – twisting, turning, no two exactly the same. But if you nose past anyone’s nostrils, you’ll discover a surprisingly sprawling space.
“The size of the nasal cavity is about the same as a large handkerchief,” said Hugh Smyth, PhD, a professor of molecular pharmaceutics and drug delivery at the University of Texas at Austin.
“It’s very accessible tissue, and it has a lot of blood flow,” said Dr. Smyth. “The speed of onset can often be as fast as injections, sometimes even faster.”
It’s nothing new to get medicines via your nose. For decades, we’ve squirted various sprays into our nostrils to treat local maladies like allergies or infections. Even the ancients saw wisdom in the nasal route.
But recently, the nose has gained scientific attention as a gateway to the rest of the body – even the brain, a notoriously difficult target.
The upshot: Someday, inhaling therapies could be as routine as swallowing pills.
The nasal route is quick, needle free, and user friendly, and it often requires a smaller dose than other methods, since the drug doesn’t have to pass through the digestive tract, losing potency during digestion.
But there are challenges.
How hard can it be?
Old-school nasal sprayers, mostly unchanged since the 1800s, aren’t cut out for deep-nose delivery. “The technology is relatively limited because you’ve just got a single spray nozzle,” said Michael Hindle, PhD, a professor of pharmaceutics at Virginia Commonwealth University, Richmond.
These traditional devices (similar to perfume sprayers) don’t consistently push meds past the lower to middle sections inside the nose, called the nasal valve – if they do so at all: In a 2020 Rhinology study (doi: 10.4193/Rhin18.304) conventional nasal sprays only reached this first segment of the nose, a less-than-ideal spot to land.
Inside the nasal valve, the surface is skin-like and doesn’t absorb very well. Its narrow design slows airflow, preventing particles from moving to deeper regions, where tissue is vascular and porous like the lungs. And even if this structural roadblock is surpassed, other hurdles remain.
The nose is designed to keep stuff out. Nose hair, cilia, mucus, sneezing, coughing – all make “distributing drugs evenly across the nasal cavity difficult,” said Dr. Smyth. “The spray gets filtered out before it reaches those deeper zones,” potentially dripping out of the nostrils instead of being absorbed.
Complicating matters is how every person’s nose is different. In a 2018 study, Dr. Smyth and a research team created three dimensional–printed models of people’s nasal cavities. They varied widely. “Nasal cavities are very different in size, length, and internal geometry,” he said. “This makes it challenging to target specific areas.”
Although carefully positioning the spray nozzle can help, even something as minor as sniffing too hard (constricting the nostrils) can keep sprays from reaching the absorptive deeper regions.
Still, the benefits are enough to compel researchers to find a way in.
“This really is a drug delivery challenge we’ve been wrestling with,” said Dr. Hindle. “It’s not new formulations we hear about. It’s new devices and delivery methods trying to target the different nasal regions.”
Delivering the goods
In the late aughts, John Hoekman was a graduate student in the University of Washington’s pharmaceutics program, studying nasal drug delivery. In his experiments, he noticed that drugs distributed differently, depending on the region targeted – aiming for the upper nasal cavity led to a spike in absorption.
The results convinced Mr. Hoekman to stake his future on nasal drug delivery.
In 2008, while still in graduate school, he started his own company, now known as Impel Pharmaceuticals. In 2021, Impel released its first product: Trudhesa, a nasal spray for migraines. Although the drug itself – dihydroergotamine mesylate – was hardly novel, used for migraine relief since 1946 (Headache. 2020 Jan;60[1]:40-57), it was usually delivered through an intravenous line, often in the ED.
But with Mr. Hoekman’s POD device – short for precision olfactory delivery – the drug can be given by the patient, via the nose. This generally means faster, more reliable relief, with fewer side effects. “We were able to lower the dose and improve the overall absorption,” said Mr. Hoekman.
The POD’s nozzle is engineered to spray a soft, narrow plume. It’s gas propelled, so patients don’t have to breathe in any special way to ensure delivery. The drug can zip right through the nasal valve into the upper nasal cavity.
Another company – OptiNose – has a “bidirectional” delivery method that propels drugs, either liquid or dry powder, deep into the nose.
“You insert the nozzle into your nose, and as you blow through the mouthpiece, your soft palate closes,” said Dr. Hindle. With the throat sealed off, “the only place for the drug to go is into one nostril and out the other, coating both sides of the nasal passageways.”
The device is only available for Onzetra Xsail, a powder for migraines. But another application is on its way.
In May, OptiNose announced that the FDA is reviewing Xhance, which uses the system to direct a steroid to the sinuses. In a clinical trial, patients with chronic sinusitis who tried the drug-device combo saw a decline in congestion, facial pain, and inflammation.
Targeting the brain
Both of those migraine drugs – Trudhesa and Onzetra Xsail – are thought to penetrate the upper nasal cavity. That’s where you’ll find the olfactory zone, a sheet of neurons that connects to the olfactory bulb. Located behind the eyes, these two nerve bundles detect odors.
“The olfactory region is almost like a back door to the brain,” said Mr. Hoekman.
By bypassing the blood-brain barrier, it offers a direct pathway – the only direct pathway, actually – between an exposed area of the body and the brain. Meaning it can ferry drugs straight from the nasal cavity to the central nervous system.
Nose-to-brain treatments could be game-changing for central nervous system disorders, such as Parkinson’s disease, Alzheimer’s, or anxiety.
