Julia B. Pitcher,* David J. Henderson-Smart and Jeffrey S. Robinson Abstract
In a world in which athletic skill is often valued more highly than intellectual prowess, we know surprisingly litde about the development of the human motor system. Even less is known about how an adverse intrauterine event or environment might program motor learning, memory and function throughout the lifespan. We are only beginning to investigate how events during development of the brain and central nervous system might predispose some individuals to older age onset of some common neurological disorders such as Parkinson's and Alzheimer's diseases. Anecdotal and empirical evidence suggests that one or more adverse events occurring in utero may result in long-term changes in neuromotor development. These changes may be evident from infancy, or not become apparent until later in life. This chapter reviews this evidence. We suggest that the research focus must shift towards neurophysiological rather than neurodevelopmental paradigms, if these programmed changes in neuromotor function and the mechanisms responsible are to be fully understood. We also introduce the idea that the impact on the individual of maladaptive neuromotor programming might be reduced by the development of early intervention therapies, which utilise the developing nervous system's capacity for plastic change.
There is emerging evidence that one of the developing systems that may be programmed by an adverse intrauterine environment is the human motor system. Programming has been described as a process whereby a disturbance of the environment, at critical stages of development of regulatory systems and their target tissues, alters development in such a way as to perma-nendy change functional capacity and predispose the individual to disease in later life. Adverse conditions in utero have been implicated in long-term alterations in brain structure and function, and possibly the later development of neurological diseases. There is increasing evidence that motor and vision disorders, schizophrenia (discussed elsewhere in this book, Ch. 17), epilepsy and autism may have their origins, at least in part, in altered prenatal neurodevelopment.1"2 Infants whose growth before birth has been restricted have increased rates of perinatal mortality and morbidity and increasingly, evidence of long-term neurological and neuromotor problems into childhood.3 The neurodevelopmental studies performed to date examining the relationship between low birthweight and neuromotor function have provided some descriptive information. However, it is not known if the motor deficits they have
*Corresponding Author: Julia B. Pitcher—Department of Obstetrics and Gynaecology, University of Adelaide, Women's and Children's Hospital, 72 King William Road, North Adelaide SA 5006, Australia. Email: [email protected]
Early Life Origins of Health and Disease, edited by E. Marelyn Wintour and Julie A. Owens. ©2006 Eurekah.com and Springer Science+Business Media.
identified persist into adulthood, what their extent and impact on neuromotor function is for the individual, and what underlying physiological determinants of that function have been impaired. Determining how aspects of the prenatal and postnatal environments alter normal development of motor function is complex, particularly as the human brain is highly plastic during development of the central nervous system and indeed throughout life.
This review will focus on and critically evaluate the evidence for altered motor function. We address some of the possible sources of altered programming of motor function in utero, the evidence for specific alterations in motor physiology from animal studies, and suggest future directions for research into the physiology of programming of altered neuromotor development. The techniques for both induction and experimental measurement of experience or activity dependent motor plasticity are introduced, and we oudine how these techniques might be developed for therapeutic intervention.
Intrauterine Growth Retardation (IUGR) versus Being Born Small for Gestational Age (SGA)
Because of the relative inaccessibility of the human fetus, surrogate markers of the prenatal environment, primarily fetal growth, as indicated by size at birth for gestational age, have been used in most studies of programming in humans. Suboptimal fetal growth is referred to as either intrauterine growth restriction (IUGR), or being born small for gestational age (SGA). IUGR and SGA are often used interchangeably, but by definition, they are different conditions. SGA is defined by the World Health Organisation as a birthweight below the tenth percentile for gestational age, whereas IUGR is a pathological condition where the fetus is unable to grow to its genetically-determined potential size, due either to abnormal genetic or environmental conditions that impair growth. So while all IUGR infants are SGA, not all SGA infants are IUGR Both SGA and IUGR are recognised as a key risk factors for neurological deficits4 and have been associated with learning difficulties, delayed language skills, behavioural problems5 and motor co-ordination and psychomotor development problems in children.6 The likelihood of these deficits is amplified in those IUGR babies whose in utero conditions are so compromised that they are delivered before term, adding the consequences of prematurity to IUGR7
Critical Periods in Fetal Brain and Nervous System Development
