Vitae annual report 2007, Vol. 30 No. 2 

Baby's Breath of Life

	The entire team is assembled: at front, David Paydarfar, MD; Elisabeth Salisbury, PhD; Premananda Indic, PhD; Xuanxuan Gan; Frank Bednarek, MD; Peter Grigg, PhD; and Daniel Robichaud.

At UMass Medical School, clinicians, basic scientists, engineers and a mathematician team up to help premature babies breathe easy. 

A sleeping baby, snug in bed, is emblematic of contentment and security. But for some of the approximately 12 percent of babies born prematurely each year in the United States, sleep can be a precarious state during which the essential act of breathing can pose a life-threatening challenge. Now, a multidisciplinary team of researchers at UMass Medical School is employing strategies gained from non-traditional approaches to identify the causes of infant apnea for the development of life-saving treatments. 

At forty weeks in utero, most babies are prepared for the transition from gaining oxygen from the placenta to gaining it from the air; in premature babies, however, the area of the central nervous system that controls breathing hasn’t matured enough to allow for nonstop breathing outside of the womb. As a consequence, premature infants experience—often during sleep—periods of shallow or stopped breathing, a serious medical condition known as apnea of prematurity (AOP). 

AOP is found in more than 50 percent of premature infants, according to 2006 statistics from the National Institutes of Health, and is almost universal in the smallest of those preemies. Defined as pauses in breathing that last for more than 20 seconds, apnea is often also associated with bradycardia, a decrease in the number of heart beats, as well as lower oxygen levels in the blood. Although clinicians in Neonatal Intensive Care Units (NICU) across the country are able to successfully treat apnea with pharmaceutical interventions, investigators have yet to understand the effects of AOP or those treatments on an infant’s long-term health.  David Paydarfar, MD, UMMS professor of neurology and physiology, is intrigued by the mysteries of AOP. As a physician-scientist, he is particularly interested in the brain’s control of respiration and the consequences when that system goes awry or is immature, as in the case of apnea. During the past three years, Dr. Paydarfar has established a multidisciplinary effort—comprising clinicians, basic scientists, engineers and a mathematician—aimed at better understanding and treating infant apnea through a number of unique approaches. 

	A cart containing all the necessary equipment for an infant study allows Elisabeth Salisbury, PhD, (above) and her colleagues in the NICU to wheel the system to the bedside of infants, who are studied with all of their usual monitoring apparatus. The cart contains two computers, one for recording signals and one that triggers a special mattress (placed in the isolette and pictured here) to provide gentle vibrations to the infant. Sensors attached to the infant record breathing and apnea, heart rate, skin temperature, oxygen levels, sleep and movement over the six to eight hours of the study. Other sensors record light and sound levels and air temperature. Here, Salisbury reviews signals that were previously recorded in a premature infant.

One such approach pairs neurobiology and physiology to determine the role of sensory stimulation on the breathing mechanism. When an infant stops breathing, a nurse or other caregiver may touch or rub the infant to encourage inhalation. This type of manipulation often wakes the infant, however, disturbing essential rest. In order to develop interventions that may restart breathing without waking the baby, investigators must understand the relationship between sensory signals and the breathing mechanism.  “Everyone has been focused on the moment when the infant stops breathing, but I believe the question is, ‘How can we prevent this to begin with?’” Paydarfar said. “Our group is conducting basic science and clinical studies to figure out not only how sensory processing normally functions in respiratory control, but also how the system experiences problems in an immature infant. Then we can begin to explore what sensory stimuli might make it work better.” 

To explore how sensory neurons function and sensory signals enter the brain to affect the breathing mechanism, Paydarfar recruited Peter Grigg, PhD, professor and interim chair of physiology and an expert in the field of sensory physiology, to develop an animal model of infant apnea. “Engineers are often inclined to solve a sensory problem with a hammer, where a feather might be better,” Dr. Grigg said. “For example, to stimulate a child with apnea, we expect that a puff of air is actually more effective than a gentle thump. Due to the obvious limitations of studying infants, we can understand these significant differences by working with animal models.” 
To test the clinical implications of discoveries in animal models, Paydarfar recruited Elisabeth Salisbury, PhD, assistant professor of neurology and pediatrics, to investigate how sensory stimulation affects breathing in premature infants.

