Nearly 15 million babies are born prematurely, or before 37 weeks of pregnancy, around the world each year.
When born too early, a baby’s immature respiratory center in the brain often fails to signal it to breathe, resulting in low oxygen levels, or hypoxia, in the brain.
Research published in the Journal of Neuroscience shows that even a brief 30-minute period of hypoxia is enough to persistently disrupt the structure and function of the brain region known as the hippocampus, which is vital for learning and memory.
“Our findings raise new concerns about the vulnerability of the preterm brain to hypoxia.
They are concerning for the long-term impact that oxygen deprivation can have on the ability of these preterm babies to learn as they grow to school age and adulthood,” said the study’s principal investigator, Stephen Back, M.D., Ph.D., Clyde and Elda Munson Professor of Pediatric Research and Pediatrics, OHSU School of Medicine, OHSU Doernbecher Children’s Hospital.
They are concerning for the long-term impact that oxygen deprivation can have on the ability of these preterm babies to learn as they grow to school age and adulthood,” said the study’s principal investigator, Stephen Back, M.D., Ph.D., Clyde and Elda Munson Professor of Pediatric Research and Pediatrics, OHSU School of Medicine, OHSU Doernbecher Children’s Hospital.
In the neonatal intensive care unit, preemies can experience up to 600 short, but impactful periods of hypoxia each week.
Consequently, more than one-third of babies who survive preterm birth are likely to have smaller brains, presumably due to brain cell loss, compared with the brains of full-term infants.
This can increase the risk of significant life-long neurodevelopmental challenges that will affect learning, memory, attention and behavior.
Using a twin preterm fetal sheep model, Back and colleagues studied the impact of both hypoxia alone, as well as in combination with ischemia — or insufficient blood flow — on the developing hippocampus.
The results confirm that, similar to human preterm survivors, growth of the hippocampus is impaired.
However, brain cells do not die as previously believed.
Rather, hippocampal cells fail to mature normally, causing a reduction in long-term potentiation, or the cellular basis of how the brain learns.
These findings are all the more unexpected because it was not appreciated that the preterm hippocampus was already capable of these learning processes. The image is in the public domain.
Remarkably, the severity of the hypoxia predicted the degree to which cells in the hippocampus failed to mature normally, explains Back.
These findings are all the more unexpected because it was not appreciated that the preterm hippocampus was already capable of these learning processes.
“We want to understand next how very brief or prolonged exposure to hypoxia affects the ability for optimal learning and memory, ” says Back.
“This will allow us to understand how the hippocampus responds to a lack of oxygen, creating new mechanisms of care and intervention both at the hospital, and at home.”
In addition to Back, OHSU researchers involved in the project include: Ev McClendon, Ph.D.; Kang Wang, Ph.D.; Kiera Degener-O’Brien; Matthew Hagen; Xi Gong, M.D.; Thuan Nguyen, M.D., Ph.D., Wendy Wu, Ph.D., and James Maylie, Ph.D.
Despite advances in neonatal and perinatal care, prematurely-born infants remain at high risk for brain injury (Ment et al., 2009) and neurodevelopmental impairment (Baron and Rey-Casserly, 2010).
Indeed, outcomes for infants with forms of brain injury common in this population, including intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH) and cystic periventricular leukomalacia(cPVL), are among the worst in newborn medicine, with rates of cognitive and motor deficits as high as 85% in some clinical populations (Rifai and Tawil, 2015).
Recent advances in neuroimaging have enabled improved characterization of the deleterious effects of premature birth and brain injury on brain growth and development, demonstrating regional and brain-wide effects. While these previous studies have demonstrated links between preterm brain injury and adverse neurodevelopmental outcomes, the mechanisms underlying these deficits remain unclear (Adams-Chapman et al., 2008; Anderson et al., 2017; Ment et al., 2005).
Across multiple neuroimaging investigations, reductions in both global and region-specific brain volumes have been demonstrated in preterm children in comparison to full-term (FT) peers.
Due to its integral role in learning and memory and associations with neurodevelopmental disorders, many studies have focused on the hippocampus, a component of the limbic system which rapidly develops from mid-gestation through the first years of life (Cheong et al., 2016; Nosarti et al., 2002; Omizzolo et al., 2013; Thompson et al., 2008).
Across these investigations, preterm children demonstrate impaired hippocampal growth (Beauchamp et al., 2008; Thompson et al., 2008) and folding (Thompson et al., 2013), changes attributed to clinical exposures including hypoxic-ischemic injury, glucocorticoid use and stress.
Further, these changes may be clinically significant, with smaller neonatal hippocampal volumes associated with worse cognitive performance during childhood (Beauchamp et al., 2008; Thompson et al., 2008).