Human brain and nervous system development begins about 2 weeks after conception and may not be completed until the third decade of life. Prenatally, it consists of a series of precisely timed events that occur during discrete time windows.8'9 These prenatal events include neural induction, neurulation, proliferation, migration, axon and dendrite formation and outgrowth, synaptogenesis, differentiation and apoptosis (see ref. 9 for review). At each of these stages, the developing brain is vulnerable to a range of insults that can lead to long-term abnormalities and dysfunction. Therefore, the nature of any neurological abnormality is likely to depend upon the type and severity of the insult and the neurodevelopmental stage at which it occurs.10 During the first and second trimesters while neurogenesis of the cerebral cortex is underway, early insults or epigenetically induced malfunctions during specific stages can result in cortical hypoplasia (reduced cell number), cortical ectopias (abnormal migration) or cortical dysplasias (abnormal dendritic shape or number).8 Abnormalities of cortical development are being increasingly implicated in developmental delay, cognitive deficits and epilepsy in children and young adults. 1 During the third trimester, the developing human brain is particularly vulnerable to inflammatory, hypoxic, ischemic and infectious insults that predominantly result in lesions. In the early part of the third trimester the white matter appears most at risk, while later in the third trimester, the cortical or deep grey matter (particularly the basal ganglia and thalamus) become most vulnerable.12'13 The cerebellar cortex also develops in the third trimester and is particularly vulnerable to undernutrition associated with placental insufficiency during this time.14
Intrauterine Growth Restriction and Corticospinal Development
IUGR infants have been shown to have abnormal brain structure, including reduced whole brain weight,15 cerebellar weight16'17 and hemispheric volume.18 Rat and guinea pig studies have shown a significant association between IUGR birthweight, brain weight and reduced numbers of CA 1 pyramidal neurons in the hippocampus (thought to have a key role in learning and memory), '20 reduced number and disturbed migration of cerebellar cells,19'21'22 reduced cerebellar apoptosis threshold,23 and the amount and distribution of nerve growth factor throughout the brain.24 Growth retarded fetal sheep have been shown to have thinner motor and visual cortices and reduced cortical synaptogenesis than their normally-grown counterparts.25'26 Normal function of the cerebral cortex and the cerebellum is essential for normal movements. The alterations in brain structure in IUGR infants and experimental animal paradigms, the frequent anecdotal observations of clumsiness and poor motor skill development in IUGR children, and the subde neurological signs reported in IUGR infants5'6 suggest that human subjects who were growth-restricted in utero may have measurable deficits in corticomotor function.
Further support for this notion comes from the consequences of prenatal and post-natal malnutrition in the rat, where neuronal loss, reduced brain weight, and a 15% reduction of the velocity at which action potentials are conducted along the corticospinal tract have been reported.27 These changes have also been associated with decreased diameter of corticospinal axons and reduced myelination of corticospinal fibres.28'29 These authors also reported a pronounced loss of large compared with small corticospinal fibres in rats nutritionally restricted from conception to adulthood.28 While one must be cautious in extrapolating from animal studies, these results clearly suggest the possibility that corticospinal and intracortical structure and function may be adversely affected in IUGR children and adults. This is likely to be manifest as poor motor development and poor motor control, particularly of fine and dextrous movements that rely heavily on the motor cortex and cerebellum, and on continuing afferent feedback to these brain structures from the periphery. However, these effects may be very subde and difficult to detect without specific, physiological assessment of motor pathways.
Assessing the Impact of Growth Restriction on Motor Development in Infants, Children and Adults
Neurodevelopmental versus Neurophysiological Approaches
No study has examined the neurophysiological nature of motor deficits following IUGR or SGA in humans, although a number of studies have assessed aspects of neurodevelopment. There are key differences between neurodevelopmental versus neurophysiological assessments. In simple terms, neurodevelopmental tests assess the age-appropriate appearance of broad cognitive and/or physical milestones with reference to the "normal" population, whereas neurophysiological tests provide direct and/or indirect measurements of the physiological function of one or more specific neural pathways. Hence neurodevelopmental assessments aim to determine whether an individual is developing at the expected rate for their age, but unlike neurophysiological assessments, they provide little or no quantitative data about which neural pathway(s) might be expressing any abnormal development. With neurophysiological assessments, it is possible to narrow down-the possibilities by examining a particular motor pathway and a motor behaviour or physiological outcome controlled primarily by that pathway.30
The results from the neurodevelopmental studies of IUGR/SGA have been equivocal. This is pardy because a proportion of IUGR infants are also born prematurely, either due to premature onset of labour, or by obstetric intervention in the best interests of the infant or mothers survival. However, there is also considerable inherent variability in outcomes depending on the age of the cohort studied, the types of assessments used, and general study design. Most studies have used various scales of infant or child motor development to determine deviations from age-appropriate development. Developmental behavioural testing essentially examines sensorimotor function.
