Can you still pee properly? So many people have overactive bladders...

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It is estimated that many people have had similar experiences: when you are in a hurry to pee, if something more urgent than the urgency of peeing suddenly occurs, your brain will immediately devote itself to dealing with that emergency - at this time, you have no urge to pee, as if the urine in your bladder that is about to explode does not exist.

For a long time, people have been curious about the signal control and feedback mechanism of the brain-bladder: Why does the brain want you to go to the toilet even though you don't have any urine? What is nocturia? What causes urinary incontinence?

You're driving, eyes on the road, when you feel a sharp pain in your lower abdomen. That giant cup of Coke you drank an hour ago has made its way through your kidneys to your bladder. "Time to find a place to park," you think to yourself, and start looking for an exit ramp. For most people, pulling into a highway rest stop to pee is a common experience.

But to neuroscientist Rita Valentino, this is something special. She studies how the brain senses, interprets, and processes signals from the bladder. Valentino is fascinated by the brain's ability to take the bladder's sensory signals, combine them with signals from the external environment (like the sights and sounds of the road), and then use this information to take action (find a safe, appropriate place to pee). "To me, this is an example of something beautiful that the brain does," she says.

Scientists once believed that our bladders were controlled by a relatively simple reflex — a "switch" between storing urine and releasing it. "Now we realize it's much more complicated than that," said Valentino, now director of the Division of Neuroscience and Behavior at the National Institute on Drug Abuse.

A complex network of brain regions, including functions such as decision-making, social interaction, and awareness of the body's internal state (also known as interoception), is also involved in this process. In addition to being extremely complex, the system is also very fragile. Scientists estimate that more than 1 in 10 adults suffer from overactive bladder (OAB) - a common group of symptoms that includes urinary urgency (the feeling of needing to urinate even when the bladder is not full), nocturia (frequent trips to the bathroom at night), and incontinence.

© Getty Images

Although existing treatments can improve symptoms in some people, they don't work for many, says Martin Michel, a pharmacologist at Johannes Gutenberg University Mainz in Germany who studies treatments for bladder diseases. Developing effective drugs is so challenging that all major pharmaceutical companies have given up on the effort. However, a recent surge in new research is opening up new areas for new hypotheses and treatments.

While treatments for bladder disorders have historically focused on the bladder itself, Valentino noted that new research suggests the brain is also a potential therapeutic target. Indira Mysorekar, a microbiologist at Baylor College of Medicine in Houston, said these studies aim to explain why certain groups, such as postmenopausal women, are more prone to bladder problems, and that we should not simply assume that symptoms such as incontinence are inevitable.

“We’re often told, especially for women, that these issues are just part of aging, and while that’s true to some extent,” she said, many common problems are avoidable and can be successfully treated. “We don’t have to live with pain or discomfort,” she said.

A delicate balance

At the most basic level, the human bladder is a stretchy bag.

In order to fill the urine's volume (most healthy adults hold 400 to 500 milliliters, or about 2 cups) it must undergo the most extreme expansion of any organ in the human body, expanding about six times from its empty state.

© wikipedia

To achieve this stretch, the smooth muscle wall surrounding the bladder, called the detrusor muscle, must relax, and at the same time, the sphincter muscle surrounding the lower opening of the bladder (the urethra) must contract, a process scientists call the "guard reflex."

Whether full or empty, the bladder spends more than 95% of its time in storage mode, allowing us to carry out daily activities without leaking. At some point—ideally when we decide it’s time to go to the toilet—the bladder switches from storage mode to release mode. To do this, the detrusor muscle must contract hard to expel urine, while the sphincter muscle surrounding the urethra relaxes simultaneously to allow urine to flow out.[1]

It's not just sensory neurons (purple) that detect stretch, pressure, pain and more in the bladder. Other types of cells, such as the umbrella cells that form the urothelial barrier to urine, can also sense and respond to mechanical forces—for example, by releasing chemical signaling molecules such as adenosine triphosphate (ATP) when the organ fills with urine. © E. Underwood/Knowable

For a century, physiologists have studied how the body coordinates the switch between storage and release. In the 1920s, a surgeon named Frederick Barrington at University College London looked for the part of the brainstem, the lowest part of the brain connected to the spinal cord, that was responsible for this switch. Barrington conducted experiments on sedated cats, using electric needles to slightly damage the part of the brainstem that handles important functions, such as sleep and breathing, called the pons.

When the cats regained consciousness, Barrington noticed that some of the cats showed the urge to urinate (scratching, spinning, or squatting) but were unable to urinate on their own. Meanwhile, cats with damage to different parts of the pons seemed to have lost the urge to urinate, urinating at random times and appearing surprised when it happened. Apparently, the pons is an important command center for urination, telling the bladder when to release urine.