While subjects with brain injury have been included in some prior studies, the effect of injury on hippocampal development was not an area of primary focus for these investigations.
Further, while white matter injury was associated with altered hippocampal development, most investigations included only limited numbers of subjects with brain injury of varying types and severities (Beauchamp et al., 2008; Thompson et al., 2008).
The pathogenesis of preterm brain injury is complex, encompassing both direct injury and widespread indirect pathology (Volpe, 2009). IVH is the most common form of preterm brain injury, typically occurring in the first three days of life in up to 31% of very preterm infants (VPT; born ≤32 weeks gestation) (Christian et al., 2016; Gale et al., 2017; Radic et al., 2015; Stoll et al., 2010, Stoll et al., 2015).
The combination of intraventricular blood and periventricular hemorrhagic infarction results in suppression of cell proliferation, white matter injury and release of inflammatory cytokines and free radicals, disrupting neural cell migration and progenitor cell formation (Del Bigio, 2011; Strahle et al., 2012; Whitelaw, 2001). High-grade IVH (i.e., Papile grade III/IV) leads to hydrocephalus requiring neurosurgical intervention in up to 28% of affected neonates (i.e., post-hemorrhagic hydrocephalus; PHH) (Christian et al., 2016).
PHH results from inflammation, blood breakdown product toxicity, ventricular wall disruption and cilia dysfunction, leading to impaired cerebrospinal fluid (CSF) absorption and flow through the ventricular system (Garton et al., 2016a; McAllister et al., 2017; Strahle et al., 2012). IVH-PHH has been strongly associated with poor outcomes, leading to disability across motor, cognitive, language and social domains in >50% of infants (Adams-Chapman et al., 2008; Ment et al., 2005). In comparison, cPVL, the most severe form of white matter injury occurring in <5% of VPT infants, results from focal, macroscopic necrosis which evolves to cystic change over weeks (Gale et al., 2017; Volpe et al., 2011). Although its pathogenic lesions are predominantly in white matter, cPVL also results in disrupted gray matter development and decreased gray matter volumes (Pierson et al., 2007; Tzarouchi et al., 2011). Despite its decreasing prevalence, the deleterious neurodevelopmental effects of cPVL are well-established and remain severe, with links to motor, cognitive, speech/language, hearing and vision impairment (Anderson et al., 2017; Hamrick et al., 2004).
While the pathogenesis of these forms of brain injury and their sequelae are well-characterized, their regional impact on developmentally important structures, including the hippocampus, remains unknown. Critically, the ventricles have a large surface area adjacent to numerous subcortical structures, including the hippocampus.
Thus, ventricular/periventricular injury and inflammation, such as that occurring in association with IVH, PHH and cPVL, place the hippocampus and other periventricular structures at unique risk for injury due to their anatomic proximity (Cherian et al., 2003). In addition, our preclinical models demonstrate increased neuronal death and smaller hippocampal volumes after IVH with PHH (Garton et al., 2016b; Lekic et al., 2012).
Further, in rodent models, intracranial hemorrhage in combination with IVH, a scenario mimicking neonatal grade IV IVH, results in greater neuronal death in the hippocampus and worse cognitive outcomes compared to IVH alone (Chen et al., 2015).
This constellation of preclinical findings suggests the hippocampus may be uniquely susceptible to clinically significant effects of IVH, PHH and cPVL (Cai et al., 2001; Debillon et al., 2000; Field et al., 1993; Hagberg et al., 2002; Marumo et al., 2001; Uehara et al., 1999). However, few studies examining the effects of preterm brain injury on morphological development of the human hippocampus have been performed.
We leverage advanced neuroimaging acquisition and analytic techniques to investigate the effects of preterm brain injury, including IVH, PHH and cPVL, on neonatal hippocampal development and neurodevelopmental outcomes at age 2 years in VPT children. F
or these investigations, we hypothesized that: 1) infants with grade III/IV IVH, PHH and cPVL would have smaller hippocampal volumes than VPT infants with no to mild brain injury and FT infants, with infants with PHH demonstrating the smallest hippocampi; 2) increased ventricular size due to brain injury would relate to smaller hippocampal volumes; and 3) smaller hippocampal size would relate to worse neurodevelopmental outcomes, with group- and domain-specific effects.
Source:
Oregon Health and Science University
Media Contacts:
Tracy Brawley – Oregon Health and Science University
Image Source:
The image is in the public domain.
Original Research: Closed access
“Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons”. Evelyn McClendon, Kang Wang, Kiera Degener-O’Brien, Matthew W. Hagen, Xi Gong, Thuan Nguyen, Wendy W. Wu, James Maylie and Stephen A. Back.
Journal of Neuroscience. doi:10.1523/JNEUROSCI.1364-19.2019
