Year Of Postnatal Life Research Articles

Adult structure and development of the human fronto‐opercular cerebral cortex (Broca's region)

Broca's area encompasses opercular and triangular part of the inferior frontal gyrus, covered by Brodmann's areas 44 and 45, respectively. Recent neuroimaging studies have revealed that, in addition to classical language functions, Broca's area has novel and unexpected functions, serving as a likely interface of action and perception important for both verbal and nonverbal communication. In this review, we focus on structural features of Broca's area in adult and developing human brain. We emphasize that: (a) in terms of architectonic classification, Broca's area displays a dual nature by virtue of its intermediate position between agranular motor‐premotor cortex and granular prefrontal associative cortex; and (b) numerous studies of morphological asymmetries are of limited value for understanding neurobiological basis of functions implemented by Broca's area. Finally, we summarize findings from our ongoing study on postnatal development of two defining cytoarchitectonic features of Broca's area in the adult brain, magnopyramidality (meaning that pyramidal neurons in layer III are larger than those in layer V) and dysgranularity (meaning that cortical layer IV is present, but poorly developed). We conclude that areal specification of areas 44 and 45 requires at least 2 (and probably 3) years of postnatal life for its gradual completion.

Preterm Growth Restraint: A Paradigm That Unifies Intrauterine Growth Retardation and Preterm Extrauterine Growth Retardation and Has Implications for the Small-for-Gestational-Age Indication in Growth Hormone Therapy

Small for gestational age (SGA) is defined as a birth weight and/or length >2 SDs below the gender-specific population reference mean for gestational age. However, there is confusion about various aspects of this term, as recently discussed.1,2 The term “intrauterine growth retardation” (IUGR) is often used for the same condition but preferably should be restricted to poor growth during pregnancy according to intrauterine growth diagrams used in obstetrics.3 SGA after a normal duration of gestation (37–42 weeks) is usually followed by rapid growth after birth (catch-up growth). It has been demonstrated that almost 90% of term SGA infants catch up in height in the first 2 years of postnatal life.4,5 On average, the human male has a birth length of 51 cm after term gestation and a final height, in the Netherlands, of 184 cm. Thus, in the 9 months before birth, he has reached almost 30% of his adult height potential. Fetal length velocity at midgestation is >10-fold higher than pubertal peak height velocity (Fig 1). Thus, very preterm infants are exposed to extrauterine life during a period that normally is characterized by rapid intrauterine growth. To survive, their energy expenditure shifts from growth-promoting actions to survival strategies to cope with the increased requirements of unintended postnatal life. Extrauterine growth retardation (EUGR) is often the result. Preterm infants whose mothers suffered from conditions such as preeclampsia are usually already growth-retarded at birth. Nonetheless, regardless of whether the child is born SGA, very preterm infants tend to be small at term, and a considerable proportion of them even meet criteria for SGA by that age. A study among 52 … Address correspondence to J.M. Wit, MD, PhD, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail: j.m.wit{at}lumc.nl

Isolated ventricular septal defects detected by color Doppler imaging: evolution during fetal and first year of postnatal life

To evaluate the development during gestation and up to 1 year postnatally of isolated small ventricular septal defects (VSDs) not visible by gray-scale imaging and detected only on color Doppler fetal echocardiography. This was a retrospective analysis of 146 fetuses with isolated VSDs detectable only on color Doppler echocardiography. Complete sequential gray-scale, color Doppler and spectral Doppler examination of the fetal heart were performed. The following variables were documented: site of the VSD, presence of extracardiac or chromosomal anomalies, outcome of the pregnancy and evolution of the defect up to 1 year postnatally. A total of 113 fetuses reached their first year of postnatal life, 23 pregnancies were terminated, there were three stillbirths/neonatal deaths, and seven were lost to follow-up. It was observed that 32.7% (n = 37) of all defects in neonates alive after 1 year closed in utero, 44.3% (n = 50) of defects closed spontaneously within the first postnatal year, and 23.0% (n = 26) of defects did not close. In all, a comparable number of perimembranous and muscular septal defects closed spontaneously in utero and during the first year of postnatal life. Among 35 fetuses with extracardiac anomalies 51.4% (n = 18) were euploid. Small VSDs, detectable only by color Doppler echocardiography, show a high spontaneous intrauterine and postnatal closure rate. These findings might be of value for prenatal parental counseling.

