Urinary incontinence is a common but frequently overlooked consequence of stroke. Now, researchers from the Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI) at the Keck School of Medicine of USC and Rancho Los Amigos National Rehabilitation Center have received a grant from the National Institutes of Health to investigate the brain changes responsible for these symptoms and develop a more personalized approach to treatment.
The project, led by Evgeniy Kreydin, MD, adjunct assistant professor of clinical urology, will combine advanced brain imaging, clinical bladder testing, and a noninvasive therapy called transcutaneous spinal cord stimulation. The researchers aim to identify imaging biomarkers, or measurable features seen on brain scans, that can help predict which stroke survivors are most likely to benefit from the treatment.
Bladder dysfunction after stroke can have a profound effect on a person's independence, dignity, and quality of life, yet treatment is often focused on the bladder rather than the neurological injury that caused the problem. This grant gives us an opportunity to understand the condition at its source and move toward treatments selected for each patient's individual pattern of brain injury."
Evgeniy Kreydin, MD, adjunct assistant professor of clinical urology, Keck School of Medicine of USC
Bladder symptoms persist in more than 30% of stroke survivors. In addition to affecting health and daily life, incontinence can increase caregiver responsibilities and make it more difficult for patients to continue living independently. Current treatments, including medications and injections into the bladder, primarily address the symptoms. While treating symptoms remains important, current therapies generally act on the bladder itself and may not address disrupted signaling between the brain, spinal cord, and bladder. These treatments can also cause side effects and may improve one problem, such as urgency, while offering limited benefit for others, such as reduced bladder sensation or difficulty emptying. By targeting the nerve circuits involved in bladder control, spinal stimulation has the potential to improve this underlying communication and provide a more individualized treatment option.
They can also cause side effects or may not be suitable for stroke survivors with other medical conditions. There are few effective options for people who have reduced bladder sensation or difficulty emptying the bladder after a stroke.
The new study will examine the networks that enable the brain, spinal cord, and bladder to communicate, providing a foundation for treatments targeting the neurological cause of the condition.
"Genitourinary system dysfunction remains one of the highest priorities in neurological disease and injury, as well as in aging," said Charles Liu, MD, PhD, professor of clinical neurological surgery, surgery, psychiatry and the behavioral sciences, and biomedical engineering, and director of the USC Neurorestoration Center. "Our team at USC has taken a multidisciplinary approach to restoring function by bringing together expertise in imaging, urology, neurosurgery, and biomedical engineering. This collaboration has already led to several important advances."
Mapping the brain's bladder-control system
Bladder control requires coordination across several parts of the brain. These regions help a person recognize that the bladder is filling, decide when it is appropriate to use the restroom, and send signals that allow the bladder to store or release urine. A stroke can damage one of these regions or interrupt the connections between them. However, researchers do not yet fully understand how the location and extent of that damage relate to specific bladder symptoms.
The study will compare stroke survivors with injuries in different areas of the brain, including the basal ganglia and pons, which are involved in bladder control. The researchers will also study people with strokes affecting the occipital lobe, a region primarily associated with vision, as well as healthy participants to serve as controls.
Participants will undergo functional magnetic resonance imaging, or fMRI, while their bladders are gradually filled and monitored. Unlike a standard MRI, which shows the brain's anatomy, fMRI measures changes associated with brain activity. This will allow the researchers to observe how bladder-control regions communicate at rest and during filling and urination.
"Bladder control depends on a coordinated conversation among multiple brain regions, and a stroke may disrupt that conversation in different ways depending on where the injury occurs," said Kay Jann, PhD, assistant professor of research neurology at the Stevens INI, and a co-investigator on the project. "Functional MRI will help us determine which functions have been impaired, for example, sensation or initiation of voiding, and whether those changes correspond to the symptoms and physiological problems experienced by each patient."
The scans will be paired with urodynamic testing, which measures how full the bladder is and when it releases urine. By comparing the brain imaging with objective measures of bladder function, the researchers hope to identify the network changes most closely associated with incontinence and other urinary symptoms.
Examining the brain's communication pathways
The team will also use diffusion MRI, an imaging method that reveals the brain's white matter pathways. "White matter acts as the brain's communication wiring, carrying vital signals that keep the brain and bladder in sync. With diffusion MRI, we can map these specific pathways to see exactly how a stroke disrupts that line of communication," Kirsten Lynch, PhD, assistant professor of research neurology at the Stevens INI and a co-investigator on the project, explained.
Using a computational technique called tractography, researchers will reconstruct the pathways connecting key bladder-control regions. The team will then examine whether damage to those pathways helps explain both the altered brain activity and the severity of participants' symptoms.
"Functional imaging can show us which regions are no longer communicating normally, while diffusion imaging helps us examine the physical pathways that carry those signals," said Jann. "Bringing those two perspectives together will give us a more complete picture of how stroke-related damage affects bladder control."
The researchers will focus on pathways connecting areas involved in attention, decision-making, body awareness, movement, and communication between the brain and brainstem. They will test whether the condition of those pathways can provide information about bladder function that is not apparent from the visible stroke injury alone.
Predicting response to spinal cord stimulation
Study participants will receive 12 weeks of transcutaneous spinal cord stimulation, or TSCS. The noninvasive treatment delivers mild electrical stimulation through electrodes placed on the skin over the spine. The stimulation is intended to influence the nerve circuits involved in bladder function and strengthen communication among the bladder, spinal cord, and brain. Earlier pilot research by the team found that the treatment reduced incontinence in many stroke survivors, but not everyone responded.
Participants will repeat the imaging and bladder testing after treatment. The team will examine whether people who improve have better-preserved brain networks before therapy or show measurable changes in connectivity following stimulation. The ultimate goal is to create a panel of imaging biomarkers that could help clinicians determine in advance whether TSCS is likely to work for a particular patient. Such a tool could reduce trial and error, shorten the time needed to find an effective treatment, and spare patients from therapies unlikely to help them.
"This project reflects the promise of neuroimaging to connect what we see in the brain with meaningful improvements in patients' lives," said Arthur W. Toga, PhD, director of the Stevens INI. "By identifying the biological features that influence treatment response, the team is working toward a future in which rehabilitation and neuromodulation therapies can be tailored to the individual rather than applied through a one-size-fits-all approach."
The research may also have implications beyond stroke. Traumatic brain injuries, neurodegenerative diseases, spinal cord injuries, and other neurological conditions can interfere with bladder control. A better understanding of the networks involved could therefore support the development of personalized neuromodulation treatments for a broader range of patients.
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