Beyond the Barrington Core

Barrington's work laid the foundation for our current understanding of the neural circuitry of bladder control. But we now know that more than just the pons is involved. When the bladder fills with urine, the detrusor muscle and the stretch-sensing cells in the lining of the bladder wall send signals of fullness along the spinal cord to a part of the brainstem called the periaqueductal gray (PAG).

The signal then travels to an area called the insula, which acts as a kind of sensor: The fuller the bladder, the more neurons in the insula fire tiny electrical pulses called action potentials. Next, the area of ​​the brain responsible for planning and making decisions—the prefrontal cortex—calculates whether this is a socially acceptable time to urinate. If so, it sends a signal back to the periaqueductal gray matter, which in turn sends an all-clear signal to the part of the pons that Barrington discovered in his cat experiments—now called Barrington's nucleus.

This signal returns to the bladder and, voila, urination occurs.

© Metro

In the past decade, super-precise tools have made it more sophisticated to map the connections and interactions between different brain regions. Valentino and her team used a technique that can monitor and analyze the electrical activity of neurons in multiple parts of the brain at the same time. When the bladder reaches a certain level of fullness, the locus coeruleus in the brainstem begins to fire in a steady rhythm.

This wave of activity travels to the brain's outer cortex and puts the brain into a more awake, alert state about 30 seconds before urination. Valentino hopes that observations like these could inform treatments for common problems like nocturia and enuresis, and they might also help explain some basic phenomena most people experience. "I think this is one of the main reasons you need to wake up to pee," Valentino says. "It's as if the locus coeruleus is saying, 'Stop what you're doing and focus on peeing.'"

Learn to control it

Controlling when and where we pee takes time to develop, as anyone who has toilet-trained a toddler can attest. When humans are born, urination is controlled not by the brain but by a spinal reflex that kicks in when the bladder reaches a certain capacity.

Only around age 3 or 4 do brain regions responsible for functions such as social awareness and decision-making go beyond reflexes, says Hanneke Verstegen, a neuroscientist at Beth Israel Deaconess Medical Center in Boston and Harvard Medical School. It’s impossible to watch how this process unfolds in the brainstem of human infants.

But Westergen and her colleagues are studying a similar process in lab mice, which develop voluntary control over urination at about 3 to 5 weeks. That’s when the mice start peeing in designated corners, she said, a behavior not unlike that of toilet-trained toddlers.

Interestingly, the more primitive automatic spinal reflexes we have as infants do not disappear completely: When spinal cord injury affects the nerves that carry signals between the bladder and the brain, the reflexes can reappear, often resulting in incontinence or other conditions that require the use of a catheter.

This is a simplified representation of some of the neural pathways and brain regions that enable most healthy people to sense when their bladder is full or filling, predict how long they can wait to urinate, and successfully execute their plan to "hold it" or "pour it." Disruptions at any level of this complex two-way neural communication system can lead to bladder disorders, experienced by millions of people around the world. © knowablemagazine

Spinal cord damage is just one of many reasons why communication between the brain and the bladder can go awry. As the brain ages, the synapses that transmit information to the bladder can also lose integrity in the area that controls urination, causing normal bladder function to malfunction—a process that is often accelerated in Parkinson's and Alzheimer's diseases.

Becky Clarkson, a medical physicist at the University of Pittsburgh, and her colleagues are using neuroimaging tools such as functional magnetic resonance imaging (fMRI) to see which parts of the brain are active through fluctuations in blood oxygen levels, thereby understanding how the brain mechanisms that control urination break down.[2] “We’re trying to figure out which pathways might be impaired,” she says. “How does the brain normally control the bladder? And how does it fail to do so?”

When the bladder is empty or partially full, it is covered in wrinkles (shown here in an artificially colored cross-section of a mouse bladder wall). In humans, this extra tissue can increase the organ's size fivefold or sixfold. © COURTESY OF PATAPOUTIAN LAB / SCRIPPS RESEARCHER INSTITUTE, LA JOLLA, CA

Most of the participants in Clarkson's study were women over 60, the demographic group with the highest rates of overactive bladder. About 11% of the general population has overactive bladder, but more than 45% of postmenopausal women report it. Scientists aren't sure what causes overactive bladder or why it's so common in middle-aged and older women. Some point to changes in the bladder itself.

One of them is Mesorekha, who has found that during menopause, a proliferation of immune cells forms tiny lumps on the lining of women’s bladders that resemble lymph nodes. These lesions increase the bladder’s sensitivity to even tiny amounts of E. coli (the bacteria that causes most urinary tract infections), leading to chronic bladder pain or overactive bladder. Another major cause of overactive bladder in both men and women is detrusor overactivity, an erratic contraction of the bladder muscle that sends false signals of fullness to the brain.[3]

Existing treatments are all aimed at calming these contractions: The most commonly used class of drugs is antimuscarinic, which blocks the activity of acetylcholine, a nerve-signaling chemical that triggers the detrusor to contract. If drugs don't work, clinicians often recommend injecting the detrusor with botulinum toxin so it doesn't contract as much. Sometimes they also try to restore normal activity in the spinal nerves that control the bladder muscles by delivering an electrical current to the spinal nerves through surgical implants or electrodes placed on the skin.