But reaching the olfactory zone is notoriously hard. “The vasculature in your nose is like a big freeway, and the olfactory tract is like a side alley,” explained Mr. Hoekman. “It’s very limiting in what it will allow through.” The region is also small, occupying only 3%-10% of the nasal cavity’s surface area.
Again, POD means “precision olfactory delivery.” But the device isn’t quite as laser focused on the region as its name implies. “We’re not at the stage where we’re able to exclusively deliver to one target site in the nose,” said Dr. Hindle.
While wending its way toward the olfactory zone, some of the drug will be absorbed by other regions, then circulate throughout the body.
“About 59% of the drug that we put into the upper nasal space gets absorbed into the bloodstream,” said Mr. Hoekman.
Janssen Pharmaceuticals’ Spravato – a nasal spray for drug-resistant depression – is thought to work similarly: Some goes straight to the brain via the olfactory nerves, while the rest takes a more roundabout route, passing through the blood vessels to circulate in your system.
A needle-free option
Sometimes, the bloodstream is the main target. Because the nose’s middle and upper stretches are so vascular, drugs can be rapidly absorbed.
This is especially valuable for time-sensitive conditions. “If you give something nasally, you can have peak uptake in 15-30 minutes,” said Mr. Hoekman.
Take Narcan nasal spray, which delivers a burst of naloxone to quickly reverse the effects of opioid an overdose. Or Noctiva nasal spray. Taken just half an hour before bed, it can prevent frequent nighttime urination.
There’s also a group of seizure-stopping sprays, known as “rescue treatments.” One works by temporarily loosening the space between nasal cells, allowing the seizure drug to be quickly absorbed through the vessels.
This systemic access also has potential for drugs that would otherwise have to be injected, such as biologics.
The same goes for vaccines. Mucosal tissue inside the nasal cavity offers direct access to the infection-fighting lymphatic system, making the nose a prime target for inoculation against certain viruses.
Inhaling protection against viruses
Despite the recent surge of interest, nasal vaccines faced a rocky start. After the first nasal flu vaccine hit the market in 2001, it was pulled due to potential toxicity and reports of Bell’s palsy, a type of facial paralysis.
FluMist came in 2003 and has been plagued by problems ever since. Because it contains a weakened live virus, flu-like side effects can occur. And it doesn’t always work. During the 2016-2017 flu season, FluMist protected only 3% of kids, prompting the Centers for Disease Control and Prevention to advise against the nasal route that year.
Why FluMist can be so hit-or-miss is poorly understood. But generally, the nose can pose an effectiveness challenge. “The nose is highly cycling,” said Dr. Hindle. “Anything we deposit usually gets transported out within 15-20 minutes.”
For kids – big fans of not using needles – chronically runny noses can be an issue. “You squirt it in the nose, and it will probably just come back out in their snot,” said Jay Kolls, MD, a professor of medicine and pediatrics at Tulane University, New Orleans, who is developing an intranasal pneumonia vaccine.
Even so, nasal vaccines became a hot topic among researchers after the world was shut down by a virus that invades through the nose.
“We realized that intramuscular vaccines were effective at preventing severe disease, but they weren’t that effective at preventing transmission,” said Michael Diamond, MD, PhD, an immunologist at Washington University in St. Louis.
Nasal vaccines could solve that problem by putting an immune barrier at the point of entry, denying access to the rest of the body. “You squash the infection early enough that it not only prevents disease,” said Dr. Kolls, “but potentially prevents transmission.”
And yes, a nasal COVID vaccine is on the way
In March 2020, Dr. Diamond’s team began exploring a nasal COVID vaccine. Promising results in animals prompted a vaccine development company to license the technology. The resulting nasal vaccine – the first for COVID – has been approved in India, both as a primary vaccine and a booster.
It works by stimulating an influx of IgA, a type of antibody found in the nasal passages, and production of resident memory T cells, immune cells on standby just beneath the surface tissue in the nose.
By contrast, injected vaccines generate mostly IgG antibodies, which struggle to enter the respiratory tract. Only a tiny fraction – an estimated 1% – typically reach the nose.
Nasal vaccines could also be used along with shots. The latter could prime the whole body to fight back, while a nasal spritz could pull that immune protection to the mucosal surfaces.
Nasal technology could yield more effective vaccines for infections like tuberculosis or malaria, or even safeguard against new – sometimes surprising – conditions.
In a 2021 Nature study, an intranasal vaccine derived from fentanyl was better at preventing overdose than an injected vaccine. “Through some clever chemistry, the drug [in the vaccine] isn’t fentanyl anymore,” said study author Elizabeth Norton, PhD, an assistant professor of microbiology and immunology at Tulane University. “But the immune system still has an antibody response to it.”
Novel applications like this represent the future of nasal drug delivery.
“We’re not going to innovate in asthma or COPD. We’re not going to innovate in local delivery to the nose,” said Dr. Hindle. “Innovation will only come if we look to treat new conditions.”
A version of this article originally appeared on WebMD.com.
How your voice could reveal hidden disease
: First during puberty, as the vocal cords thicken and the voice box migrates down the throat. Then a second time as aging causes structural changes that may weaken the voice.
But for some of us, there’s another voice shift, when a disease begins or when our mental health declines.
This is why more doctors are looking into voice as a biomarker – something that tells you that a disease is present.
Vital signs like blood pressure or heart rate “can give a general idea of how sick we are. But they’re not specific to certain diseases,” says Yael Bensoussan, MD, director of the University of South Florida, Tampa’s Health Voice Center and the coprincipal investigator for the National Institutes of Health’s Voice as a Biomarker of Health project.