Relationship between serum concentrations of leptin, soluble leptin receptor, testosterone and IGF-I, and growth during the first year of postnatal life in the male rhesus monkey, Macaca mulatta

Subnormal leptin levels in low birth weight infants may allow for catch-up growth during infancy. Scant data are available that relate growth with circulating leptin during normal infancy in primates. The current study objective was to examine the association between serum leptin, its soluble receptor (sOB-R), testosterone and IGF-I concentrations, and body weight during infancy in male rhesus monkeys. Hormone levels were assessed longitudinally in animals (n = 7) from birth until 1 year of age. Body weight increased during the first 6 months of life and was strongly correlated with rising IGF-I levels and, as IGF-I plateaued and then declined during the second half of the year, body weight gain decelerated. In contrast, leptin levels declined gradually with age during the first year of life in conjunction with increasing body weight. There was no association between body weight gain and serum leptin levels or between serum testosterone and leptin values. Since sOB-R levels also declined with leptin values, it does not appear that levels of bioavailable leptin changed during infancy. The data do not support the contention that leptin regulates growth during infancy, but the close association between IGF-I levels and body weight suggested that this hormone may regulate growth in infant male monkeys. The failure to observe an association between serum testosterone and leptin concentrations suggested that leptin is not involved in the activation of the hypothalamic-pituitary -testicular axis during this developmental period.

Apoptosis in Atherosclerosis: Virtue or Vice

Apoptosis is a genetically controlled, cell autonomous pathway for cellular demise with distinct ligands, signaling pathways and characteristic morphologic alterations. It may determine the evolution, progression and biologic behavior of atherosclerotic lesions. Prior to the appearance of atherosclerotic lesions, endothelial cell apoptosis may be the basis of endothelial dysfunction that often precedes the formation of macroscopic lesions. In early lesions, it is plausible that a biphasic pattern of cellular turnover involving apoptosis may modulate cellular growth and senescence in early years of postnatal life. The progression of fatty streaks may depend on cellular content and extent of oxidization of LDL that may influence the rate of foam cell apoptosis and removal of cellular debris. In established atherosclerotic lesions apoptosis of different cell types may contribute to plaque erosion (endothelial cells), plaque progression (macrophages and T cells) and plaque thinning and rupture (VSMCs and macrophages). The exact role of apoptosis in acute ischemic events, however, remains unresolved. Visualization of apoptotic macrophages at sites of plaque rupture suggests a role in precipitating acute events. On the other hand, it appears that some strategies that limit atherosclerosis tend to increase macrophage and VSMC apoptosis. Macrophage apoptosis, by removing a potent source of inflammatory cytokines from the lesion, can favorably influence disease progression. Modulation of apoptosis as a therapeutic tool in atherosclerosis requires further studies to elucidate the molecular pathways and cellular signaling involved in apoptotic cell death. Keywords: restenosis, smooth muscle cells(smcs), atherogenic, atherosclerotic disease, tumor necrosis factor (tnf), anti-apoptotic proteins, adapter molecules, caspase-independent pathways, macrophages, oxidized-ldl

Psychoneuroendocrine processes in human pregnancy influence fetal development and health

Individual differences in psychoneuroendocrine function play an important role in health and disease. Developmental models postulate that these individual differences evolve through a progressive series of dynamic time-, place- and context-dependent interactions between genes and environments in fetal, infant and adult life. The effects of early experience have longer-lasting and more permanent consequences than those later in life. Experimental studies in animals have provided convincing evidence to support a causal role for stress-related psychoneuroendocrine processes in negatively influencing critical developmental and health outcomes over the life span, and have also offered valuable insights into putative physiological mechanisms. However, the generalizability of these findings from animals to humans may be limited by the existence of large inter-species differences in physiology and the developmental time-line. We have initiated a program of research in behavioral perinatology and conducted studies over the past several years to examine the effects of stress-related psychoneuroendocrine processes in human pregnancy on fetal developmental and health outcomes. Our findings support a significant and independent role for maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis, and specifically by placental corticotropin-releasing hormone. Our findings also suggest that the use of a fetal challenge paradigm offers a novel way to quantify fetal neurobehavioral maturity in utero, and that the maternal environment exerts a significant influence on the fetal neurodevelopmental processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first few years of postnatal life. A description of this body of work is followed by the elucidation of questions for further research and a discussion of implications for life-span development and health.

Epidemiology and Impact of Iodine Deficiency in Pediatrics

Introduction Iodine is a micronutrient present in the human body in minute amounts (15-20 mg), almost exclusively in the thyroid gland. Iodine is an essential component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), comprising 65 and 59 percent of their respective weights. Thyroid hormones, and therefore iodine, regulate many key biochemical reactions, especially protein synthesis and enzymatic activity. They also play a determining role in the process of early growth and development of most organs, especially that of the brain, which occurs in humans during the fetal and first two to three years of postnatal life. Consequently, iodine deficiency, if severe enough to affect thyroid hormone synthesis during this critical period, will result in hypothyroidism and brain damage. The clinical consequence will be irreversible mental retardation (1). The dietary intake of iodine recommended by the World Health Organization (WHO), the United Nation Children’s Fund (UNICEF) and the International Council for Control of Iodine Deficiency Disorders (ICCIDD) (2), are 90 μg per day from 0 to 59 months, 120 μg/d from 6 to 12 years, 150 μg/d for adolescents and non pregnant adults and 200μg/d during pregnancy and lactation (2).

