Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte lineage progression and functional maturation of axons to structural development of selected cerebral white-matter tracts as determined by diffusion tensor imaging (DTI). Immunohistochemical studies showed that late oligodendrocyte progenitors appear at gestational age 22 [embryonic day 22 (E22)], whereas immature oligodendrocytes appear at E25, and both increase rapidly with time (ϳ13 cells/mm 2 /d) until the onset of myelination. Myelination began at postnatal day 5 (P5) (E36) in the internal capsule (IC) and at P11 in the medial corpus callosum (CC), as determined by localization of sodium channels and myelin basic protein. DTI of the CC and IC showed that fractional anisotropy (FA) increased rapidly between E25 and P1 (E32) (ϳ11% per day) and plateaued (Ͻ5% per day) after the onset of myelination. Postnatal maturation of the compound action potential (CAP) showed a developmental pattern similar to FA, with a rapid rise between E29 and P5 (in the CC, 18% per day) and a slower rise from P5 to P11 (in the CC, Ͻ5% per day). The development of immature oligodendrocytes after E29 coincides with changes in FA and CAP area in both the CC and IC. These findings suggest that developmental expansion of immature oligodendrocytes during the premyelination period may be important in defining structural and functional maturation of the white matter.

Abstract-Disorders of the maternal-placental-fetal unit often results in fetal brain injury, which in turn results in one of the highest burdens of disease, because of the lifelong consequences and cost to society. Investigating hypoxia-ischemia in the perinatal period requires the factoring of timing of the insult, determination of end-points, taking into account the innate development, plasticity, and enhanced recovery. Prenatal hypoxia-ischemia is believed to account for a majority of cerebral palsy cases. We have modeled sustained and repetitive hypoxia-ischemia in the pregnant rabbit in utero to mimic the insults of abruptio placenta and labor, respectively. Rabbits have many advantages over other animal species; principally, their motor development is in the perinatal period, akin to humans. Sustained hypoxia-ischemia at 70% (E22) and 79% (E25) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the E22 and E25 survivors and persisted for at least 11 days. Noninvasive imaging using MRI suggests that white matter injury in the internal capsule could explain some of the hypertonia. Further investigation is underway in other vulnerable regions such as the basal ganglia, thalamus and brain stem, and development of other noninvasive determinants of motor deficits. erebral palsy is a nonprogressive disorder of the developing brain principally affecting the motor system. Cerebral palsy affects 2 to 3 per 1000 newborns, with a conservative estimate of its impact on society being Ϸ$5 billion per year. Cerebral palsy can be associated with epilepsy and abnormalities of speech, vision, and intellect. The impact of diseases affecting the newborn are much higher than diseases that affect the elderly because of the burden of disease when one considers mortality, years of life lost, and years of productive life lost. If one compares the economic impact of disease of an elderly person at the end of life compared with that of disease of a fetus or baby, the impact of the latter is far more. Lifetime costs for all persons of cerebral palsy are estimated to total $11.5 billion. 1 These costs underscore the need to urgently develop preventive and secondary therapeutic measures for the fetus and newborn. Little progress has been made over the past few decades on the prevalence of cerebral palsy. [2][3][4] The lack of development of new therapies has been partly because of the malpractice climate in United States. 5 Progress is also slow because of the unique obstacles facing investigators studying brain injury in the perinatal period, principally related to the issue of timing. 6 During the progression of neurological development, the timing of the insult and of end points becomes crucial in any study. The investigator has to take into account not only the plasticity of the stage of development but also th...

We investigated the contributions of commensal bacteria to brain structural maturation by magnetic resonance imaging and behavioral tests in four and 12 weeks old C57BL/6J specific pathogen free (SPF) and germ free (GF) mice. SPF mice had increased volumes and fractional anisotropy in major gray and white matter areas and higher levels of myelination in total brain, major white and grey matter structures at either four or 12 weeks of age, demonstrating better brain maturation and organization. In open field test, SPF mice had better mobility and were less anxious than GF at four weeks. In Morris water maze, SPF mice demonstrated better spatial and learning memory than GF mice at 12 weeks. In fear conditioning, SPF mice had better contextual memory than GF mice at 12 weeks. In three chamber social test, SPF mice demonstrated better social novelty than GF mice at 12 weeks. Our data demonstrate numerous significant differences in morphological brain organization and behaviors between SPF and GF mice. This suggests that commensal bacteria are necessary for normal morphological development and maturation in the grey and white matter of the brain regions with implications for behavioral outcomes such as locomotion and cognitive functions.