“We’re learning that there are patterns” in voice changes that can indicate a range of conditions, including diseases of the nervous system and mental illnesses, she says.
Speaking is complicated, involving everything from the lungs and voice box to the mouth and brain. “A breakdown in any of those parts can affect the voice,” says Maria Powell, PhD, an assistant professor of otolaryngology (the study of diseases of the ear and throat) at Vanderbilt University, Nashville, Tenn., who is working on the NIH project.
You or those around you may not notice the changes. But researchers say voice analysis as a standard part of patient care – akin to blood pressure checks or cholesterol tests – could help identify those who need medical attention earlier.
Often, all it takes is a smartphone – “something that’s cheap, off-the-shelf, and that everyone can use,” says Ariana Anderson, PhD, director of the University of California, Los Angeles, Laboratory of Computational Neuropsychology.
“You can provide voice data in your pajamas, on your couch,” says Frank Rudzicz, PhD, a computer scientist for the NIH project. “It doesn’t require very complicated or expensive equipment, and it doesn’t require a lot of expertise to obtain.” Plus, multiple samples can be collected over time, giving a more accurate picture of health than a single snapshot from, say, a cognitive test.
Over the next 4 years, the Voice as a Biomarker team will receive nearly $18 million to gather a massive amount of voice data. The goal is 20,000-30,000 samples, along with health data about each person being studied. The result will be a sprawling database scientists can use to develop algorithms linking health conditions to the way we speak.
For the first 2 years, new data will be collected exclusively via universities and high-volume clinics to control quality and accuracy. Eventually, people will be invited to submit their own voice recordings, creating a crowdsourced dataset. “Google, Alexa, Amazon – they have access to tons of voice data,” says Dr. Bensoussan. “But it’s not usable in a clinical way, because they don’t have the health information.”
Dr. Bensoussan and her colleagues hope to fill that void with advance voice screening apps, which could prove especially valuable in remote communities that lack access to specialists or as a tool for telemedicine. Down the line, wearable devices with voice analysis could alert people with chronic conditions when they need to see a doctor.
“The watch says, ‘I’ve analyzed your breathing and coughing, and today, you’re really not doing well. You should go to the hospital,’ ” says Dr. Bensoussan, envisioning a wearable for patients with COPD. “It could tell people early that things are declining.”
Artificial intelligence may be better than a brain at pinpointing the right disease. For example, slurred speech could indicate Parkinson’s, a stroke, or ALS, among other things.
“We can hold approximately seven pieces of information in our head at one time,” says Dr. Rudzicz. “It’s really hard for us to get a holistic picture using dozens or hundreds of variables at once.” But a computer can consider a whole range of vocal markers at the same time, piecing them together for a more accurate assessment.
“The goal is not to outperform a ... clinician,” says Dr. Bensoussan. Yet the potential is unmistakably there: In a recent study of patients with cancer of the larynx, an automated voice analysis tool more accurately flagged the disease than laryngologists did.
“Algorithms have a larger training base,” says Dr. Anderson, who developed an app called ChatterBaby that analyzes infant cries. “We have a million samples at our disposal to train our algorithms. I don’t know if I’ve heard a million different babies crying in my life.”
So which health conditions show the most promise for voice analysis? The Voice as a Biomarker project will focus on five categories.
Voice disorders (cancers of the larynx, vocal fold paralysis, benign lesions on the larynx)
Obviously, vocal changes are a hallmark of these conditions, which cause things like breathiness or “roughness,” a type of vocal irregularity. Hoarseness that lasts at least 2 weeks is often one of the earliest signs of laryngeal cancer. Yet it can take months – one study found 16 weeks was the average – for patients to see a doctor after noticing the changes. Even then, laryngologists still misdiagnosed some cases of cancer when relying on vocal cues alone.
Now imagine a different scenario: The patient speaks into a smartphone app. An algorithm compares the vocal sample with the voices of laryngeal cancer patients. The app spits out the estimated odds of laryngeal cancer, helping providers decide whether to offer the patient specialist care.
Or consider spasmodic dysphonia, a neurological voice disorder that triggers spasms in the muscles of the voice box, causing a strained or breathy voice. Doctors who lack experience with vocal disorders may miss the condition. This is why diagnosis takes an average of nearly 4.5 years, according to a study in the Journal of Voice, and may include everything from allergy testing to psychiatric evaluation, says Dr. Powell. Artificial intelligence technology trained to recognize the disorder could help eliminate such unnecessary testing.
Neurological and neurodegenerative disorders (Alzheimer’s, Parkinson’s, stroke, ALS)
For Alzheimer’s and Parkinson’s, “one of the first changes that’s notable is voice,” usually appearing before a formal diagnosis, says Anais Rameau, MD, an assistant professor of laryngology at Weill Cornell Medicine, New York, and another member of the NIH project. Parkinson’s may soften the voice or make it sound monotone, while Alzheimer’s disease may change the content of speech, leading to an uptick in “umms” and a preference for pronouns over nouns.
With Parkinson’s, vocal changes can occur decades before movement is affected. If doctors could detect the disease at this stage, before tremor emerged, they might be able to flag patients for early intervention, says Max Little, PhD, project director for the Parkinson’s Voice Initiative. “That is the ‘holy grail’ for finding an eventual cure.”
