Leonardo Bonilha, M.D. Ph.D., sees his clinical work and his research work as a seamless whole.
“I actually don’t see it as two different things. I think my job as a physician is to help people, but also to better understand diseases so treatments can improve,” said the SmartState endowed chair for brain imaging.
A neurologist, Bonilha splits his research interests between two important problems – epilepsy and aphasia. Epilepsy is one of the world’s oldest recognized conditions, going back to 4000 B.C., notes the World Health Organization. Doctors and researchers are still trying to fully understand the disease. Aphasia is a condition in which a person can’t produce or can’t understand language. It’s caused by damage to the brain, usually because of stroke.
Since joining the MUSC faculty in 2012, Bonilha has built a multidisciplinary lab with a varied group of researchers whose backgrounds include language pathology, neurology, biomedical imaging, biomedical engineering and neuropsychology.
“One of the main themes of the lab is to better understand the complexity of brain networks and how our brain functions emerge from the organization and the dynamics within the networks of neurons,” he said.
Training new researchers is an important part of his job. It’s not just a matter of more hands making lighter work; through the research, they see how these diseases affect people and begin thinking in a cross-disciplinary fashion.
“They form their careers and their thinking in terms of how to be researchers in the field,” he said. “Really, how we make an impact is by having multiple people thinking about these issues – talented and passionate investigators collaborating across disciplines.”
Teamwork across MUSC, and even across the state, is key as well. He works with the Stroke Recovery Research Center, housed in the College of Health Professions, as well as the Center for the Study of Aphasia Recovery (C-STAR), housed at the University of South Carolina (UofSC) led by Julius Fridriksson, Ph.D. Before completing his neurology residency at MUSC, Bonilha was an assistant research professor in the Department of Communication Sciences and Disorders in the Arnold School of Public Health at UofSC, and those professional ties helped to launch the Bonilha lab and have fostered continued collaboration.
“We are a strong group because of our collaborations. In fact, South Carolina is probably one of the best places in the country for aphasia research because of the pioneering work at UofSC and the synergism between our groups,” Bonilha said.
“There are no clear guidelines right now regarding which speech treatments are better for each patient,” said Janina Wilmskoetter, Ph.D., a postdoctoral scholar in Bonilha’s lab.
About 2 million people in the U.S. live with aphasia, according to the National Aphasia Association. Although aphasia can result from brain trauma or brain tumors, most often it is the result of a stroke. There are several subtypes of aphasia, but even within the same subtype, there is enough variability that the most effective treatment isn’t immediately apparent.
Language therapy is a well-established treatment for aphasia, but there are different types and it remains unclear how to best match a person with aphasia with the form of language therapy that would be most beneficial. “The choice of language therapy remains trial and error,” Wilmskoetter explained.
Bonilha’s team is working to provide clarity. He’s currently principal investigator on two aphasia studies funded by the National Institute on Deafness and Other Communication Disorders (NIDCD). The first study uses brain scans to understand the structural brain features common in patients who show improvement and how their brains change as a result of therapy, with the eventual goal of developing guideposts to match the right type of therapy to the right patient.
The second study is testing the results of a little-used type of language therapy called speech entrainment. It’s a therapy that Bonilha, along with collaborators at the University of South Carolina, has studied for several years. Bonilha and his team are expanding their understanding of how well this technique works with a five-year, multi-site study dubbed SpARc, or Speech Entrainment for Aphasia Recovery. Stroke survivors with non-fluent aphasia – meaning they can understand language and know what they want to communicate but have trouble getting out more than a few words at a time – who enroll in the study at MUSC, UofSC or the University of Utah will be divided into four groups: a control group that receives no treatment and groups that receive the therapy for three, four-and-a-half or six weeks.
Anna Doyle, manager of aphasia clinical trials in the Bonilha lab, said participants watch a video of a closeup of a person’s mouth speaking, then attempt to speak the words along with the video while wearing headphones to block out the sound of their own voices. Speech entrainment therapy takes advantage of a natural communication pattern in which people’s speech becomes more similar to each other’s over the course of a conversation, but in the therapy, all stimuli are blocked out except for the video and sound of the speaker’s mouth and voice.
Doyle, who worked as a speech language pathologist before turning to research, said she particularly likes this approach. Speaking can be frustrating for people with non-fluent aphasia because they’re aware of their errors yet can’t fix them. In this method, they simply keep going, mimicking the video speaker as best as they can without focusing on errors.
“The goal is for them to get out as many correct words as they can,” she said.
Participants will be assessed three months after treatment on the number of verbs per minute they can speak while engaging in both procedural and narrative storytelling. In other words, they’ll be asked to explain an everyday task, like how to make scrambled eggs, and to retell a common fairy tale, like the story of Little Red Riding Hood.
Verbs per minute was chosen as a measurement because verbs tend to be harder to use, Doyle said. It’s easier to point out an object and give it a name than to say what it does, especially once verb conjugation enters the picture. Verbs add significant meaning to a sentence and are part of what makes speech fluent, so it is a good measure to judge improvements in fluent speech for those with non-fluent aphasia.
This five-year study has just gotten underway with its first subject. Doyle said the COVID-19 pandemic somewhat delayed the study’s start and forced the organizers to get creative in delivering the therapy. Originally designed as an in-person therapy, the study will now be conducted virtually.