In addition to physiology, technology offers a variety of tools that can provide insights into what may trigger an apnea episode. Investigators record dozens of biological signals from affected infants in response to temperature, light or stage in the sleep cycle. These signals produce an extraordinary amount of data that must be collected, stored and analyzed for clues to the causes of apnea.
“We are doing experiments with many variables; they may be connected to an outcome of apnea, but the question becomes, ‘How do you make conclusions when you have such a large number of variables?’” Grigg said. 

To address this problem, research engineers Daniel Robichaud II and Xuanxuan Gan, and mathematician and electrical engineer Premananda P. Indic, PhD, instructor in neurology, joined the team. According to Robichaud, who is responsible for streamlining and simplifying the software that analyzes the data from animals and humans, the work has fortified his commitment to biomedical informatics.  “I enjoy the project because what I do has the real result of helping little ones down the road. It also makes a great answer to the inevitable question of, ‘What good is your research?’ There is a very real and significant answer.”  Gan, who was recruited to build bioinstrumentation to better and less invasively gather the data while also developing software to create predictions of clinical outcomes based on the information, has also gained an appreciation for the collaborative process. “When I see our predictions link together with the actual activity of infants in the NICU, I am truly gratified,” she said. 

Dr. Indic jokes that, when he was recruited to the group, he felt like the outsider. “I used to feel like an alien because I had a background in math and theoretical analysis. But I could immediately appreciate the enormity of the problem and knew that I could apply concept and theory to the effort to solve it.”

Specifically, Indic uses mathematical approaches to understand the neural activity of the breathing mechanism—how neurons communicate with one another. Because the neurons are in motion, or oscillating, and firing rhythmically, it is particularly challenging to explore the signals that encourage or disrupt neuronal communication and affect the ability to breathe. 

“Math helps because it makes predictions that are not intuitive,” said Paydarfar. “If we can model in advance some of our theories of how certain signals impact function, it can ultimately affect how we conduct our clinical studies.” 

Clinical trials are at the heart of this multidisciplinary research effort. Using the UMass Memorial Medical Center NICU as a living laboratory, Paydarfar and colleagues are able to systematically evaluate the technologies and strategies derived from their bench research. UMass Memorial Medical Center Chief of Neonatology Francis J. Bednarek, MD, professor of pediatrics and obstetrics & gynecology, has been at the forefront of the treatment of premature infants for more than three decades and was eager to join Paydarfar’s team. “In the three decades since I began my neonatology career, most investigations have been focused on the moment the apnea occurs. I think one of the reasons more progress hasn’t been made is this focus on the terminal event and not the factors that lead to it. That is why our studies are so exciting,” Dr. Bednarek said.  As medical safety officer for investigations in the NICU, Bednarek provides crucial insight into those approaches that will work for clinical trials. 

“Working in the NICU is a unique opportunity because it is not just the medical personnel who are seeing clinical data for the first time. Viewing the output, parents can see—physiologically—what happens when there is a pause in breathing. That is a powerful thing that reinforces why this research is so important,” Bednarek said. 

Dr. Salisbury directs the clinical studies and guides not only parents through the process, but also her fellow scientists as she helps them acclimate to the sensitivities of working within such an environment. “To do a bedside study, you have to be at the bedside. I bring the engineers to the NICU so that they understand the impact of their interventions on the environment and the infant,” said Salisbury. In addition to the supportive parents and her colleagues, Salisbury credits the success of the trials to the extraordinary cooperation of the nurses and physicians on Bednarek’s staff. “The parents who participate in this vital research are coming from a very traumatic place, and the nurses are rightfully very protective. We didn’t just walk in the door and say, ‘This is what we’re doing.’ Instead, we said, ‘These babies are under your care and we would like to work with you.’” 

According to Paydarfar, the successful launch of this research initiative owes much to the collaborative spirit at UMMS and UMass Memorial. “We have been able to get everyone involved as stakeholders because they realize that the research is related to treatment and that we are trying to advance knowledge while we take care of these infants,” he explained. “Everyone participates with enthusiasm and commitment.” 

While a complete understanding of the causes of infant apnea could be years away, Paydarfar is confident that with the team he has assembled from so many disciplines, progress will bring the possible causes into view. “Ideally, with advanced technologies that incorporate insights from neurology, physiology and mathematical modeling, we can prevent apnea before it starts,” he said. “We want to develop technology that stimulates the infant before the apnea occurs. Whatever we come up with may help thousands of other infants—or maybe it won’t—but the key is that we’re not giving up.”