ReviewFunctional plasticity before the cradle: A review of neural functional imaging in the human fetus
Introduction
In the fetal period, complex structural and functional changes occur rapidly and collaboratively, together driving further establishment of brain systems. Indeed, the processes of development are likely the push and pull of mutual influences between neuroanatomical architecture and functional activity (Shatz, 1996). The science that examines brain development at the beginning of life is developmental neurobiology. That field is credited with remarkable insights that have arisen mostly from research in animal models. Studies of brain development in the human fetus have followed more slowly, drawing substantially from post mortem and behavioral approaches (Hepper and Shahidullah, 1994, Kiuchi et al., 2000). However, in the past several decades, with the emergence of more advanced neuroimaging methodologies, windows into human fetal brain development are opening wider. The present review focuses specifically on the neuroimaging methodologies that have been applied to the study of human fetal functional brain development, with discussion of what we have learned and where we envision the future is going.
Research examining functional brain development at the beginning of life has broad implications for neuroscience and for clinical practice. The benefit to neuroscience resides in the predominant belief that to understand brain organization, one must understand how the brain is formed. In recent years, interest in life-span neuroscience has grown. This shift is likely the result of shared influence between the ways development and decline inform general understanding, and increased rates of neurodevelopmental and neurodegenerative disorders in the human population. Because foundations of the central nervous system are created during the fetal period, prevailing theory asserts that abnormalities originating in this period will impact consequent neural network patterns and growth (Tau and Peterson, 2010). The objective of fetal functional neuroimaging in both normal and at risk populations is therefore to thoroughly characterize functional and mechanistic features as well as deficiencies of the early forming brain. This work is foundational in that it renders models of healthy development, against which abnormal development may be compared. The resulting comparison is useful for improved classification and identification of biomarkers that predict negative developmental outcomes. Thus, research on the human brain during the remarkably plastic time of fetal development is a major enterprise with great significance for both health and disease.
Significant insights into the development of the human nervous system have arisen from application of functional neuroimaging techniques to preterm and term infants. For example, newborn functional magnetic resonance imaging (fMRI) studies have identified functional intrinsic connectivity networks (ICNs) in infants, and have differentiated these from neural network configurations in third trimester, preterm neonates (Doria et al., 2010, Fransson et al., 2007, Fransson et al., 2009, Fransson et al., 2011, Smyser et al., 2010). Infant fMRI studies have shown that neural networks cover greater anatomical distances later in development (Smyser et al., 2010) and that the most developed functional connectivity appears to exist in regions related to sensation and action (Fransson et al., 2011). Preterm and term infant fMRI studies have greatly contributed to identification and characterization of whole brain functional systems development at the earliest time points in human life. With recent advances to fetal functional imaging, infant fMRI studies have provided a solid foundation for emerging research into functional network development in utero.
The earliest attempt to study fetal brain function was performed using EEG methodology to record fetal brain activity during labor (Bernstine et al., 1955). More recently, MEG and fMRI methods have achieved success investigating sensory system and unconstrained neural function prenatally. Here unconstrained is defined as spontaneous neural activity which occurs naturally and without direct stimulation. Additionally, resting-state fMRI (rs-fMRI) studies have begun to derive information about functional connectivity in major brain systems in the developing fetus. This review summarizes the results and achievements of fetal EEG, MEG, fMRI, and rs-fMRI studies in mapping plasticity and neural functional changes in fetal life. Table 1 and Fig. 1 summarize this literature. We also discuss important technological advancements, future paths for examination of sensory system and unconstrained brain activity research in utero, and their implications for earlier identification of neuropathologies and future development of early clinical interventions.
Section snippets
Prenatal functional development of the human brain
Building upon the significant insight that has been derived from human fetal anatomical MRI (Clouchoux et al., 2012, Rajagopalan et al., 2011) and post-mortem (Jammes, 1983, Kinoshita et al., 2001) studies, fetal functional neuroimaging studies are breaking new ground and providing the first measurements of human brain function in utero. This section will discuss fetal brain function and the approaches and advances that have delivered new understanding of fetal brain plasticity and development.
The future
Over the past 20 years, the importance of understanding the functional development of the fetal brain has gained emphasis, spurring on improvements to the methods and technology, and providing greater insight into why this early stage of neurodevelopment is so critical for human development. Although functional fetal imaging research has achieved important findings, as a whole the field has been restricted by small sample sizes and methodological challenges. In the below sections, implications
Summary
This review has discussed the relevant fetal functional neuroimaging studies as well as what has been learned, how methodological challenges have influenced findings, and target areas for future development. We have also emphasized the importance of neuroimaging research in the human fetus as this review represents a window into an extraordinarily plastic and foundational developmental period. If fetal functional data can be acquired via optimized methods of fMRI, rs-fMRI, and MEG in both risk
Acknowledgements
This research was supported, in part, by the Merrill Palmer Skillman Institute for Child and Family Development; the Department of Pediatrics; Wayne State University (WSU) School of Medicine; the WSU Perinatal Initiative; WSU's Perinatology Virtual Discovery Grant (made possible by W. K. Kellogg Foundation award P3018205); and by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver NICHD, NIH, DHHS. This project was also supported by an award from the Wayne
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