A Deep Dive Into
Neuroscience through the Lifespan from Cells to Society
From revolutionary stroke and epilepsy research to infant brain development to new potential treatments for Alzheimer’s disease, neuroscience discoveries at the University of Virginia have helped patients at every stage of the life cycle and led researchers to a better understanding of the human body’s most important organ.
Now, catalyzed by the UVA Brain Institute, scientists, researchers and clinicians are building on those discoveries and taking crucial next steps. How can we prevent seizures? How can we foster brain development in premature babies? Can we stop Alzheimer’s in its tracks?
“At UVA, our researchers are working on everything from basic science research, changing how we fundamentally understand the brain, to clinical trials that make a difference in patients’ lives every day,” said Jaideep Kapur, Eugene Meyer III Professor of Neuroscience, professor of neurology and director of the Brain Institute. “This work is making a difference from birth through aging, and it is exciting to be a part of.”
Take a look at some of the most significant, life-changing neuroscience discoveries to come out of UVA in recent years, and look ahead to many more.
Improving Care for Strokes
If you experience a stroke, the rapid treatment protocols that medical providers take you through can be traced back to UVA and neurology and neurosurgery professor Dr. E. Clarke Haley, Jr.
Haley, who retired in 2016 after 40 years at UVA, studied the use of the clot-busting drug alteplase to treat acute ischemic stroke. His research helped establish the drug as the standard of care, and also helped develop a series of rapid treatment protocols focused on treating acute stroke as an emergency and transporting, evaluating and treating the patient within 90 minutes of onset. His work led to researching the next generation of clot busters (tenecteplase), which has now become the standard at UVA.
Haley’s entire body of work has helped improve outcomes and quality of life for stroke patients. Now, researchers like Dr. Karen C. Johnston, the Harrison Distinguished Professor of Neurology and associate vice president for clinical and translational research, are carrying that work forward. Johnston has been carrying out large acute stroke clinical trials nationally and recently led the work that demonstrated the best treatment for high blood sugars in acute stroke patients.
Confronting the Dangers of Epilepsy
In addition to stroke research, UVA is known as a leader in the study of epilepsy, building on the leadership of Professors of Neurology Dr. Fritz E. Dreifuss and Dr. Eric Lothman. Dreifuss and Lothman founded UVA’s Comprehensive Epilepsy Program in 1977 and together developed clinical classifications for epilepsy and seizure that are still in use today.
“Their legacy lives in our research and our clinical endeavors,” said Shure Professor of Neurology and Pediatrics Dr. Howard Goodkin, director of the Division of Pediatric Neurology and chair of UVA’s Department of Neurology.
“There is a great breadth of epilepsy research here, from very clinical to very basic science questions,” Goodkin said. “By my count, we have among the largest number of people devoted to epilepsy research in the country.”
Many are concentrated on status epilepticus, a condition marked by prolonged or recurrent seizures. Researchers at UVA defined the mechanisms of the collapse of brain inhibition during these seizures and the measures that can be taken to restore normal function. These discoveries led to the Established Status Epilepticus Treatment Trial, a multi-center, federally funded trial based at UVA, aiming to improve the treatment of status epilepticus in children. That trial, led by Kapur, was completed in 2019, providing definitive scientific evidence on treatment of prolonged seizures and shaping treatment guidelines in the U.S. and internationally.
Other recent research has explored the use of advanced imaging to target treatment in the brain, learned why some seizures prove deadly, examined emergency drugs to treat status epilepticus and, in July, identified a brain repair process that could help treat seizure-related brain injuries.
Brain Development, From Birth Onward
Some neuroscience discoveries at UVA focus on the UVA Medical Center’s smallest patients: premature babies in the Neonatal Intensive Care Unit.
