What is the pathophysiology of inflammation-induced cortical injury in the perinatal brain?

Abstract

Perinatal exposure to infection/inflammation is highly associated with neural injury, and subsequent impaired cortical growth, disturbances in neuronal connectivity, and impaired neurodevelopment. However, our understanding of the pathophysiological substrate underpinning these changes in brain structure and function is limited. The objective of this review is to summarize the growing evidence from animal trials and human cohort studies that suggest exposure to infection/inflammation during the perinatal period promotes regional impairments in neuronal maturation and function, including loss of high-frequency electroencephalographic activity, and reduced growth and arborization of cortical dendrites and dendritic spines resulting in reduced cortical volume. These inflammation-induced disturbances to neuronal structure and function are likely to underpin subsequent disturbances to cortical development and connectivity in fetuses and/or newborns exposed to infection/inflammation during the perinatal period, leading, in the long term, to impaired neurodevelopment. The combined use of early electroencephalography monitoring with neuroimaging techniques that enable detailed evaluation of brain microstructure, and the use of therapeutics that successfully target systemic and central nervous system inflammation could provide an effective strategy for early detection and therapeutic intervention.

Keywords: anti-inflammatory therapies; cerebral cortex; chorioamnionitis; electroencephalography; magnetic resonance imaging; neonatal sepsis; neurodevelopment; neuroinflammation; neurons.

Figure 1

Summary of the main findings of inflammation-induced effects on EEG activity, neuronal arborization, cortical growth, and neurodevelopmental outcomes. The left panel shows the trajectory of healthy cortical development in the fetal sheep brain, including development of the EEG (with increased beta activity), growth and arborization of cortical dendrites, and increased cortical volumes, measured using high-field MRI. The right panel shows the trajectory of brain development in fetal sheep exposed to progressive systemic inflammation, including impaired electroencephalogram activity (with reduced beta activity), and reduced growth and arborization of cortical dendrites. A representative example of cortical reconstructions of a cerebral hemisphere from a fetal sheep exposed to progressive systemic inflammation, acquired using high-field MRI, shows a reduction in cortical volume. These observations are consistent with studies in human neonates that show reductions in cortical volume and functional connectivity after exposure to perinatal infection/inflammation. These disturbances to cortical development are likely to have a significant role in the pathophysiology of poor neurodevelopmental outcomes, including motor and cognitive impairments. Created with BioRender.com. Representative EEG traces and MRI cortical reconstructions are unpublished data from the Galinsky laboratory. EEG: Electroencephalography; MRI: magnetic resonance imaging.