Review
Functional plasticity before the cradle: A review of neural functional imaging in the human fetus

https://doi.org/10.1016/j.neubiorev.2013.03.013Get rights and content

Highlights

  • The organization of the brain is highly plastic in fetal life.

  • Recently, functional neuroimaging has directly examined and measured human fetal brain function.

  • Biomarkers of neurological development may be defined through functional neuroimaging methods.

  • Fetal programming asserts maternal environment directly influences later developmental outcomes.

  • Improved future fMRI and MEG studies may lead to new diagnostic and clinical applications.

Abstract

The organization of the brain is highly plastic in fetal life. Establishment of healthy neural functional systems during the fetal period is essential to normal growth and development. Across the last several decades, remarkable progress has been made in understanding the development of human fetal functional brain systems. This is largely due to advances in imaging methodologies. Fetal neuroimaging began in the 1950–1970's with fetal electroencephalography (EEG) applied during labor. Later, in the 1980's, magnetoencephalography (MEG) emerged as an effective approach for investigating fetal brain function. Most recently, functional magnetic resonance imaging (fMRI) has arisen as an additional powerful approach for examining fetal brain function. This review will discuss major developmental findings from fetal imaging studies such as the maturation of prenatal sensory system functions, functional hemispheric asymmetry, and sensory-driven neurodevelopment. We describe how with improved imaging and analysis techniques, functional imaging of the fetus has the potential to assess the earliest point of neural maturation and provide insight into the patterning and sequence of normal and abnormal brain development.

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

References (119)

  • R. Gagnon et al.

    Human fetal behavioral states after vibratory stimulation

    Am. J. Obstet. Gynecol.

    (1989)
  • O.A. Glenn

    Normal development of the fetal brain by MRI

    Semin. Perinatol.

    (2009)
  • K.A. Gordon et al.

    Auditory brainstem activity and development evoked by apical versus basal cochlear implant electrode stimulation in children

    Clin. Neurophysiol.

    (2007)
  • P.A. Habas

    A spatiotemporal atlas of MR intensity, tissue probability and shape of the fetal brain with application to segmentation

    Neuroimage

    (2010)
  • N. Haddad et al.

    Correlation between fetal brain activity patterns and behavioral states: an exploratory fetal magnetoencephalography study

    Exp. Neurol.

    (2011)
  • M. Holst et al.

    Development of auditory evoked fields in human fetuses and newborns: a longitudinal MEG study

    Clin. Neurophysiol.

    (2005)
  • J. Hykin et al.

    Fetal brain activity demonstrated by functional magnetic resonance imaging

    Lancet

    (1999)
  • R. Jardri et al.

    Assessing fetal response to maternal speech using a noninvasive functional brain imaging technique

    Int. J. Dev. Neurosci.

    (2012)
  • R. Jardri et al.

    Fetal cortical activation to sound at 33 weeks of gestation: a functional MRI study

    Neuroimage

    (2008)
  • M. Kiuchi et al.

    The relationship between the response to external light stimulation and behavioral states in the human fetus: how it differs from vibroacoustic stimulation

    Early Hum. Dev.

    (2000)
  • J.P. Lecanuet et al.

    Fetal responses to acoustic stimulation depend on heart rate variability pattern, stimulus intensity and repetition

    Early Hum. Dev.

    (1986)
  • J.P. Lecanuet et al.

    Fetal sensory competencies

    Eur. J. Obstet. Gynecol. Reprod. Biol.

    (1996)
  • J.M. Lengle et al.

    Improved neuromagnetic detection of fetal and neonatal auditory evoked responses

    Clin. Neurophysiol.

    (2001)
  • T. Matuz et al.

    Habituation of visual evoked responses in neonates and fetuses: a MEG study

    Dev. Cogn. Neurosci.

    (2012)
  • B. Mazoyer et al.

    Cortical networks for working memory and executive functions sustain the conscious resting state in man

    Brain Res. Bull.

    (2001)
  • J. McCubbin et al.

    Bootstrap significance of low SNR evoked response

    J. Neurosci. Methods

    (2008)
  • C. Micheli et al.

    Verification of fetal brain responses by coregistration of fetal ultrasound and fetal magnetoencephalography data

    Neuroimage

    (2010)
  • C. Moon et al.

    Two-day-olds prefer their native language

    Infant Behav. Dev.

    (1993)
  • J.K. Moore et al.

    Time course of axonal myelination in the human brainstem auditory pathway

    Hear. Res.

    (1995)
  • J.D. Power et al.

    Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion

    Neuroimage

    (2012)
  • B. Ray et al.

    Development of the human fetal cochlear nerve: a morphometric study

    Hear. Res.

    (2005)
  • M.G. Rosen et al.

    An approach to the study of brain damage. The principles of fetal electroencephalography

    Am. J. Obstet. Gynecol.

    (1973)
  • F. Rousseau et al.

    Registration-based approach for reconstruction of high-resolution in utero fetal MR brain images

    Acad. Radiol.

    (2006)
  • M.S. Scher

    Automated EEG-sleep analyses and neonatal neurointensive care

    Sleep Med.

    (2004)
  • E. Schleussner et al.

    Prenatal evidence of left-right asymmetries in auditory evoked responses using fetal magnetoencephalography

    Early Hum. Dev.

    (2004)
  • E. Schleussner et al.

    Fetal magnetoencephalography: a non-invasive method for the assessment of fetal neuronal maturation

    BJOG

    (2001)
  • V. Schöpf et al.

    Watching the fetal brain at ‘rest’

    Int. J. Dev. Neurosci.

    (2012)
  • A. Serag

    Construction of a consistent high-definition spatio-temporal atlas of the developing brain using adaptive kernel regression

    Neuroimag

    (2012)
  • A. Sharma et al.

    The influence of a sensitive period on central auditory development in children with unilateral and bilateral cochlear implants

    Hear. Res.

    (2005)
  • C. Sheridan et al.

    Early development of brain responses to rapidly presented auditory stimulation: a magnetoencephalographic study

    Brain Dev.

    (2010)
  • C.J. Sheridan et al.

    Neonatal and fetal response decrement of evoked responses: a MEG study

    Clin. Neurophysiol.

    (2008)
  • H. Beck et al.

    Synaptic plasticity in the human dentate gyrus

    J. Neurosci.

    (2000)
  • H. Bengoetxea et al.

    Enriched and deprived sensory experience induces structural changes and rewires connectivity during the postnatal development of the brain

    Neural Plas.

    (2012)
  • T. Blum et al.

    First magnetoencephalographic recordings of the brain activity of a human fetus

    BJOG

    (1985)
  • A.D. Borgstedt et al.

    Fetal electroencephalography. Relationship to neonatal and one-year developmental neurological examinations in high-risk infants

    Am. J. Dis. Child.

    (1975)
  • C. Chiron et al.

    The right brain hemisphere is dominant in human infants

    Brain

    (1997)
  • R.R. Clancy et al.

    Neonatal electroencephalography

  • C. Clouchoux et al.

    Normative fetal brain growth by quantitative in vivo magnetic resonance imaging

    Am. J. Obstet. Gynecol.

    (2012)
  • D.L. Collins

    3D Model-Based Segmentation of Individual Brain Structures from Magnetic Resonance Imaging Data

    (1994)
  • M. Corbetta et al.

    Neural systems for visual orienting and their relationships to spatial working memory

    J. Cogn. Neurosci.

    (2002)
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