Again, the smartphone shows potential. In a 2022 Australian study, an AI-powered app was able to identify people with Parkinson’s based on brief voice recordings, although the sample size was small. On a larger scale, the Parkinson’s Voice Initiative collected some 17,000 samples from people across the world. “The aim was to remotely detect those with the condition using a telephone call,” says Dr. Little. It did so with about 65% accuracy. “While this is not accurate enough for clinical use, it shows the potential of the idea,” he says.
Dr. Rudzicz worked on the team behind Winterlight, an iPad app that analyzes 550 features of speech to detect dementia and Alzheimer’s (as well as mental illness). “We deployed it in long-term care facilities,” he says, identifying patients who need further review of their mental skills. Stroke is another area of interest, because slurred speech is a highly subjective measure, says Dr. Anderson. AI technology could provide a more objective evaluation.
Mood and psychiatric disorders (depression, schizophrenia, bipolar disorders)
No established biomarkers exist for diagnosing depression. Yet if you’re feeling down, there’s a good chance your friends can tell – even over the phone.
“We carry a lot of our mood in our voice,” says Dr. Powell. Bipolar disorder can also alter voice, making it louder and faster during manic periods, then slower and quieter during depressive bouts. The catatonic stage of schizophrenia often comes with “a very monotone, robotic voice,” says Dr. Anderson. “These are all something an algorithm can measure.”
Apps are already being used – often in research settings – to monitor voices during phone calls, analyzing rate, rhythm, volume, and pitch, to predict mood changes. For example, the PRIORI project at the University of Michigan is working on a smartphone app to identify mood changes in people with bipolar disorder, especially shifts that could increase suicide risk.
The content of speech may also offer clues. In a University of California, Los Angeles, study published in the journal PLoS One, people with mental illnesses answered computer-programmed questions (like “How have you been over the past few days?”) over the phone. An app analyzed their word choices, paying attention to how they changed over time. The researchers found that AI analysis of mood aligned well with doctors’ assessments and that some people in the study actually felt more comfortable talking to a computer.
Respiratory disorders (pneumonia, COPD)
Beyond talking, respiratory sounds like gasping or coughing may point to specific conditions. “Emphysema cough is different, COPD cough is different,” says Dr. Bensoussan. Researchers are trying to find out if COVID-19 has a distinct cough.
Breathing sounds can also serve as signposts. “There are different sounds when we can’t breathe,” says Dr. Bensoussan. One is called stridor, a high-pitched wheezing often resulting from a blocked airway. “I see tons of people [with stridor] misdiagnosed for years – they’ve been told they have asthma, but they don’t,” says Dr. Bensoussan. AI analysis of these sounds could help doctors more quickly identify respiratory disorders.
Pediatric voice and speech disorders (speech and language delays, autism)
Babies who later have autism cry differently as early as 6 months of age, which means an app like ChatterBaby could help flag children for early intervention, says Dr. Anderson. Autism is linked to several other diagnoses, such as epilepsy and sleep disorders. So analyzing an infant’s cry could prompt pediatricians to screen for a range of conditions.
ChatterBaby has been “incredibly accurate” in identifying when babies are in pain, says Dr. Anderson, because pain increases muscle tension, resulting in a louder, more energetic cry. The next goal: “We’re collecting voices from babies around the world,” she says, and then tracking those children for 7 years, looking to see if early vocal signs could predict developmental disorders. Vocal samples from young children could serve a similar purpose.
And that’s only the beginning
Eventually, AI technology may pick up disease-related voice changes that we can’t even hear. In a new Mayo Clinic study, certain vocal features detectable by AI – but not by the human ear – were linked to a three-fold increase in the likelihood of having plaque buildup in the arteries.
“Voice is a huge spectrum of vibrations,” explains study author Amir Lerman, MD. “We hear a very narrow range.”
The researchers aren’t sure why heart disease alters voice, but the autonomic nervous system may play a role, because it regulates the voice box as well as blood pressure and heart rate. Dr. Lerman says other conditions, like diseases of the nerves and gut, may similarly alter the voice. Beyond patient screening, this discovery could help doctors adjust medication doses remotely, in line with these inaudible vocal signals.
“Hopefully, in the next few years, this is going to come to practice,” says Dr. Lerman.
Still, in the face of that hope, privacy concerns remain. Voice is an identifier that’s protected by the federal Health Insurance Portability and Accountability Act, which requires privacy of personal health information. That is a major reason why no large voice databases exist yet, says Dr. Bensoussan. (This makes collecting samples from children especially challenging.) Perhaps more concerning is the potential for diagnosing disease based on voice alone. “You could use that tool on anyone, including officials like the president,” says Dr. Rameau.
But the primary hurdle is the ethical sourcing of data to ensure a diversity of vocal samples. For the Voice as a Biomarker project, the researchers will establish voice quotas for different races and ethnicities, ensuring algorithms can accurately analyze a range of accents. Data from people with speech impediments will also be gathered.
Despite these challenges, researchers are optimistic. “Vocal analysis is going to be a great equalizer and improve health outcomes,” predicts Dr. Anderson. “I’m really happy that we are beginning to understand the strength of the voice.”
A version of this article first appeared on WebMD.com.
: First during puberty, as the vocal cords thicken and the voice box migrates down the throat. Then a second time as aging causes structural changes that may weaken the voice.
But for some of us, there’s another voice shift, when a disease begins or when our mental health declines.
This is why more doctors are looking into voice as a biomarker – something that tells you that a disease is present.