“I think it’s really great that we’re able to do it online, because our population is more vulnerable,” she said. “They’re really happy to be able to do it in the comfort of their own homes.”
While the SpARc study gets started, Wilmskoetter is using structural MRI scans to analyze the results of two aphasia studies led by C-STAR with the goal of understanding who is likely to respond to treatment and, ultimately, how to promote recovery in more patients.
One study, now completed, used transcranial direct current stimulation (tDCS), or electric stimulation of the brain, during language therapy to see whether it improved results. The second ongoing study, called Prediction of Outcome of Language Rehabilitation, or POLAR, compares semantic treatment to phonological treatment. In semantic treatment, patients learn to analyze the meaning of words. In phonological treatment, patients learn to analyze the sounds in the words they want to say.
Wilmskoetter isn’t directly analyzing the outcomes of each study to determine effectiveness of a particular treatment. Instead, she is comparing patients’ MRI scans with their results to determine which features in residual brain tissue can predict which patients are more likely to recover. Residual brain tissue is that which is not directly affected by the stroke.
From there, she’s looking at what happens in the brain when someone gets better. Researchers think that for people with lots of healthy white matter connecting language areas that are not affected by the stroke, their brains can recruit more nearby brain areas to take over additional language functions.
With all this information, the lab then wants to make the leap to figuring out how to elicit these positive brain structural changes after stroke to improve recovery.
Overall, the idea behind all of the lab’s work is to find how to match the best treatment to the right patient, she said, so that clinicians can look at a patient and determine that with this type of stroke and this type of brain health, one treatment or the other would be best.
“The idea is to find the best solution early on,” Wilmskoetter said.
The second line of research in the Bonilha lab is epilepsy. Epilepsy is one of the most common neurological disorders, affecting about 50 million people worldwide, according to the World Health Organization. Epilepsy can be caused by head injury or stroke, but in about half of cases, the cause is unknown, the WHO states. According to the Centers for Disease Control and Prevention, more than 53,000 people in South Carolina live with epilepsy.
Medication is often enough to control epilepsy in two thirds of patients. For the other third, surgery may hold the hope for cure.
The problem, said Ezequiel Gleichgerrcht, M.D., Ph.D., an epilepsy fellow who also conducts research in the Bonilha lab, is that doctors still can’t know whether a particular patient will benefit from surgery. About 30% of patients who receive surgery do not become seizure free.
“We still don’t understand why some people are different regarding their treatment response. And so far, none of the studies that use just the standard of care imaging – looking visually at the MRI or looking at the EEG or predicting the pathology they found when they look under the microscope – none of those variables alone or in combination predict accurately who will be seizure-free after the surgery,” he said.
Thus, the Bonilha lab is leading a five-year National Institutes of Health study taking place across five sites to come up with better predictions of who will benefit from epilepsy surgery.
The study builds on previous research conducted in the Bonilha lab. Past studies have been retrospective – meaning they looked back at previous patients’ records – and they were confined to MUSC patients. A single site study is somewhat limited in its findings, Gleichgerrcht said. More recently, a multi-site study with data from six busy academic epilepsy centers, led by MUSC’s Bonilha lab, demonstrated that the single-site findings could be replicated in independent samples using artificial intelligence methods.
This new study will gather data from Hofstra/Northwell in New York, Emory in Atlanta, the University of Pittsburgh and the University of Pennsylvania, and it will be prospective, meaning it will look at the records of current and future patients, once recruited.
“This is one of many outcomes that can be measured – seizure freedom. It’s a very important outcome because it’s the one that defines a lot of the patient’s quality of life. However, there are other contributors to quality of life.”
Ezequiel Gleichgerrcht, M.D., Ph.D.
The study won’t determine the care the patients receive. Their doctors will continue to make their best assessments as to whether the patients are good candidates for surgery and whether they should undergo laser ablation or resection.
“I think that’s what makes it a very attractive study. You’re still doing standard of care. No one gets more or less than if they were not participating,” Gleichgerrcht said.
Epilepsy patients already get MRI scans. For those who agree to participate in the study, their scans will be fed into a machine learning system. The computer has already developed an algorithm for likely success based on scans during previous studies, but as more scans and surgery results are entered, the computer will continually learn and hopefully find common features among those for whom the surgery worked.
The hope is that one day, an automated algorithm could offer a prediction, on an individual patient basis, about whether surgery would likely be successful, Gleichgerrcht said. There’s a long way to go before that point, he said, but this study is an important step forward.
And although this study doesn’t cover other beneficial outcomes, it’s possible that eventually other benefits could be predicted as well.
“This is one of many outcomes that can be measured – seizure freedom. It’s a very important outcome because it’s the one that defines a lot of the patient’s quality of life. However, there are other contributors to quality of life,” he said, listing among them memory and the ability to hold down a job.
Bonilha said Wilmskoetter, Doyle and Gleichgerrcht are great examples of the next generation of researchers who will become leaders in the field and generate medical discoveries to help people who suffer from these diseases.
“Being a clinician scientist is part of the commitment to medical discovery, which ultimately means improving treatment and improving outcomes.”