Hypertonia and postural deficits are observed in cerebral palsy and similar abnormalities are observed in postnatal rabbits after antenatal hypoxia-ischemia. To explain why some kits become hypertonic, we hypothesized that white matter injury was responsible for the hypertonia. We compared newborn kits at postnatal day 1 (P1) with and without hypertonia after in vivo global fetal hypoxia-ischemia in pregnant rabbits at 70% gestation. The aim was to examine white matter injury by diffusion tensor magnetic resonance imaging indices, including fractional anisotropy (FA). At P1, FA and area of white matter were significantly lower in corpus callosum, internal capsule, and corona radiata of the hypertonic kits (n=32) than that of controls (n=19) while nonhypertonic kits (n=20) were not different from controls. The decrease in FA correlated with decrease in area only in hypertonia. A threshold of FA combined with area identified only hypertonic kits. A reduction in volume and loss of phosphorylated neurofilaments in corpus callosum and internal capsule were observed on immunostaining. Concomitant hypertonia with ventriculomegaly resulted in a further decrease of FA from P1 to P5 while those without ventriculomegaly had a similar increase of FA as controls. Thus, hypertonia is associated with white matter injury, and a population of hypertonia can be identified by magnetic resonance imaging variables. The white matter injury manifests as a decrease in the number and density of fiber tracts causing the decrease in FA and volume. Furthermore, the dynamic response of FA may be a good indicator of the plasticity and repair of the postnatal developing brain.

Perinatal brain injury results in one of the highest burdens of disease in view of the lifelong consequences and is of enormous cost to society. This makes it imperative to develop better animal models that mimic the human condition. Many neurodevelopmental deficits, such as cerebral palsy, are believed to be a result of prenatal hypoxia-ischemia in humans. Fetal global hypoxia-ischemia is most commonly a consequence of acute placental insufficiency. Our laboratory has modeled in utero sustained and repetitive hypoxia-ischemia in the pregnant rabbit to mimic the insults of abruptio placenta and labor, respectively. Sustained hypoxia-ischemia at 70% (22 days' gestation) and 79% (25 days' gestation) and repetitive hypoxia-ischemia at 90% gestation (28 days' gestation) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the 22 and 25 days' gestation survivors but not in the 28 days' gestation group. Hypertonic survivors were artificially fed and found to have the motor deficits persist for at least 11 postnatal days. A spectrum of brain abnormalities is found on magnetic resonance imaging. This is the first animal model to mimic cerebral palsy. The findings also suggest a window of vulnerability during brain development when the injury results in hypertonia in newborn pups.

The objective of the study was to assess predictive value of serial diffusion tensor MRI (DTI) for the white matter injury and neurodevelopmental outcome in a cohort of premature infants. Twenty-four infants less than 32 weeks’ gestation were stratified to a control group (n = 11), mild brain injury with grades 1–2 of intraventricular hemorrhage (n = 6) and severe brain injury with grades 3–4 intraventricular hemorrhage (n = 4). Serial DTI studies were performed at around 30 and 36 weeks’ gestation. Fractional anisotropy (FA) and apparent diffusion coefficient were calculated. Twelve infants were followed up for developmental outcome. Developmental testing was performed with the Bayley Scales of Infant Development to obtain psychomotor index (Performance Developmental Index). Apparent diffusion coefficient was higher in the severe injury group at the second MRI in the central and occipital white matter, and corona radiata; FA was lower in optic radiation compared to controls. Performance Developmental Indexscore correlated with FA on the scan taken at the 30th week and inversely with the change of FA between scans in internal capsule and occipital white matter. A low value of FA at 30 weeks and a higher change of FA predicted less favorable motor outcome at 2 years and suggests that early subtle white matter injury can be detected in premature infants even without obvious signs of injury.

Serial fetal brain scans indicate that the immediate response of a fetus to H-I is crucial to the development of hypertonia. If the fetal brain can be scanned at the time of insult, ADC changes can predict which fetuses will have an unfavorable outcome.

A set of sensory, motor, cognitive and emotional tasks were combined in a simple, rapid-presentation task battery and tested on a group of 31, normal, healthy subjects aged 22 to 76. Five tasks were selected on the basis of widespread use in fMRI and their ability to produce robust and reliable regional activations. They were: 1) a visual task designed to activate the occipital cortex; 2) a bimanual motor task designed to activate motor areas; 3) a verb generation task designed to activate speech processing areas; 4) an n-back task designed to activate areas associated with working memory and executive function; and 5) an emotional pictures task designed to provoke strong emotional responses that typically activate limbic structures. Most of the tasks produced reliable activations in individual subjects, and assessments of the distribution and reliability of individual subject activations in each targeted area are provided. The emotional pictures task did not demonstrate adequate sensitivity in a priori target regions, only in the a posteriori defined inferior temporal region. Age and gender specific differences were found in the activation patterns for both the cognitive and emotional tasks. The battery provides a prescribed means for researchers to obtain reliable functional localizers within 20-25 minutes of scanning, which can be used to support more elaborate mapping studies of brain function. The dataset can also serve as reliability metric for new fMRI labs and novice investigators seeking to test their acquisition and analysis techniques with minimal time investment and expense.