Fetal and neonatal origins of altered brain development
Introduction
There is growing evidence that abnormal development of the brain during gestation contributes to many neurological disorders that manifest throughout the entire lifespan. For example, epidemiological studies have shown that cerebral palsy, a heterogeneous group of non-progressive motor impairment disorders, appears to be more frequently the result of prenatal rather than perinatal or postnatal causes [1]. Schizophrenia, one of the most debilitating of mental disorders, affecting ∼1% of the population, cannot be accounted for entirely by genetic inheritance and it has been proposed that prenatal insults in individuals with risk factors (such as genetic inheritance) will lead to the development of the symptoms of schizophrenia in the teenage or young adult years [2]. Further examples of the importance of the critical in utero period for brain development include the association between intrauterine growth restriction (IUGR) and the later manifestation of cognitive, sensory and motor problems. There are clearly multiple mechanisms which impact on brain development including genetic background and changes in the intrauterine environment. This review focuses on hypoxic–ischemic injury, inflammatory/infective insults and preterm birth, summarizing the lesions, experimental models and mechanisms of injury.
Section snippets
Factors which can affect the normal development of the brain
The timing of gestational insults, their severity and their nature are likely to be important factors in determining the pattern of brain injury and the extent to which it will affect the function of the individual after birth.
Experimental animal models
The development of specific neuroprotective strategies for perinatal brain damage remains limited by the current lack of understanding of the cerebral pathologies and their causative pathways. Important insights into the nature of cerebral injury in the premature infant have been made with human autopsy studies [10]. However, with the markedly improved survival of the premature infant over the last decade and changing parental and medical attitudes, autopsy material has become increasingly
Key clinical guidelines
- 1.
Clinicians must recognize that patterns of cerebral injury vary according to gestational age at insult and the nature of insult. This will impact on the methods of diagnosis and the likely long-term consequences of the lesion:
- a.
Term infants with hypoxic–ischemic injury will suffer more neuronal injury with resulting seizures and combined cognitive and motor deficits.
- b.
Preterm infants with hypoxic–ischemic and/or inflammatory insults will suffer more primary cerebral white matter injury with
- a.
Directions for the future
- 1.
Considerable advances have been made in the neurobiological understanding of the nature of cerebral insults and their consequences to the immature brain. However we must continue to define the pattern and mechanisms of cerebral injury. Further development of animal models will help define the mechanisms while advanced MRI imaging techniques will assist in defining the pattern of injury in human brains.
- 2.
This information will underpin the development of rational neuroprotective strategies and
Acknowledgements
This work has been supported by grants from the NH and MRC (Australia) and NIH (USA). The assistance of Mr. Todd Briscoe in the preparation of the manuscript is gratefully acknowledged.
References (27)
- et al.
Novel treatments after experimental brain injury
Semin Neonatol
(2000) - et al.
Extracellular glutamate levels and neuropathology in cerebral white matter following repeated umbilical cord occlusion in the near term fetal sheep
Neuroscience
(2003) - et al.
Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia
Schizophr Res
(1999) - et al.
An animal model of chronic placental insufficiency: relevance to neurodevelopmental disorders including schizophrenia
Neuroscience
(2004) - et al.
Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits
Am J Obstet Gynecol
(1997) - et al.
Antecedents of cerebral palsy. Multivariate analysis of risk
N Engl J Med
(1986) - et al.
Neuropathology and the neurodevelopmental model. The neuropathology of schizophrenia
Prog Int
(2000) Neurology of the newborn
(2001)- et al.
White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term
AJNR Am J Neuroradiol
(2003) - et al.
Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion
J Neurosci
(1998)
Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn
Pediatr Res
Causes of cerebral palsy
Curr Opin Pediatr
Developmental neuropathology and impact of perinatal brain damage: III. Grey matter lesions of the neocortex
J Neuropathol Exp Neurol
Cited by (243)
Consequences of oxygen deprivation on myelination and sex-dependent alterations
2023, Molecular and Cellular NeuroscienceChange of gut microbiome structure in preterm infants with hypoxic ischemic encephalopathy induced by apnea
2023, Pediatrics and NeonatologyInterventions for the prevention or treatment of epidural-related maternal fever: a systematic review and meta-analysis
2022, British Journal of AnaesthesiaRemote and at-home data collection: Considerations for the NIH HEALthy Brain and Cognitive Development (HBCD) study
2022, Developmental Cognitive Neuroscience
- 1
Tel.: +61 3 9345 4830; fax: +61 3 9345 4840.