Effects of three courses of maternally administered dexamethasone at 0.7, 0.75, and 0.8 of gestation on prenatal and postnatal growth in sheep.

To evaluate the effects of repeated low doses of maternally administered dexamethasone (DM) on growth in sheep during fetal life and the first 2 years of postnatal life. Ewes received 3 courses of DM (1 course: four 2-mg intramuscular injections at 12-hour intervals) or saline beginning at 103, 110, and 117 days of gestation (dGA). At 119 dGA, fetal BW and organ weight were recorded. Total placentome number, weight, and morphologic distributions were recorded. Placentome glucocorticoid receptor expression was determined by immunocytochemistry. Newborn BW and organ weight were recorded within 12 hours of birth. Duration of gestation was recorded. Measurements were collected on body weight (BW), biparietal diameter (BPD), crown-to-rump length, thoracic girth circumference, abdominal girth circumference, and radial bone length for 2 months. Maternal estradiol and progesterone levels were measured daily from 135 dGA. At 119 dGA, DM significantly decreased BW. Placentome glucocorticoid receptor expression increased after DM exposure. DM did not significantly decrease BW at birth but did prolong gestation length. DM decreased maternal estradiol before lambing. DM decreased newborn brain weight and BPD. After 2 weeks of age, no effect of DM on postnatal growth could be found. This study shows that repeated maternal DM treatment at doses threefold lower than what women in preterm labor receive results in decreased fetal BW, prolonged gestation length, decreased newborn brain weight, and BPD.

Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin.

Haemangioma is the most common tumour of endothelial origin, occurring in 4-10% of Caucasian infants. It is characterized by rapid growth during the first year of postnatal life, followed by spontaneous regression from 1 to 7 years of age. The cell surface adhesion molecule CD146 has been identified as an endothelial cell marker. Despite advances in understanding the functional role of CD146 in normal endothelial cells and tumour progression, its expression and a possible role in an endothelial tumour have not been studied. As part of an investigation of endothelial cell alterations in infantile haemangioma, differential expression studies were performed with several known antigens and endothelial cell markers. Using immunohistochemical and flow cytometric analyses, cultured human dermal microvascular endothelial cells isolated from newborn foreskin (HDMEC) were compared with endothelial cells derived from haemangioma tissue (HemECs). In addition, immunohistochemistry was used to compare haemangioma tissues with normal human skin. Unexpectedly, cultured HemECs showed a significantly lower level of CD146 than HDMECs by both flow cytometric analysis and immunofluorescence staining. Using immunohistochemical studies, it was further demonstrated that endothelia in all haemangioma tissues, regardless of the tumour phase, showed negative immunoreactivity for CD146. In contrast, strong positive staining for CD146 was observed in the pericyte-like cells that surround the endothelial layers. These findings are believed to be relevant to the molecular basis of haemangioma. Furthermore, it is possible that antibodies against CD146 may be useful for separating haemangioma-derived endothelial cells from normal endothelial cells and pericytes.

Motor Development During the First Year: A Comparative Study

This investigation of the motor development characteristics of Brazilian infants during the 1st year of postnatal life compared the findings with those of a widely used U.S. sample (N. Bayley, 1993). Analysis of the 12 monthly assessments indicated that Brazilian infants' scores increased with age, with the greatest increase occurring over the first 8 months. As a general comparison, the results are similar to the U.S. patterns of development. However, the Brazilian sample exhibited mean scores significantly lower than the U.S. sample's in the 3rd, 4th, and 5th months. More specific analyses indicated that the difference within these months was on tasks of sitting and grasping. Possible explanations for the differences focus on variations in child-rearing practices and the influence of biological maturation in early movement behaviors.

Intrauterine programming of adult body composition.