Vital signs like blood pressure or heart rate “can give a general idea of how sick we are. But they’re not specific to certain diseases,” says Yael Bensoussan, MD, director of the University of South Florida, Tampa’s Health Voice Center and the coprincipal investigator for the National Institutes of Health’s Voice as a Biomarker of Health project.
“We’re learning that there are patterns” in voice changes that can indicate a range of conditions, including diseases of the nervous system and mental illnesses, she says.
Speaking is complicated, involving everything from the lungs and voice box to the mouth and brain. “A breakdown in any of those parts can affect the voice,” says Maria Powell, PhD, an assistant professor of otolaryngology (the study of diseases of the ear and throat) at Vanderbilt University, Nashville, Tenn., who is working on the NIH project.
You or those around you may not notice the changes. But researchers say voice analysis as a standard part of patient care – akin to blood pressure checks or cholesterol tests – could help identify those who need medical attention earlier.
Often, all it takes is a smartphone – “something that’s cheap, off-the-shelf, and that everyone can use,” says Ariana Anderson, PhD, director of the University of California, Los Angeles, Laboratory of Computational Neuropsychology.
“You can provide voice data in your pajamas, on your couch,” says Frank Rudzicz, PhD, a computer scientist for the NIH project. “It doesn’t require very complicated or expensive equipment, and it doesn’t require a lot of expertise to obtain.” Plus, multiple samples can be collected over time, giving a more accurate picture of health than a single snapshot from, say, a cognitive test.
Over the next 4 years, the Voice as a Biomarker team will receive nearly $18 million to gather a massive amount of voice data. The goal is 20,000-30,000 samples, along with health data about each person being studied. The result will be a sprawling database scientists can use to develop algorithms linking health conditions to the way we speak.
For the first 2 years, new data will be collected exclusively via universities and high-volume clinics to control quality and accuracy. Eventually, people will be invited to submit their own voice recordings, creating a crowdsourced dataset. “Google, Alexa, Amazon – they have access to tons of voice data,” says Dr. Bensoussan. “But it’s not usable in a clinical way, because they don’t have the health information.”
Dr. Bensoussan and her colleagues hope to fill that void with advance voice screening apps, which could prove especially valuable in remote communities that lack access to specialists or as a tool for telemedicine. Down the line, wearable devices with voice analysis could alert people with chronic conditions when they need to see a doctor.
“The watch says, ‘I’ve analyzed your breathing and coughing, and today, you’re really not doing well. You should go to the hospital,’ ” says Dr. Bensoussan, envisioning a wearable for patients with COPD. “It could tell people early that things are declining.”
Artificial intelligence may be better than a brain at pinpointing the right disease. For example, slurred speech could indicate Parkinson’s, a stroke, or ALS, among other things.
“We can hold approximately seven pieces of information in our head at one time,” says Dr. Rudzicz. “It’s really hard for us to get a holistic picture using dozens or hundreds of variables at once.” But a computer can consider a whole range of vocal markers at the same time, piecing them together for a more accurate assessment.
“The goal is not to outperform a ... clinician,” says Dr. Bensoussan. Yet the potential is unmistakably there: In a recent study of patients with cancer of the larynx, an automated voice analysis tool more accurately flagged the disease than laryngologists did.
“Algorithms have a larger training base,” says Dr. Anderson, who developed an app called ChatterBaby that analyzes infant cries. “We have a million samples at our disposal to train our algorithms. I don’t know if I’ve heard a million different babies crying in my life.”
So which health conditions show the most promise for voice analysis? The Voice as a Biomarker project will focus on five categories.
Voice disorders (cancers of the larynx, vocal fold paralysis, benign lesions on the larynx)
Obviously, vocal changes are a hallmark of these conditions, which cause things like breathiness or “roughness,” a type of vocal irregularity. Hoarseness that lasts at least 2 weeks is often one of the earliest signs of laryngeal cancer. Yet it can take months – one study found 16 weeks was the average – for patients to see a doctor after noticing the changes. Even then, laryngologists still misdiagnosed some cases of cancer when relying on vocal cues alone.
Now imagine a different scenario: The patient speaks into a smartphone app. An algorithm compares the vocal sample with the voices of laryngeal cancer patients. The app spits out the estimated odds of laryngeal cancer, helping providers decide whether to offer the patient specialist care.
Or consider spasmodic dysphonia, a neurological voice disorder that triggers spasms in the muscles of the voice box, causing a strained or breathy voice. Doctors who lack experience with vocal disorders may miss the condition. This is why diagnosis takes an average of nearly 4.5 years, according to a study in the Journal of Voice, and may include everything from allergy testing to psychiatric evaluation, says Dr. Powell. Artificial intelligence technology trained to recognize the disorder could help eliminate such unnecessary testing.
Neurological and neurodegenerative disorders (Alzheimer’s, Parkinson’s, stroke, ALS)
For Alzheimer’s and Parkinson’s, “one of the first changes that’s notable is voice,” usually appearing before a formal diagnosis, says Anais Rameau, MD, an assistant professor of laryngology at Weill Cornell Medicine, New York, and another member of the NIH project. Parkinson’s may soften the voice or make it sound monotone, while Alzheimer’s disease may change the content of speech, leading to an uptick in “umms” and a preference for pronouns over nouns.
With Parkinson’s, vocal changes can occur decades before movement is affected. If doctors could detect the disease at this stage, before tremor emerged, they might be able to flag patients for early intervention, says Max Little, PhD, project director for the Parkinson’s Voice Initiative. “That is the ‘holy grail’ for finding an eventual cure.”