The problem with all these detrusor-control treatments is that they can have adverse side effects, including, in a few cases, affecting the ability to urinate. “It’s a very fine line—if you do too much, you can’t urinate; if you don’t do enough, you can have storage problems,” he said. Antimuscarinics have been linked to symptoms of cognitive decline, particularly in older adults, raising safety concerns.

Additionally, not all people with overactive bladder have an overactive detrusor muscle, prompting some scientists to question whether the problem in some patients lies elsewhere in the body, such as inside the brain.

Get home safely

If you've ever arrived home after a long day at work and, the moment you unlocked the door, you felt a sudden, overwhelming urge to pee, you've experienced what scientists know is a close connection between the brain and the bladder.

© ESTHER AARTS

This type of urgency, called latchkey incontinence, has nothing to do with how full your bladder is. (It’s also different from when we can’t control the urge to pee when we sneeze, cough, or jump: That common problem is called stress incontinence, and it’s usually caused by weak pelvic floor muscles.) Some scientists think the urgency of overactive bladder may be conditioned, just as Russian physiologist Ivan Pavlov trained dogs in the 1890s to associate food with the sound of a metronome.

Clarkson and his team hypothesize that for some people, this reflex may be formed from years of waiting to get home to use their own toilet. For others, it may be triggered by various situations, such as the sound of running water. If this strong feeling happens occasionally, it is normal, but if it happens frequently, the researchers believe it can be a concern. Clarkson and other research teams have found that women with overactive bladders tend to have abnormal brain activity patterns.

In one experiment in Clarkson's lab, subjects lay flat in an fMRI while a catheter filled their bladder with fluid until they said they had had enough. Then a technician removed some of the fluid and refilled it, and the process was repeated multiple times. In this way, Clarkson and his team built a model of how the brain controls the bladder, involving areas such as the insula (which processes signals of fullness from the bladder) and the prefrontal cortex (which helps determine when and where it is appropriate to urinate).

Two other areas, the supplementary motor area (SMA) and the anterior cingulate cortex (ACC), appear to work together to judge the urgency of urination and execute pelvic floor muscle contractions to help us hold our urine until we find a toilet. For some people with overactive bladder, these areas tend to be more active, which can lead to an overwhelming sense of urgency even when their bladder is only partially full. "We think of this almost as an emergency station," Clarkson says. "When you have the slightest urge to pee, you have to go and deal with it."

A few years ago, one of Clarkson's colleagues noticed that the intense urge to urinate in overactive bladder was similar to the urge that ex-smokers feel in certain situations, such as in a bar where they used to smoke. Intrigued, Clarkson teamed up with Cynthia Conklin, a smoking cessation researcher at the University of Pittsburgh, to use methods from smoking research to investigate how women with overactive bladder respond to personal triggers. The women were shown pictures of locations that triggered their urge to urinate, such as their front door or the entrance to a supermarket.

Compared with the "safe" photos, viewing these triggers increased activity in brain areas associated with attention, decision-making, and bladder control. Clarkson says certain behavioral therapies seem to help women with overactive bladder respond more calmly to urgency triggers. For example, her team's preliminary data suggests that mindfulness techniques such as body scan meditation can prompt participants to relax from head to toe and reduce the intensity of their bladder. They have also found that a noninvasive brain stimulation called transcranial direct current stimulation (tDCS) can ease feelings of urgency.

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Clarkson and her team have also explored differences in brain activity between women who did and did not respond to treatment with Botox and pelvic floor muscle therapy, and they are currently investigating whether taking commonly prescribed bladder medications may lead to changes in the brain.

Many older women and men seeking treatment for overactive bladder are already taking multiple anticholinergic drugs, including the most commonly used bladder medication, antimuscarinics. Given that taking too many of these drugs can cause cognitive problems, Clarkson hopes to increase non-drug treatment options. “If we can get people off medication, that would be great,” she says.

Causes of Overactive Bladder

Most researchers agree that the main obstacle to finding more effective treatments for overactive bladder is that the diagnosis is so vague: It's not a single disease but a loose set of symptoms that can be caused by many different conditions, from Parkinson's disease to spinal cord injuries to diabetes, or none of the above. But these cases are often lumped together and talked about as if they were all the same disease, said Aaron Mickle, a neuroscientist at the Medical College of Wisconsin.