Epidemiological studies suggest an association between weight in infancy and the risk of osteoporosis in later life. The extent to which this reflects environmental influences on skeletal growth and metabolism before birth or during the first year of postnatal life remains uncertain. We therefore examined the association between birth weight and adult body composition (bone, lean, and fat mass) in a cohort of 143 men and women, aged 70-75 yr, who were born in Sheffield, UK, and still lived there. The subjects underwent assessment of body composition by dual energy x-ray absorptiometry. Neonatal anthropometric information included birth weight, birth length, head size, and abdominal circumference. There were significant (P < 0.01) positive associations between birth weight and adult, whole body, bone, and lean mass among men and women. These were mirrored in significant (P < 0.03) associations between birth weight and bone mineral content at the lumbar spine and femoral neck. Associations between birth weight and whole body fat were weaker and not statistically significant. The associations of birth weight with whole body bone mineral and lean mass remained statistically significant after adjustment for age, sex, and adult height. They also remained significant after adjustment for cigarette smoking, alcohol consumption, dietary calcium intake, and physical inactivity. These data are in accord with previous observations that anthropometric measures in infancy are associated with skeletal size in adulthood. The presence of these relationships at birth adds to the evidence that bone and muscle growth may be programmed by genetic and/or environmental influences during intrauterine life.

Chapter 9 The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system

Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.

Quantitative histomorphometric analysis of the human growth plate from birth to adolescence

Longitudinal bone growth occurs via the transformation of growth plate cartilage into bone through a series of cell and matrix changes, termed endochondral ossification. In this study, we characterize the development of trabecular bone from growth plate cartilage in the human rib from birth to adolescence. The height of the proliferative and hypertrophic zones within the growth plate and the primary bone spongiosa decreased with increasing age, with the greatest change observed in the first year of postnatal life. Within these zones, an internal rearrangement of tissue structure occurred. The matrix volume fraction (either cartilage or bone) increased with age in each of the zones. A concomitant increase in cartilage septae thickness and bone trabecular thickness was observed. A decrease in cartilage septae number was seen in the proliferative zone and a decrease in bone trabeculae number was also observed in the primary spongiosa. However, no difference in cartilage septae number was noted in the hypertrophic zone, the region at which cartilage is transformed into bone. Together the proliferative and hypertrophic regions of the growth plate and the bone primary spongiosa appear to constitute the active growth region, with concomitant changes observed that result in longitudinal growth. In contrast, bone mineral volume in the secondary spongiosa was stable over the ages examined; however, trabecular architecture underwent consolidation as trabecular number decreased and trabecular thickness increased. The integration of the structural transformation from cartilage to bone is crucial in achieving the dual purposes of longitudinal growth and peak bone mass. The structure developed during childhood will have an important bearing on the response to bone-altering disease in later life.

Ossification centers of human femur.

The purpose of the present work was to investigate the appearance of ossification centers in human femur by Dual-energy X-ray Absorptiometry (DXA), comparing densitometric data with morphogenetic events. Posteroanterior scans were performed on 31 dried femora (from 11.5 weeks of conceptual age to 1 year of postnatal life) by a Hologic QDR 1000 X-ray densitometer with Ultra-Hi-Resolution software. The results were expressed as bone mineral content (BMC, g) and bone mineral density (BMD, g/cm2). The analyses were performed on a rectangular area corresponding to the minimum width and total length of the shaft. The rectangular area was divided into five equal sections along its longitudinal axis, and BMC was calculated on each section. To distinguish the ossification area of the lesser trochanter with respect to the area of the greater trochanter, the proximal femoral end was divided into two portions, medial and lateral, respectively; BMC and BMD were calculated on each portion. Our data show that the ossification center of the femoral shaft extends prevalently in the proximal direction. A denser area was recognizable on the densitometric images at the level of the lesser trochanter from the 19th week of prenatal life and at the level of the greater trochanter at term. During development, the trends of BMC and BMD are similar in both trochanteric areas, but these parameters are fairly constantly higher at the level of the lesser trochanter. Our findings disagree with the data of the current literature on the postnatal appearance of the trochanteric ossification centers and suggest a different biomechanical interpretation of the secondary ossification of the femur.

Handedness and cortisol in tufted capuchin monkey infants.

In this research, we examined the relationship between handedness and levels of plasma cortisol in infant monkeys (Cebus apella). Specifically, we sought to test the hypothesis that stress functioning is related to hemispheric specialization and is manifested in a positive correlation between cortisol levels and the frequency of right- versus left-hand use. We found a significant relationship between stress cortisol at age 6 months and lateral bias towards greater use of the right versus left hand at ages 6 and 12 months. These data suggest an early developmental influence of stress reactivity on the emergence of hemispheric specialization for manual control in infant monkeys through the 1st year of postnatal life.