Neurobiologist Jianhua “J.C.” Cang, for example, studies the connection between what we see and how our brain processes our vision – a critical connection that begins in the hypersensitive neonatal period when the brain’s neural system is forming. His and his colleagues’ 2010 discovery, demonstrating that this period of plasticity is critical for vision later in life, is in most textbooks. In the Department of Psychology, Assistant Professor of Neuroscience Adema Ribic is studying the impact of preterm birth on visual cortex development in preterm mice, and the impact of visual enrichment on brain responses to visual stimuli in preterm babies in the NICU.
Dr. Karen Fairchild, a neonatologist and professor of pediatrics, is the principal investigator on a federally funded multicenter clinical trial called “VentFirst.” The study, begun in 2016, aims to reduce intraventricular hemorrhage – a brain bleed seen in about 30% of extremely pre-term babies – by examining the benefits of helping extremely preterm babies breathe before clamping the umbilical cord. The current standard of care calls for assisting breathing and giving oxygen after clamping the cord. Fairchild and her team hope that delaying cord clamping could help ease pressure changes in the brain that might lead to bleeding. The trial is ongoing, with results expected next year.
In addition to the VentFirst trial, Fairchild identified several other areas of research at UVA related to infant brain development. These include predictive analytics, using a baby’s vital signs to predict risk of brain injury and disability; and near infrared spectroscopy, or NIRS, monitoring. The technology has been used for decades in anesthesia and other units to monitor the amount of oxygen in organs like the brain, but UVA is one of five U.S. sites participating in an international study using NIRS in the NICU, testing it against the standard method of monitoring oxygen in the blood.
UVA is also conducting inpatient and outpatient neurological rehabilitation studies; one led by Dr. Santina Zanelli and Dr. Lisa Letzkus studying interventions parents can do with their babies to improve brain development; and one, led by Dr. Jennifer Burnsed, teaching parents physical therapy and play therapy techniques after their child is discharged.
Meghan Puglia, a developmental cognitive neuroscientist and assistant professor of neurology, is the principal investigator of a new NIH-sponsored study of baby brain development to identify the early emerging brain characteristics that can predict atypical development even before the behavioral symptoms of disorders like autism can be seen. This work will allow for earlier intervention, which can drastically improve developmental outcomes.
Finally, Dr. Katheryn Frazier directs a follow-up clinic at UVA Children’s monitoring high-risk patients from the time they are discharged until they are 2 years old, specifically focused on motor development, language and problem-solving. Fairchild said they are working to expand coverage through age 5, when the children start school.
How the Brain Cleans Itself
In 2016, Jonathan Kipnis, at the time a professor neuroscience at UVA, made a stunning discovery that prompted fellow UVA neuroscientist Kevin Lee to declare, simply, “They’ll have to rewrite the textbooks.” Essentially, Kipnis and his team spotted an entire structure in the body that neurologists were not aware of, a network of vessels that connect the brain directly to the immune system.
In a healthy brain, these vessels seem to act as a cleaning mechanism, removing built-up proteins, for example. Since that 2016 discovery, UVA researchers have been working to understand what happens when the brain does not clean itself, a factor in a wide range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases and even simply aging.
In 2020, graduate student researcher Catherine R. Lammert and neuroscience professor John Lukens published research linking the improper removal of faulty brain cells to lifelong neurological issues. In such cases, cells with damaged DNA are not removed from the central nervous system, as they normally would be, but are instead incorporated into it, resulting in accumulating DNA damage in the brain. Lammert and Lukens linked the issue to a wide range of neurological disorders, from loss of movement control, called ataxia, to Alzheimer’s and Parkinson’s diseases or autism.
UVA researchers have also made several important discoveries about autism, which affects one in 59 American children.
New research published in April shows how autism spectrum disorders manifest differently in boys and girls. Combining genetic research with brain imaging, researchers including UVA’s Kevin Pelphrey and John D. Van Horn identified differences in genes and the “genetic burden” of the condition in boys and girls, and ways the brains of girls with autism spectrum disorders respond differently to social cues than girls without autism.
Another study, led by Lukens, got a lot of attention in 2018 when it linked autism risk in babies to the health of the mother’s microbiome – the collection of organisms naturally living in our gut – during pregnancy. That discovery opened new avenues of potential treatments that Lukens and others are investigating.