The development of the sensorimotor system is dependent upon the rate and degree of maturation of both the motor and somatosensory systems; not only do the central and peripheral branches of these tracts develop at different rates, alterations in the development of one or both tracts will affect sensorimotor development.31 Normal inter-individual variability in these rates of development add a not insignificant degree of heterogeneity to outcomes and reduce the sensitivity of these tests, particularly in identifying more subde deficits that might exist in one or both systems. So while these studies have been very useful in helping to identify the nature of the impact of IUGR on neuromotor development, we know virtually nothing of the physiological mechanisms responsible for the alterations.
The Fetus—Motor Behaviour in Utero
Early postnatal motor experiences have been shown to be important for the development of motor skills in humans and animals. However, little is known about the role of early postnatal motor experience in motor development30 and even less of the influence, if any, of in utero motor experience. Longitudinal studies using real-time ultrasound have revealed that the fetus begins moving as early as the seventh week of gestation with slow neck extensions, then starde-type movements.32'33 A few days later, more general movements begin appearing including breathing and jaw movements. By about 13 weeks, swallowing and rhythmical sucking appears that is of the same rate as those observed in breast-feeding term infants.34 Rather than being voluntary movements under cortical control, there is evidence from animal studies that these movement patterns may originate endogenously from central pattern generators.34 In the adult, for example, walking is thought to be under the general control of central pattern generators for locomotion located in the spinal cord and possibly utilising afferent feedback.
In the only study published of motor behaviour in IUGR fetuses in utero, Bekedam et al36 made hour-long real-time ultrasound assessments of ten IUGR and ten AGA fetuses. Compared to AGA fetuses, IUGR fetuses tended to display a limited repertoire of slow movements, with litde variability in movement velocity or amplitude, although there were some AGA fetuses with a similar movement profile. In particular, IUGR fetuses displayed distincdy reduced starde, twitching and isolated limb movements. However, there is no direct evidence that this reduced activity is not simply an energy saving strategy rather than reflecting a pathological alteration in neuromotor function.
The Neonate and Older Infant—General Movements
There are a handful of studies of the neurodevelopmental outcomes of IUGR in neonates. Most of these have come from Heinz Prechd's group in the Netherlands and the principal assessment of choice has been Prechd's Method, a qualitative assessment of "general movements" that is believed to reflect early postnatal brain development and predict later neurodevelopmental outcome in high-risk infants32'33'37 (see ref. 38 for review). General movements are endogenously generated, frequently occurring movement patterns of the head, trunk and limbs that are observable from birth until approximately 20 weeks postnatal age.39 They are divided into two postnatal periods: the "writhing" period (birth to 8 weeks) and the "fidgety movements" period (approximately 8 to 20 weeks). Writhing refers to movements that are often elliptical in form, are small to moderate in amplitude, of slow to medium speed and generally performed close to the body.39'40 Fidgety movements are characterised by small, circular, low amplitude movements of moderate speed and variable acceleration in a range of directions.39,4 They are continually present except when the infant is focussing their attention, crying or is distracted. Their frequency of occurrence during the 12-week period has a parabolic trajectory; they begin appearing as isolated movements, gradually become more frequent and then slowly disappear.39 The absence of fidgety movements has been shown to predict the later development of cerebral palsy with a sensitivity of 95% and a specificity of 96%.32 The presence of abnormal fidgety movements is strongly predictive of neurodevelopmental outcomes at 2 years of age.33' ' 1
Compared with AGA infants matched for age, gender and socio-economic status, IUGR infants exhibit more abnormal general movements, regardless of their gestational age at birth.82"84 Abnormal movements, particularly those that occur in the early and late fidgety periods and that do not normalise soon after birth, are strongly predictive of a poor or abnormal neurodevelopmental outcome at 2 years of age.82"84 General movement quality in both AGA and IUGR infants appears not to be aifected by prematurity, which suggests that normal motor outcomes in early childhood are critically dependent upon normal fetal growth.82 Cramped synchronised general movements, which are abnormal and predictive of cerebral palsy, tend to appear later postnatally in IUGR than in AGA infants.85 Abnormalities or the absence of fidgety movements has been associated with poor neurodevelopmental outcomes in term and preterm babies with perinatal brain lesions of a range of severity. However, most IUGR infants who demonstrate abnormal general movements have no evidence of lesions or other structural abnormalities on ultrasound scan.83,84 This suggests that a suboptimal intrauterine substrate supply to the fetus has a longer term influence on neurodevelopment that is not necessarily due to lesion-type injuries from hypoxic-ischaemic or haemorrhagic insults in utero6 One hypothesis might be that IUGR perturbs normal development of central pattern generators. However, abnormal movement patterns in IUGR infants will often normalise after they reach their term age,83'84 with normal neurodevelopmental outcomes at 2 years of age, suggesting that the development of normal early postnatal movements can "catch up", at least in some infants.