Again, the smartphone shows potential. In a 2022 Australian study, an AI-powered app was able to identify people with Parkinson’s based on brief voice recordings, although the sample size was small. On a larger scale, the Parkinson’s Voice Initiative collected some 17,000 samples from people across the world. “The aim was to remotely detect those with the condition using a telephone call,” says Dr. Little. It did so with about 65% accuracy. “While this is not accurate enough for clinical use, it shows the potential of the idea,” he says.
Dr. Rudzicz worked on the team behind Winterlight, an iPad app that analyzes 550 features of speech to detect dementia and Alzheimer’s (as well as mental illness). “We deployed it in long-term care facilities,” he says, identifying patients who need further review of their mental skills. Stroke is another area of interest, because slurred speech is a highly subjective measure, says Dr. Anderson. AI technology could provide a more objective evaluation.
Mood and psychiatric disorders (depression, schizophrenia, bipolar disorders)
No established biomarkers exist for diagnosing depression. Yet if you’re feeling down, there’s a good chance your friends can tell – even over the phone.
“We carry a lot of our mood in our voice,” says Dr. Powell. Bipolar disorder can also alter voice, making it louder and faster during manic periods, then slower and quieter during depressive bouts. The catatonic stage of schizophrenia often comes with “a very monotone, robotic voice,” says Dr. Anderson. “These are all something an algorithm can measure.”
Apps are already being used – often in research settings – to monitor voices during phone calls, analyzing rate, rhythm, volume, and pitch, to predict mood changes. For example, the PRIORI project at the University of Michigan is working on a smartphone app to identify mood changes in people with bipolar disorder, especially shifts that could increase suicide risk.
The content of speech may also offer clues. In a University of California, Los Angeles, study published in the journal PLoS One, people with mental illnesses answered computer-programmed questions (like “How have you been over the past few days?”) over the phone. An app analyzed their word choices, paying attention to how they changed over time. The researchers found that AI analysis of mood aligned well with doctors’ assessments and that some people in the study actually felt more comfortable talking to a computer.
Respiratory disorders (pneumonia, COPD)
Beyond talking, respiratory sounds like gasping or coughing may point to specific conditions. “Emphysema cough is different, COPD cough is different,” says Dr. Bensoussan. Researchers are trying to find out if COVID-19 has a distinct cough.
Breathing sounds can also serve as signposts. “There are different sounds when we can’t breathe,” says Dr. Bensoussan. One is called stridor, a high-pitched wheezing often resulting from a blocked airway. “I see tons of people [with stridor] misdiagnosed for years – they’ve been told they have asthma, but they don’t,” says Dr. Bensoussan. AI analysis of these sounds could help doctors more quickly identify respiratory disorders.
Pediatric voice and speech disorders (speech and language delays, autism)
Babies who later have autism cry differently as early as 6 months of age, which means an app like ChatterBaby could help flag children for early intervention, says Dr. Anderson. Autism is linked to several other diagnoses, such as epilepsy and sleep disorders. So analyzing an infant’s cry could prompt pediatricians to screen for a range of conditions.
ChatterBaby has been “incredibly accurate” in identifying when babies are in pain, says Dr. Anderson, because pain increases muscle tension, resulting in a louder, more energetic cry. The next goal: “We’re collecting voices from babies around the world,” she says, and then tracking those children for 7 years, looking to see if early vocal signs could predict developmental disorders. Vocal samples from young children could serve a similar purpose.
And that’s only the beginning
Eventually, AI technology may pick up disease-related voice changes that we can’t even hear. In a new Mayo Clinic study, certain vocal features detectable by AI – but not by the human ear – were linked to a three-fold increase in the likelihood of having plaque buildup in the arteries.
“Voice is a huge spectrum of vibrations,” explains study author Amir Lerman, MD. “We hear a very narrow range.”
The researchers aren’t sure why heart disease alters voice, but the autonomic nervous system may play a role, because it regulates the voice box as well as blood pressure and heart rate. Dr. Lerman says other conditions, like diseases of the nerves and gut, may similarly alter the voice. Beyond patient screening, this discovery could help doctors adjust medication doses remotely, in line with these inaudible vocal signals.
“Hopefully, in the next few years, this is going to come to practice,” says Dr. Lerman.
Still, in the face of that hope, privacy concerns remain. Voice is an identifier that’s protected by the federal Health Insurance Portability and Accountability Act, which requires privacy of personal health information. That is a major reason why no large voice databases exist yet, says Dr. Bensoussan. (This makes collecting samples from children especially challenging.) Perhaps more concerning is the potential for diagnosing disease based on voice alone. “You could use that tool on anyone, including officials like the president,” says Dr. Rameau.
But the primary hurdle is the ethical sourcing of data to ensure a diversity of vocal samples. For the Voice as a Biomarker project, the researchers will establish voice quotas for different races and ethnicities, ensuring algorithms can accurately analyze a range of accents. Data from people with speech impediments will also be gathered.
Despite these challenges, researchers are optimistic. “Vocal analysis is going to be a great equalizer and improve health outcomes,” predicts Dr. Anderson. “I’m really happy that we are beginning to understand the strength of the voice.”
A version of this article first appeared on WebMD.com.
: First during puberty, as the vocal cords thicken and the voice box migrates down the throat. Then a second time as aging causes structural changes that may weaken the voice.