Myrtle McGraw's Unrecognized Conceptual Contribution to Developmental Psychology

In the late nineteenth century and through much of the twentieth century, the notion of the early developmental autonomy of motor behavior pervaded behavioral embryology and the developmental psychology of infant behavior. In the midst of this predeterministic climate of opinion concerning motor development, Myrtle McGraw briefly and tentatively broached the probabilistic epigenetic notion of a bidirectional or reciprocal relationship between structural maturation and function, whereby structural maturation of the nervous system is influenced by functional activity as well as the other way around. Myrtle McGraw thus anticipated our current understanding of the role of experience in the cortical and motor maturation of infants in the first year of postnatal life. It is all the more remarkable that she made this contribution when the theoretical climate of opinion was epitomized by predeterministic epigenetic thinking. In the same vein, McGraw's second unrecognized contribution is her clear formulation of a suitably flexible critical period concept in 1935, one that is consonant with our current understanding.

The effects of stress and trauma on brain and memory: a view from developmental cognitive neuroscience.

Many aspects of brain development depend on experience. Because the major macro-morphological events of brain development occur over the first 2-3 years of postnatal life, this time period can be considered both a period of opportunity as well as a period of vulnerability. In this paper we describe how experience with stress early in life can have a negative impact on certain aspects of brain development, and specifically, those neural circuits that underlie memory. We also describe the effects of traumatic events on the development of the neural basis of memory. In support of our argument, we review the literature on brain, stress, and memory in the context of development. Based on this review, we suggest that the developing brain is particularly vulnerable to the harmful physiological effects of stress, which in turn has the potential to lead to impairments in memory. Unfortunately, there are few empirical data that directly address this hypothesis. In this context we offer a number of suggestions for future research.

Amamantamiento y desarrollo infantil

Esta reseña focaliza las ventajas y desventajas que ofrece la lactancia para el desarrollo mental del niño. Los estudios se refieren a tres temas: 1) correlación entre tipo de alimentación y rendimiento en diversas pruebas de desarrollo mental antes y después de los primeros tres años de vida; 2) prevención de deficiencias de nutrimentos que afectan adversamente el desarrollo del niño y prevención de secuelas en el desarrollo en niños nacidos antes de termino y con bajo peso; y 3) contaminación de la leche de pecho por drogas y contaminantes ambientales.Se presenta una visión sobre los efectos del amamantamiento dentro los tres temas a tratar. Nuestra evaluación indica que los estudios no permiten llegar a conclusiones definitivas, particularmente en el caso de los temas uno y tres. La mejor evidencia disponible se refiere al segundo tema; sobre todo en el caso de los efectos de los ácidos grasos en el desarrollo del cerebro y aquellas provenientes de estudios longitudinales de niños que nacieron antes de termino y con muy bajo peso. En nuestra opinión es necesario obrar con mucha cautela en la evaluación de las recomendaciones de la Organización Mundial de la Salud sobre la lactancia en aquellos casos en los que la leche de pecho puede estar contaminada por drogas o por contaminantes ambientales.

Localization of the central sulcus and adjacent sulci in human: a study by MRI.

Variations in localization of the central sulcus and the sulci around the central sulcus namely the superior frontal sulcus, precentral sulcus, postcentral sulcus, marginal ramus of cingulate sulcus were studied in vertex sections retrospectively by magnetic resonance imaging (MRI) method in 3580 cases. Out of total number of cases, 1000 who did not show any macroscopic intracranial pathology were carefully selected for research. Additionally, 0-1 age group was excluded from the study because the sulci develop in first year of postnatal life, excluding the possibility of considering these as anatomical variations. Thus, the total number of cases is decreased to 990. 16 variations related to localization of the superior frontal sulcus, precentral sulcus, central sulcus, postcentral sulcus and the marginal ramus of the cingulate sulcus were identified. The asymmetries of the sulci, the most variable sulci and the distribution of the variations according to sex were statistically analysed.

RETT SYNDROME: NEUROBIOLOGICAL CHANGES UNDERLYING SPECIFIC SYMPTOMS

Rett syndrome (RS) is a progressive disorder that is predominant in females. It is associated with cortical atrophy, stereotyped hand movements mimicking hand-washing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The cause of RS is unknown; no consistent genetic abnormalities, at either the cellular or mitochondrial levels, have been identified. The diagnosis still depends solely upon clinical evidence. The clinical progression of RS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of appropriate trophic factors. Neuropathological studies have confirmed (1) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Biochemical studies have identified (1) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of β-endorphin levels in the thalamus and glutamate levels in the CSF; (4) no evidence for mitochondrial dysfunction. These data suggest that there is a primary deficit in cholinergic function that might underlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RS is a neurodevelopmental disorder that has its greatest effects upon a limited number of neural systems during the first few years of postnatal life. © 1997 Elsevier Science Ltd. All Rights Reserved.