While the results from the general movements studies have been relatively homogeneous, the findings from studies using different infant development instruments have been equivocal. Lacey and colleagues (in ref. 42) compared infants born small for gestational age with AGA infants on development of state stability, posture and movement. SGA infants scored significantly lower than AGA infants on every item, including stage of independent feeding, leg antigravity posturing, limb resistance strength and traction, arm movements and head turning. However, Newman and colleagues5 found no differences in motor abilities when comparing 65 4-month-old SGA with 71 AGA babies. Motor function was assessed on two instruments: the Neuromotor and Motor Development Assessment and the Griffiths Scale of Infant Development. SimUarly, in a much larger study of 265 SGA and 329 AGA babies, SGA babies scored equally well on the motor scale of the Bayley Scales of Infant Development at 13 months of age as their AGA controls, but scored poorly on the mental development scale.43 Martikainens44 study further muddies the waters; she classified SGA infants as either symmetric or asymmetric (based on a proportionate or disproportionate biparietal diameter to crown-rump length at birth) and compared them with preterm and term AGA babies at 18 months of age using the Denver Development Screening test. Unfortunately, this version of the test has very limited value as a research instrument as it has been shown to have poor sensitivity and specificity.45 The symmetrically growth restricted babies performed more poorly than any other group on fine and gross motor development, speech and social abilities. There is considerable debate as to the significance of differentiating morphometric discrepancies in fetal growth restriction, and this will not be discussed in detail here.
The development of clinical imaging techniques has provided the opportunity to examine alterations in brain structure and activation in vivo, although to date their use in assessing the short and long-term effects of IUGR has been very limited. Roelants-van Rijn and colleagues46 recendy investigated 14 preterm SGA neonates to ascertain whether IUGR associated with placental insufficiency alters cerebral metabolism, and whether this precedes the adverse neurodevelopmental outcome often seen at 2 years of age (using the Griffiths Scales of Infant Development). Compared with preterm AGA infants, the SGA infants had similar cerebral metabolism and neurodevelopment at 2 years. However, the authors admit that the study was significandy underpowered; they would have required a minimum of 110 SGA babies to detect a difference in the N-acetylaspartate:choline ratio on proton magnetic resonance spectroscopy. A reduced N-acetylaspartate signal can indicate diminished neuronal density and possibly altered neuronal mitochondrial function.46
A proportion of growth-restricted infants will be so compromised in utero that they are delivered preterm. In assessing the neurodevelopmental outcomes in these children it is often hard to differentiate the short and/or longer-term effects due to IUGR from those due to preterm delivery.47'48 Being able to differentiate these effects can assist in identifying the nature of longer-term risks associated with IUGR earlier in gestation, compared with those experienced by the full- or near-term IUGR individual. These former babies also present a dilemma for the obstetrician, since delaying the delivery could increase the risk of hypoxia, haemorrhage and further neurological compromise, while preterm delivery is associated with the risks of intraventricular haemorrhage, respiratory distress syndrome and cerebral palsy. The outcome also differs between males and female neonates, with males being more likely to die if born preterm and IUGR.47 The evidence to date suggests that while compromised cognitive and IQ development at 2 years of age is associated with low birthweight rather than gestational age, motor development is compromised by low birthweight, reduced birthweight ratio (the actual birthweight compared with the expected birthweight for gestational age) and a shorter gestational age.47,49
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