But for some of us, there’s another voice shift, when a disease begins or when our mental health declines.
This is why more doctors are looking into voice as a biomarker – something that tells you that a disease is present.
Vital signs like blood pressure or heart rate “can give a general idea of how sick we are. But they’re not specific to certain diseases,” says Yael Bensoussan, MD, director of the University of South Florida, Tampa’s Health Voice Center and the coprincipal investigator for the National Institutes of Health’s Voice as a Biomarker of Health project.
“We’re learning that there are patterns” in voice changes that can indicate a range of conditions, including diseases of the nervous system and mental illnesses, she says.
Speaking is complicated, involving everything from the lungs and voice box to the mouth and brain. “A breakdown in any of those parts can affect the voice,” says Maria Powell, PhD, an assistant professor of otolaryngology (the study of diseases of the ear and throat) at Vanderbilt University, Nashville, Tenn., who is working on the NIH project.
You or those around you may not notice the changes. But researchers say voice analysis as a standard part of patient care – akin to blood pressure checks or cholesterol tests – could help identify those who need medical attention earlier.
Often, all it takes is a smartphone – “something that’s cheap, off-the-shelf, and that everyone can use,” says Ariana Anderson, PhD, director of the University of California, Los Angeles, Laboratory of Computational Neuropsychology.
“You can provide voice data in your pajamas, on your couch,” says Frank Rudzicz, PhD, a computer scientist for the NIH project. “It doesn’t require very complicated or expensive equipment, and it doesn’t require a lot of expertise to obtain.” Plus, multiple samples can be collected over time, giving a more accurate picture of health than a single snapshot from, say, a cognitive test.
Over the next 4 years, the Voice as a Biomarker team will receive nearly $18 million to gather a massive amount of voice data. The goal is 20,000-30,000 samples, along with health data about each person being studied. The result will be a sprawling database scientists can use to develop algorithms linking health conditions to the way we speak.
For the first 2 years, new data will be collected exclusively via universities and high-volume clinics to control quality and accuracy. Eventually, people will be invited to submit their own voice recordings, creating a crowdsourced dataset. “Google, Alexa, Amazon – they have access to tons of voice data,” says Dr. Bensoussan. “But it’s not usable in a clinical way, because they don’t have the health information.”
Dr. Bensoussan and her colleagues hope to fill that void with advance voice screening apps, which could prove especially valuable in remote communities that lack access to specialists or as a tool for telemedicine. Down the line, wearable devices with voice analysis could alert people with chronic conditions when they need to see a doctor.
“The watch says, ‘I’ve analyzed your breathing and coughing, and today, you’re really not doing well. You should go to the hospital,’ ” says Dr. Bensoussan, envisioning a wearable for patients with COPD. “It could tell people early that things are declining.”
Artificial intelligence may be better than a brain at pinpointing the right disease. For example, slurred speech could indicate Parkinson’s, a stroke, or ALS, among other things.
“We can hold approximately seven pieces of information in our head at one time,” says Dr. Rudzicz. “It’s really hard for us to get a holistic picture using dozens or hundreds of variables at once.” But a computer can consider a whole range of vocal markers at the same time, piecing them together for a more accurate assessment.
“The goal is not to outperform a ... clinician,” says Dr. Bensoussan. Yet the potential is unmistakably there: In a recent study of patients with cancer of the larynx, an automated voice analysis tool more accurately flagged the disease than laryngologists did.
“Algorithms have a larger training base,” says Dr. Anderson, who developed an app called ChatterBaby that analyzes infant cries. “We have a million samples at our disposal to train our algorithms. I don’t know if I’ve heard a million different babies crying in my life.”
So which health conditions show the most promise for voice analysis? The Voice as a Biomarker project will focus on five categories.
Voice disorders (cancers of the larynx, vocal fold paralysis, benign lesions on the larynx)
Obviously, vocal changes are a hallmark of these conditions, which cause things like breathiness or “roughness,” a type of vocal irregularity. Hoarseness that lasts at least 2 weeks is often one of the earliest signs of laryngeal cancer. Yet it can take months – one study found 16 weeks was the average – for patients to see a doctor after noticing the changes. Even then, laryngologists still misdiagnosed some cases of cancer when relying on vocal cues alone.
Now imagine a different scenario: The patient speaks into a smartphone app. An algorithm compares the vocal sample with the voices of laryngeal cancer patients. The app spits out the estimated odds of laryngeal cancer, helping providers decide whether to offer the patient specialist care.
Or consider spasmodic dysphonia, a neurological voice disorder that triggers spasms in the muscles of the voice box, causing a strained or breathy voice. Doctors who lack experience with vocal disorders may miss the condition. This is why diagnosis takes an average of nearly 4.5 years, according to a study in the Journal of Voice, and may include everything from allergy testing to psychiatric evaluation, says Dr. Powell. Artificial intelligence technology trained to recognize the disorder could help eliminate such unnecessary testing.
Neurological and neurodegenerative disorders (Alzheimer’s, Parkinson’s, stroke, ALS)
For Alzheimer’s and Parkinson’s, “one of the first changes that’s notable is voice,” usually appearing before a formal diagnosis, says Anais Rameau, MD, an assistant professor of laryngology at Weill Cornell Medicine, New York, and another member of the NIH project. Parkinson’s may soften the voice or make it sound monotone, while Alzheimer’s disease may change the content of speech, leading to an uptick in “umms” and a preference for pronouns over nouns.
