"Deficits linked to pre-term births are an important and poorly understood cause of neurological morbidity.In Science Translational Medicine, Dean et al report studies that used elegant structural analyses of brain development in a strategically chosen animal model of human pre-term birth. Their findings of a disruption in neuronal development, and especially in connectivity, provide a new framework to understand the pathophysiology of this important clinical problem.Incisive translational studies like these are the essential early foundations of better diagnostics, and eventually, therapeutics."
- Eric Orwoll, M.D.
Associate Dean for Clinical Science
February 26, 2013
Research conducted at OHSU Doernbecher Children's Hospital challenges long-held belief that low blood flow to the premature brain necessarily kills brain cells
Researchers in the Stephen Back Labare challenging the way pediatric neurologists think about brain injury in the pre-term infant. In a study titled, Prenatal Cerebral Ischemia Disrupts MRI-Defined Cortical Microstructure Through Disturbances in Neuronal Arborization, published online in Science Translational Medicine, the researchers report for the first time that low blood flow and oxygen to the developing brain does not, as previously thought, cause an irreversible loss of brain cells, but rather disrupts the cells' ability to fully mature. This discovery opens up new avenues for potential therapies to promote regeneration and repair of the premature brain.
"As neurologists, we thought ischemia killed the neurons and that they were irreversibly lost from the brain. But this new data challenges that notion by showing that ischemia, or low blood flow to the brain, can alter the maturation of the neurons without causing the death of these cells," said Stephen Back, M.D., Ph.D., lead investigator and professor in the department of pediatrics, in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital.
As a result, Dr. Back said his team can focus greater attention on "developing the right interventions, at the right time early in development, to promote neurons to more fully mature and reduce the often serious impact of preterm birth. We now have a much more hopeful scenario to potentially improve outcome from premature birth."
Researchers at OHSU Doernbecher have conducted a number of studies in preterm fetal sheep to define how disturbances in brain blood flow lead to injury in the developing brain. Their findings have led to important advances in the understanding of the causes of brain injury in critically ill newborn infants.
For this study, Dr. Back and colleagues used pioneering high field MRI studies that they recently found allows injury to the developing brain to be identified much earlier than previously feasible (Riddle et al., Annals of Neurology, 2011). They applied high field MRI to look at the cerebral cortex, or "thinking" part of the brain, which controls the complex tasks involved with learning, attention and social behaviors that are frequently impaired in children who survive preterm birth. Specifically, they observed how brain injury in the cerebral cortex of fetal sheep evolved over one month and found no evidence that cells were dying or being lost. They did notice, however, that more brain cells were packed into a smaller volume of brain tissue, which led to, upon further examination, the discovery that the brain cells weren't fully mature.
In a related study published in the same online issue ofScience Translational Medicine, investigators at The Hospital for Sick Children and the University of Toronto studied 95 premature infants using MRI and found that impaired growth of the infants was the strongest predictor of the MRI abnormalities, suggesting that interventions to improve infant nutrition and growth may lead to improved cortical development.
"I believe these studies provide hope for the future for preterm babies with brain injury, because our findings suggest that neurons are not being permanently lost from the human cerebral cortex due to ischemia. This raises the possibility that neurodevelopmental enrichment — or perhaps improved early infant nutrition — as suggested by the companion paper, might make a difference in terms of improved cognitive outcome," said Dr. Back.
"Together, these studies challenge the conventional wisdom that preterm birth is associated with a loss of cortical neurons. This finding may change the way neurologists think about diagnosing and treating children born prematurely," said Jill Morris, Ph.D., a program director at the National Institute's of Health's National Institute Neurological Disorders and Stroke.
More than 65,000 premature babies are born in the United States each year. Children who survive preterm birth commonly suffer from a wide range of life-long disabilities, including impaired walking due to cerebral palsy. Currently, children have a 10 times greater risk of acquiring cerebral palsy than of being diagnosed with cancer. By the time they reach school age, between 25 and 50 percent of children born prematurely are also identified with a wide range of learning disabilities, social impairment and attention deficit disorders.