UVA’s Supporting Transformative Autism Research, or STAR, initiative, based in the School of Education and Human Development, brings together a vast array of autism research across Grounds, aiming to spark discovery, improve care, and equip communities – from medical providers to teachers or caregivers – to support people with autism. Led by Micah Mazurek, the Novartis U.S. Foundation Professor of Education, the initiative has trained more than 1,060 individuals, facilitated 71 research studies and supported 108 peer-reviewed publications from collaborators.
Overall, as Pelphrey, the Harrison-Wood Jefferson Scholars Foundation Professor, put it in this 2019 story, there are many reasons to be optimistic about our understanding and treatment of autism. “We have progressed from identifying the differences in how the brain functions in autism to being able to predict how an individual child will respond, and how best to intervene and optimize their development,” he said.
Changing the Trajectory of Aging and Alzheimer’s
As some UVA neurologists work to give babies the best possible start in life, many others are working to improve cognitive function as we age. UVA’s Memory Clinic sees more than 1,500 patients annually and the Virginia Alzheimer’s Disease Center within the Brain Institute is leading transformative aging research that spans from understanding the disease at a cellular level to exploring its social impact.
On the research side, George Bloom, a professor of biology, cell biology and neuroscience, leads a research program dedicated to Alzheimer’s, studying how brain cells change as the disease progresses. One important discovery out of his lab, in concert with several other labs, demonstrated that toxic forms of a protein called amyloid beta can damage a healthy protein, called tau, and essentially turn it against the brain, killing neurons and causing synapse failure. This destruction often happens years before Alzheimer’s symptoms begin, Bloom said, and he hopes the discovery will lead to new drugs to disrupt that process. Bloom has also partnered with a team of investigators across the University to take findings from his lab about Alzheimer’s prevention to human trials.
UVA scientists have also done a lot of work around concussions and traumatic brain injuries, studying both how to treat patients and how these injuries can affect the brain long-term, including increasing the risk of Alzheimer’s.
In 2020, for example, a research team led by John Lukens of UVA’s Department of Neuroscience and Center for Brain Immunology and Glia, found that even mild concussions can impair the brain’s ability to cleanse itself of toxins, raising the risk of Alzheimer’s disease, dementia and other neurodegenerative problems. At the time, Lukens said the research reinforced the need to give people – especially athletes, military service members and others at high risk – time to heal after a blow to the head.
Another recent finding, published in September by Dr. Heather A. Ferris of UVA Health’s Division of Endocrinology and Metabolism, linked cholesterol manufactured in the brain to the development of Alzheimer’s.
Aside from treating patients themselves, many at UVA are also focused on treating those caring for people with dementia or Alzheimer’s. Caregivers can make a tremendous difference in their loved one’s life, but often at great cost; they are more likely to have poorer quality of life and poorer health markers than non-caregivers.
UVA researchers and clinicians aim to provide support to caregivers both in person during clinic visits and via technology, such as an in-home system developed by BP America Professor of Computer Science Jack Stankovic. The system monitors caregivers’ stress levels and, when needed, provides prompting texts with suggested ways to settle down or take a quick break.
“Our current health care system for people with dementia relies significantly on unpaid caregivers, and often those caregivers are spouses, the same age or older than those with dementia,” said Carol Manning, Harrison Distinguished Teaching Professor of Neurology, director of the Memory and Aging Care Clinic and director of the Virginia Alzheimer’s Disease Center. Studies have found that caregivers of people with dementia are at increased risk for dementia themselves, relative to people who are not caregivers.
“There is no cure for dementia, but we do know of some modifiable risk factors, such as diet, exercise and sleep,” Manning said. “Our caregivers are in the best position to modify those risk factors in patients, and our research examines how we can provide the best support for caregivers so that they can provide optimal care and improve patient outcomes.”