Mikkel is studying how different conditions affect the lining of the bladder, the urothelium—a soft, self-renewing tissue layer that stretches and flattens to accommodate changes in bladder capacity. Although scientists once thought of the urothelium as a passive barrier that prevented the bladder wall from leaking, it is now clear that it plays a key role in transmitting signals about bladder filling. One reason the urothelium is so sensitive is that many of its cells contain multiple types of mechanically activated ion channels—proteins that sit on the cell membrane and are actually doors into the cell.

These channels open when the cell membrane is stretched, jostled, or otherwise deformed, allowing positively charged ions to flow into the cell, explains Kate Poole, a physiologist at the University of New South Wales in Australia and author of a 2022 article on mechanically activated ion channels in mammals in the Annual Review of Physiology.[4] Sensory neurons that extend into the urothelium contain these force-sensitive channels; when the influx of positive ions in these nerves reaches a certain threshold, they communicate directly with nerves in the spine and brain via electrical impulses.

Curiously, however, non-neuronal cells in the urothelium also contain a variety of mechanically activated ion channels, suggesting that they can also signal bladder filling.

In 2023, Aaron Mikkel selectively stimulated some non-neuronal urothelial cells using optogenetics (remote activation or deactivation of selected cells in an animal using a laser beam). This was enough to activate sensory neurons and trigger bladder contractions, the first time this had been successfully done.

Mikkel hopes to eventually develop a wireless optogenetic system that could continuously monitor and modulate the activity of specific types of bladder cells in humans. (Although optogenetics is currently used primarily in laboratory animals, researchers are exploring its use in humans.) Other research groups are studying force-sensitive channels in bladder cells as drug targets, as well as other channels that respond to various nerve signaling chemicals and hormones. These channels include a group of force-sensitive spiral-shaped proteins called Piezo channels, which play an important role in bladder sensing.

In 2020, a study published in the journal Nature showed[5] that people with a rare mutation that affects a channel called Piezo2 have trouble sensing a full bladder, in addition to other serious defects, such as difficulty walking. Some people must urinate on a set schedule or press on their bladder with their hands to urinate.

One of several force-sensing protein channels found in the bladder, the three-pronged propeller-shaped Piezo2 channel sits on the cell membrane. It opens in response to mechanical forces such as stretch and pressure. Recently, researchers have shown that humans and rats with mutations that affect Piezo2 function have problems with urination. These problems include a reduced ability to sense when the bladder is full or overflowing. © GOULTARD59 / WIKIMEDIA COMMONS

Some scientists hope to target Piezo2 channels to treat various bladder disorders. One advantage of targeting these channels is that they are "intrinsically druggable," Poole said, meaning that researchers can often find small molecules that can turn them on or off even though they normally respond to mechanical stimulation. But there is a drawback: Like other ion channels that researchers are trying to target in the bladder, Piezo2 channels are found throughout the body, including in the lungs, joints, and heart.

Therefore, any drug that affects channels in the bladder could also affect other parts of the body, raising safety concerns. Michel points out that a drug that acts on another type of ion channel in the bladder (these channels allow potassium ions to enter cells) was once tested in clinical trials, but the trial had to be stopped because the drug was found to cause liver problems.

Currently, at least in theory, there is a way to overcome this obstacle: gene therapies that specifically target bladder tissue, as they are already injected directly into the detrusor muscle or through a catheter into the urethra. In 2023, scientists published preliminary but encouraging data from a trial of 67 patients using gene therapy for bladder potassium channels.

From left to right: Normal bladder when empty; Normal bladder when full (feeling the urge to urinate); Overactive bladder (feeling the urge to urinate even when the bladder is almost empty). © AARE Urocare

Although scientists who study the bladder and urinary tract have traditionally worked separately from those who study the spinal cord and brain, these long-separate fields are beginning to collaborate to put more of the pieces of the brain-bladder puzzle together. For example, Mikel recently teamed up with a neuroimaging lab that will help him watch the brains of mice respond to optogenetic stimulation of their urothelial cells. “In the past, we never looked at the brain,” Valentino says. But the new research “is making us think more about these other targets,” she says.

References:

[1]www.annualreviews.org/content/journals/10.1146/annurev.pharmtox.41.1.691[2]onlinelibrary.wiley.com/doi/abs/10.1002/nau.24559

[2]www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-010617-052615

[4]www.annualreviews.org/content/journals/10.1146/annurev-physiol-060721-100935

[5]www.nature.com/articles/s41586-020-2830-7

By Emily Underwood

Translated by tim

Proofreading/tamiya2

Original article/www.smithsonianmag.com/science-nature/how-do-we-know-when-to-pee-180984448/

This article is based on the Creative Commons License (BY-NC) and is published by tim on Leviathan

The article only reflects the author's views and does not necessarily represent the position of Leviathan