TOWARD THE FUTURE
For the last 15 years, a focus of the Back Lab has been on human brain development and how injury to the brain occurs. They specifically focused on white matter injury, which is particulary common in preterm survivors. Moving forward, the lab has shifted toward a broader investigation of the human brain, by integrating their understanding of white matter injury and gray matter injury, and investigating how the two might conspire to create the cognitive learning disabilities that preterm babies sustain throughout life.
"Since preterm survivors display such a broad range of behavioral disabilities, my lab is interested in looking more broadly at the network of related brain regions that may be affected in these children," said Dr. Back. "Having a integrated understanding of the brain injury, will provide us with better clues as to how and why these disorders develop. Additionally, we need to do more work to figure out how persistent this affect throughout the life of a child. Does it stay with them for their lifetime? Or is it a transient disturbance that disrupts brain development during a critical period?"
While the paper represents a major push by the Back team to redefine how insults to the brain affect its development, the research could also have far reaching implications beyond their own study of hypoxia and ischemia, by extending into neurodevelopmental disorders related to prematurity such as autism and anesthesia exposure-related cognitive and learning disabilities.
"For many disorders where the brain appears to be functioning normally, our work might show that when you dig deeper and look more carefully at the fine structure of the neurons, you realize that they aren't developing normally," said Dr. Back. "As science becomes increasingly collaborative, our work could help lead to breakthroughs in other areas."
Top Photo: Dr. Back
Figure 1: During normal brain development in our fetal model, neurons (brain cells) rapidly grow processes called dendrites that allow them to communicate with other neurons. In panel A, a neuron equivalent to that from a 28-week-old human fetus displays very few dendritic processes and appears very simple. Panel B shows that four weeks later, neurons appear to be much more complex with many dendritic processes and branches present
Figure 2: When fetal brains are exposed to decreased oxygen and blood flow (hypoxia and ischemia), the neurons do not appear to mature normally. On the left is a tracing of a brain cell (neuron) from a control (Con) animal showing normal development of its complex branching pattern. On the right is a tracing of a neuron of the same age as the control, which was exposed to a brief period of hypoxia/ischemia (HI). This cell displays fewer processes and a simpler branch pattern. Thus, despite being the same age as the control animal, brain cells in the HI animal are more immature
Figure 3: In the companion paper by Vinall et al., MRI anisotropy measurements of water diffusion demonstrated that human cortical development is abnormal in survivors of preterm birth. Here we address the cellular basis for the abnormal cortical MRI.
The figure on the left (A) is the cortical neuron tracing that was used to generate the 3D structure on the right (B). From the 3D structure in B, a calculation of theoretical water diffusion along the cell’s processes was generated. With this approach, it was determined that water diffusion (anisotropy) was abnormal in the immature cells from the ischemic animals when compared with controls.
The anisotropy disturbances predicted from the cell-based calculations were in close agreement with the anisotropy disturbances detected by MRI of the cerebral cortex.
Thus, the cortical MRI abnormalities observed in the preterm survivors were in close agreement with the predictions of abnormal water diffusion calculated from the structure of the individual cortical cells.
- This article is based on a media release previously published by OHSU
Justin Dean, Ph.D.
Evelyn McClendon, PhD
Kelly Hansen, BA
Aryan Azimi-Zonooz, MD
Kevin Chen. BA
Arty Riddle, PhD
Xi Gong, MD
Elica Sharifnia, BA
Matthew Hagen, BA
Tahir Ahmad, BA
Lindsey Leigland, Ph.D.
A. Roger Hohimer, Ph.D.
Chris Kroenke, Ph.D
Stephen Back, M.D.
About the Paper of the Month
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.
More Published Papers
The entire list of OHSU papers published this month is here.