Following the Signal That May Restore Bladder Control

The tibial nerve runs down the lower leg and branches near the ankle. When clinicians stimulate it with a small electrical current, something unexpected happens – bladder function tends to improve.

There's just one problem. Nobody knows why, says Jim Hokanson, PhD, an assistant professor in the Marquette University and Medical College of Wisconsin (MCW) Joint Department of Biomedical Engineering.

"We stimulate at the ankle and you'll actually get the foot to move," says Dr. Hokanson. "That confirms the electrodes are in the right spot. Then – hand wave, hand wave, hand wave – bladder function tends to get better.”

He laughs, but the point is serious. The neural pathway between the ankle and the bladder is poorly understood. Now, Dr. Hokanson – along with Aaron Mickle, PhD, associate professor in MCW’s physiology department – hopes to shed some light on how that pathway works with the help of two new R01 grants.

A $3.8 million grant will support work on fine-tuning electrical nerve stimulation to treat bladder problems caused by spinal cord injuries, while a second $3.7 million grant will help the researchers map the neural circuitry that may explain why the treatment works. Together, the projects have implications for other patients who struggle with incontinence, an especially common problem as people age.

Deciding on Urology

Dr. Hokanson didn't start his career in urology. He became interested in brain-computer interfaces as an undergraduate at Washington University in St. Louis after a professor's seminar showed recordings of brain signals from monkeys who could move a cursor on a screen simply by thinking.

He followed that thread to Pittsburgh, where his doctoral work focused on artificial sensory feedback for people with amputations. The lab eventually drew a visit from President Obama, who fist-bumped a robotic hand equipped with sensors while the man on the other end – a person with an amputation – felt the bump as if it were real.

"Really cool stuff," Dr. Hokanson says.

While he was there, he met two postdocs who were interested in applying what they were learning in the lab to neuromodulation – altering nerve activity through targeted delivery of electrical stimulation – and using it to help patients with urological dysfunction.

“Their conversations about how profoundly bladder and bowel dysfunction affected people with spinal cord injuries stayed with me,” he says. “When I went to do my own postdoc at Duke University, I switched from sensory motor work into urology.”

Profound Negative Effects on Patients’ Lifestyles

At Duke, he met patients dealing with incontinence and was touched by their stories. In one case, he met a retired man who had planned to travel the world with his wife, only to find that urinary incontinence made him feel like he couldn't.

"They had worked their whole life and put all this time into planning their travels, and now this thing that they had never thought about dealing with happened,” he says. “It was just so frustrating for them."

In a 2022 publication, Dr. Hokanson cataloged the downstream effects of urological dysfunction – social isolation, depression, disrupted sleep, and financial burden.

"Even though it may not kill you, it can actually be quite bad for your health," he says. “It's a big factor that plays into people being institutionalized rather than staying in their own homes.”

Practical Implications for Patients

Dr. Hokanson describes himself as an engineer first. He likes being able to draw a line from a lab finding to a specific implication for patients.

"I like it when it's very clear,” he says. “This is step one, step two, and then step three is when the patient is better."

One of the new grants will generate practical guidance on how to administer tibial nerve stimulation – what dose, what frequency, what timing relative to spinal cord injury – while also collecting spinal cord cells that could eventually explain why the therapy works in the first place.

The researchers – with the help of Nikki Lytle, PhD, an assistant professor in MCW’s Division of Surgical Oncology who has experience using a technique called single-cell RNA sequencing – hope to identify which spinal cord cells respond to the electrical signal.

"Once you've identified the cell types that care about your stimulation, there are other techniques where you can go in and manipulate those cell types," Dr. Hokanson says.

That kind of circuit-level understanding could eventually help clinicians predict which patients will respond to which therapy – something the field currently cannot do.

What Success Looks Like

Dr. Hokanson hopes the grants’ findings feed directly into clinical trials.

"My hope is that I can turn to my clinical collaborators and say, 'Here's what we're seeing – let's try this and see if we see something similar in people.'"

Tibial nerve stimulation is already practiced clinically, he says, which means the translation path is shorter than for a new drug or device. "It's not as big a lift. We're already trying this. The question is, how can we make it better?"

The second grant, centered more heavily on circuit mapping, will allow Drs. Hokanson and Mickle to dig deeper into why tibial nerve stimulation affects the bladder.

They will use a technique in which viruses that glow are injected into the bladder and the tibial nerve, then tracked as they travel through the nervous system. Wherever the two sets of signals intersect is, likely, where the therapeutic effect originates.

"Eventually," he says, explaining his future vision for patients struggling with incontinence, “when someone comes in, we’ll be able to say, 'Here's what's dysfunctional and this particular therapy will help with that.’

“Right now, it's just symptom-based,” he says. “You have incontinence. Go do this. When in reality, that symptom could be caused by five, ten, fifteen different things, or some combination."

He adds. "That's what I think about with my research in general: how do we get more specific in terms of matching therapies to patients?"