Many risks are higher among underserved patient populations. Ishan Williams, an associate professor of nursing, studies quality of life among caregivers, particularly focused on rural, underserved and often marginalized racial and ethnic populations. Her work helps to support caregivers and patients as patients age, and incorporates health policy, looking at how governments and communities can support patients and caregivers.
Focused Ultrasound Blazes New Trails
UVA is also home to some of the most notable breakthroughs in the use of focused ultrasound technology, which allows physicians, guided by an MRI machine, to target specific areas of the brain with heat generated by concentrated, high-intensity soundwaves.
Dr. Jeffrey Elias, a professor of neurosurgery and director of UVA’s Stereotactic and Functional Neurosurgery Department, was among the first in the world to use focused ultrasound technology to treat essential tremor, a condition akin to Parkinson’s disease. Some of his patients went from not being able to steadily hold a pen or a drink to having full, steady use of their hands.
Elias is now examining how focused ultrasound can help with other symptoms of Parkinson’s disease, and his colleagues around UVA are applying the technology to other conditions, including metastatic breast cancer cells and glioblastoma – the deadliest brain tumor.
Elias, Associate Professor of Psychiatry and Neurobehavioral Sciences Wendy Lynch, Assistant Professor of Neurological Surgery Dr. Chang Chia Liu and others are also studying applications in the fight against addiction and chronic pain. There are two clinical trials in progress, one using focused ultrasound to treat neuropathic pain from nerve injuries and one treating pain associated with cancer.
Interoception and Immunology
Advancing technology and research has brought scientists closer to understanding inner workings of the brain that have been obscured for centuries. For example, some scientists at UVA are focused on an internal sense called interoception, often referred to as the body’s “sixth sense.”
This is the sense that responds to internal sensations – telling us when we are hungry, when we feel pain, when we need to breathe. Neuroscientist Doug Bayliss, professor and chair of the pharmacology department, said interoception is just as important as any of the five well-known senses.
“Interoceptive systems should get equal attention, because they have important consequences for everything from how we breathe to how we control eating, sleep, blood pressure or pain,” Bayliss said in a Q&A about the concept.
Bayliss’ lab studies how the brain controls breathing with sensors that detect higher levels of carbon dioxide needing to be exhaled. He and retired pharmacology colleague Patrice Guyenet are studying abnormalities in those sensor neurons, which could lead to conditions like congenital hypoventilation syndrome, a rare disorder that causes patients to stop breathing during sleep. Other UVA researchers are studying hunger, how the immune system senses pathogens and connections between the brain and the microbiome in our gut. [UVA researchers have connected the microbiome to numerous health concerns.]
The research on interoception ties into another advancing area of interest: neuroimmunology, or the combined study of the central nervous system and the immune system. Current UVA research is building on Kipnis and company’s groundbreaking 2016 discovery of vessels linking the brain and the immune system.
For example, a lab led by assistant neuroscience professor Upkong Eyo is studying microglia, a type of immune cell resident in the brain. Understanding how microglia help regulate brain development could help researchers understand behavioral or developmental disorders and neurodegenerative diseases like Alzheimer’s.
Associate professor Tajie H. Harris and researchers in her lab are using advance imaging to map out the vessels that the Kipnis team discovered in 2016 and to understand how the immune system functions in the brain. One example Harris has worked in is the brain’s reaction to Toxoplasma gondii, a parasite that affects about one-third of the world’s population. Many infections are asymptomatic, but acute infections can lead to systemic disease.
A new addition to the UVA team, Harald Sontheimer, also brings extensive expertise in this field. Sontheimer, who joined UVA earlier this year and was just named chair of the Department of Neuroscience, has led labs and a startup biotechnology company devoted to novel treatments for brain cancer. He founded the center for Glial Biology in Medicine at the University of Alabama at Birmingham and the School of Neuroscience at Virginia Tech before coming to UVA.
“UVA has a vibrant and collegial neuroscience community where team science makes major discoveries possible,” Sontheimer said. “The historical strength particularly in neuroimmunology, epilepsy and neuro-oncology, three areas I personally work in, were a major draw for me to join UVA.”