UC leads first trial testing treatment of spreading depolarizations

May 20, 2023

University of Cincinnati researchers have enrolled the first four patients in a first-of-its-kind trial that will test a treatment for abnormal brain activity sometimes referred to as a "brain tsunami."

The Improving Neurotrauma by Depolarization Inhibition with Combination Therapy (INDICT) trial is focusing on treating the phenomenon, known officially as spreading depolarizations (SD).

UC's Jed Hartings, PhD, principal investigator of the trial, explained that just like a battery, brain cells have a stored, or polarized, charge that enables them to send electrical signals to each other.

During SD, the brain cells lose their charge, becoming depolarized and unable to send electrical signals to each other.

"This happens en masse in a local area of tissue and then spreads out like a wave, like ripples in a pond, and it interrupts every aspect of cell function," said Hartings, professor and vice chair of research in the Department of Neurosurgery in UC's College of Medicine. "I sometimes explain that the brain cells become a swollen sack of saline, just a big bag of saltwater, that's not functional anymore."

UC's Jed Hartings, PhD, principal investigator of the INDICT trial. Photo/Julie Forbes/University of Cincinnati.

SDs can occur continuously in patients for up to a couple of days, but they can also continue on and off up to two weeks after a severe brain injury.

"It's a big open question whether or not these might continue for many weeks or a month, and it's also a big question to what extent do they occur in less severe injuries that don't require surgery," Hartings said. "There's strong emerging evidence that they would occur even in something as mild as a concussion."

Hartings noted that because SDs cause a complete shutdown in affected brain regions, they generate an electrical discharge measured at about 10 times the size of a typical seizure.

"These SDs affect such large areas that, if they were visible, you could track their movement with the naked eye as they march across centimeters of brain tissue, as opposed to millimeters or microns," said Hilary Perez, PhD, clinical research manager in the Department of Neurosurgery.

Jed Hartings, PhD professor and vice chair of research in the Department of Neurosurgery in UC's College of Medicine

Hartings said SDs were first discovered in animals in 1944, but research into how they affect human brains began around 2002.

"I think in the past maybe five to 10 years we’ve turned the corner and our results have shown that these are very common and that they are detrimental," Hartings said. "They’re consistently associated with worse patient outcomes."

Research has focused on patients that have required surgery because an electrode strip needs to be placed in the brain to monitor for SDs. However, it is estimated that SDs affect patients with virtually every type of acute brain injury, including different kinds of strokes and traumatic brain injuries (TBI).

"It's across the spectrum and we have been monitoring all those different types of patients as an international research community," he said. "It's in the range of 60% to 100% of all patients in these different disease categories. It's just mind-boggling. This is the iceberg that's been submerged under the water that we never knew about."

There is currently no standard of care or treatment for SDs, and the INDICT trial is the first Phase 2 trial testing the feasibility of treating patients with SDs.

"This is a pretty exciting moment for us here and globally in this community. We really rebooted and created a field of science globally, both basic scientists in the laboratory as well as clinical scientists who monitor the brain," Hartings said. "There's a large basic science community that's been trying to understand these events better now that we know that they have clinical significance. Now this is for the first time in this global community that we actually have a trial that's trying to intervene and treat them."

Due to the need for surgery to place the electrode strip for monitoring, the trial is focused on patients with TBIs requiring surgery. Laura Ngwenya, MD, PhD, neurosurgical director of the study, said it is standard practice to place these electrode strips to monitor for seizures, but they will now be additionally used to look for SDs.

Laura Ngwenya, MD, PhD, neurosurgical director of the study. Photo/UC Health.

Ngwenya, Brandon Foreman, MD, an associate director of neurocritical care research and neuromonitoring expert, and their teams will then monitor patients while they are in the intensive care unit for signs of SDs. The trial will test three different tiers of treatments.

Certain ranges of blood pressure, blood sugar and body temperature measurements are associated with a higher likelihood of having SDs, Ngwenya said, so the first tier of treatment will focus on managing those levels.

"SDs can occur if the blood pressure is too low or if the sugar is too low," said Ngwenya, associate professor and director of neurotrauma in the Department of Neurosurgery in UC's College of Medicine. "Essentially the first tier is just managing all of those physiologic numbers and getting those numbers in a good range."

The second tier continues managing the physiologic measurements into a slightly higher range in combination with a low dose of the drug ketamine, which has been shown to be able to stop SDs. Tier three involves a higher dose of ketamine.

"We have been studying SDs, especially in the traumatic brain injury population, for about the past 10 to 15 years, and we know that when patients have SDs they have worse outcomes," Ngwenya said. "This is the first step for us to say, ‘Can we treat SDs when we see them?’ Because eventually we want to know if we treat them will we have better outcomes for patients."

The trial plans to enroll approximately 70 patients total across trial sites at UC, the University of Pennsylvania and the University of California San Francisco.

"This is the first step for us to say, ‘Can we treat SDs when we see them?’ Because eventually we want to know if we treat them will we have better outcomes for patients," says Laura Ngwenya, MD, PhD. Photo/UC Health.

As a feasibility study, Hartings said the first goal of the trial is to test the practicality of the process of monitoring for SDs and then responding with treatments in a real-world clinical setting.

Brandon Foreman, MD, an associate director of neurocritical care research and neuromonitoring expert. Photo/UC Health.

"While we’re used to monitoring patients for seizures in the intensive care unit, this is really the first large-scale attempt for clinicians involved in this study to monitor for spreading depolarizations in real time," said Foreman, associate professor in the Department of Neurology and Rehabilitation Medicine in UC's College of Medicine.

"This is a pretty novel stream of information that requires a certain degree of expertise to read and detect these events in real time, and then continually adjust care based on what the pattern of spreading depolarizations might be in that particular patient," Hartings added. "The concept that we can treat these in real time hasn't been proven yet, so that's the first step of feasibility."

The study's second goal is to determine if the treatments have an effect to positively impact brain health and prevent SDs.

Ngwenya said the study INDICT also marks the first step of providing personalized treatments for every patient with a TBI.

Jed Hartings, PhD principal investigator of the trial

"We’re not just giving ketamine to every single patient that has a severe TBI. We’re only doing the treatment if we see that they’re having these SDs," she said. "So it allows an individualized treatment, or the term that's sometimes used is personalized medicine, and that's something that we’ve been striving for in the traumatic brain injury field."

Hartings began to study SDs in animal models shortly after he earned his doctorate and said it is rewarding to see the progress that has been and continues to be made in moving research in this area forward.

"It's really a great success story of bench to bedside medicine, and of collaboration between physicians and academics from different disciplines," he said. "Since the initial animal studies, we’ve formed an international coalition of researchers and clinicians who have advanced and developed the science, from neurosurgeons all the way to computer scientists. Now we are testing a clinical methodology to see how these advances could positively impact patients."

Featured image at top of neurons. Photo credit/iStockPhoto.

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