With Parkinson’s, vocal changes can occur decades before movement is affected. If doctors could detect the disease at this stage, before tremor emerged, they might be able to flag patients for early intervention, says Max Little, PhD, project director for the Parkinson’s Voice Initiative. “That is the ‘holy grail’ for finding an eventual cure.”
Again, the smartphone shows potential. In a 2022 Australian study, an AI-powered app was able to identify people with Parkinson’s based on brief voice recordings, although the sample size was small. On a larger scale, the Parkinson’s Voice Initiative collected some 17,000 samples from people across the world. “The aim was to remotely detect those with the condition using a telephone call,” says Dr. Little. It did so with about 65% accuracy. “While this is not accurate enough for clinical use, it shows the potential of the idea,” he says.
Dr. Rudzicz worked on the team behind Winterlight, an iPad app that analyzes 550 features of speech to detect dementia and Alzheimer’s (as well as mental illness). “We deployed it in long-term care facilities,” he says, identifying patients who need further review of their mental skills. Stroke is another area of interest, because slurred speech is a highly subjective measure, says Dr. Anderson. AI technology could provide a more objective evaluation.
Mood and psychiatric disorders (depression, schizophrenia, bipolar disorders)
No established biomarkers exist for diagnosing depression. Yet if you’re feeling down, there’s a good chance your friends can tell – even over the phone.
“We carry a lot of our mood in our voice,” says Dr. Powell. Bipolar disorder can also alter voice, making it louder and faster during manic periods, then slower and quieter during depressive bouts. The catatonic stage of schizophrenia often comes with “a very monotone, robotic voice,” says Dr. Anderson. “These are all something an algorithm can measure.”
Apps are already being used – often in research settings – to monitor voices during phone calls, analyzing rate, rhythm, volume, and pitch, to predict mood changes. For example, the PRIORI project at the University of Michigan is working on a smartphone app to identify mood changes in people with bipolar disorder, especially shifts that could increase suicide risk.
The content of speech may also offer clues. In a University of California, Los Angeles, study published in the journal PLoS One, people with mental illnesses answered computer-programmed questions (like “How have you been over the past few days?”) over the phone. An app analyzed their word choices, paying attention to how they changed over time. The researchers found that AI analysis of mood aligned well with doctors’ assessments and that some people in the study actually felt more comfortable talking to a computer.
Respiratory disorders (pneumonia, COPD)
Beyond talking, respiratory sounds like gasping or coughing may point to specific conditions. “Emphysema cough is different, COPD cough is different,” says Dr. Bensoussan. Researchers are trying to find out if COVID-19 has a distinct cough.
Breathing sounds can also serve as signposts. “There are different sounds when we can’t breathe,” says Dr. Bensoussan. One is called stridor, a high-pitched wheezing often resulting from a blocked airway. “I see tons of people [with stridor] misdiagnosed for years – they’ve been told they have asthma, but they don’t,” says Dr. Bensoussan. AI analysis of these sounds could help doctors more quickly identify respiratory disorders.
Pediatric voice and speech disorders (speech and language delays, autism)
Babies who later have autism cry differently as early as 6 months of age, which means an app like ChatterBaby could help flag children for early intervention, says Dr. Anderson. Autism is linked to several other diagnoses, such as epilepsy and sleep disorders. So analyzing an infant’s cry could prompt pediatricians to screen for a range of conditions.
ChatterBaby has been “incredibly accurate” in identifying when babies are in pain, says Dr. Anderson, because pain increases muscle tension, resulting in a louder, more energetic cry. The next goal: “We’re collecting voices from babies around the world,” she says, and then tracking those children for 7 years, looking to see if early vocal signs could predict developmental disorders. Vocal samples from young children could serve a similar purpose.
And that’s only the beginning
Eventually, AI technology may pick up disease-related voice changes that we can’t even hear. In a new Mayo Clinic study, certain vocal features detectable by AI – but not by the human ear – were linked to a three-fold increase in the likelihood of having plaque buildup in the arteries.
“Voice is a huge spectrum of vibrations,” explains study author Amir Lerman, MD. “We hear a very narrow range.”
The researchers aren’t sure why heart disease alters voice, but the autonomic nervous system may play a role, because it regulates the voice box as well as blood pressure and heart rate. Dr. Lerman says other conditions, like diseases of the nerves and gut, may similarly alter the voice. Beyond patient screening, this discovery could help doctors adjust medication doses remotely, in line with these inaudible vocal signals.
“Hopefully, in the next few years, this is going to come to practice,” says Dr. Lerman.
Still, in the face of that hope, privacy concerns remain. Voice is an identifier that’s protected by the federal Health Insurance Portability and Accountability Act, which requires privacy of personal health information. That is a major reason why no large voice databases exist yet, says Dr. Bensoussan. (This makes collecting samples from children especially challenging.) Perhaps more concerning is the potential for diagnosing disease based on voice alone. “You could use that tool on anyone, including officials like the president,” says Dr. Rameau.
But the primary hurdle is the ethical sourcing of data to ensure a diversity of vocal samples. For the Voice as a Biomarker project, the researchers will establish voice quotas for different races and ethnicities, ensuring algorithms can accurately analyze a range of accents. Data from people with speech impediments will also be gathered.
Despite these challenges, researchers are optimistic. “Vocal analysis is going to be a great equalizer and improve health outcomes,” predicts Dr. Anderson. “I’m really happy that we are beginning to understand the strength of the voice.”
A version of this article first appeared on WebMD.com.