Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed "encephalopathy of prematurity". The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.

/pdf/brain-injury-in-premature-infants-a-complex-amalgam-of-44m95zo04a.pdf

Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances

Maturation of the adrenocortical stress response: Neuroendocrine control mechanisms and the stress hyporesponsive period

Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus

Glucocorticoids appear capable of damaging or destroying hippocampal neurons. There is a progressive loss of such neurons with age, and the process can be prevented by adrenalectomy at mid-age or accelerated by prolonged exposure to high circulating titers of glucocorticoids. The present study examines possible mechanisms for this steroid action. Rats were either adrenalectomized, intact, or treated with corticosterone (CORT) sufficient to produce prolonged elevations of titers in the high physiological range. After 1 week, unilateral hippocampal microinfusions were made with either kainic acid (KA) or 3-acetylpyridine (3-AP). Doses of these hippocampal neurotoxins were chosen to produce small-sized lesions. Treatment with CORT exacerbated the extent of damage following neurotoxin infusion, whereas adrenalectomy attenuated the damage. Additional studies eliminated some potential mechanisms for this phenomenon. CORT did not directly alter the intrinsic toxicity of the compounds but, rather, altered the sensitivity of target cells to them. As evidence, no potentiation of damage in CORT-treated animals occurred in KA-sensitive brain regions lacking CORT receptors. Since CORT did not increase the diffusion or binding of [3H]KA in the hippocampus, it appears unlikely that CORT potentiated toxin-induced damage by influencing the specific mechanism of action of any toxin. Finally, the general nature of the CORT potentiation of damage was supported by the markedly different postulated mechanisms of toxicity of KA and 3-AP. We hypothesize that CORT exerts its extensive catabolic effects upon target cells to produce generalized metabolic vulnerability in hippocampal neurons possessing high concentrations of CORT receptors, thereby sensitizing them to varied metabolic insults.

https://www.jneurosci.org/content/jneuro/5/5/1228.full.pdf

A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults

Brain abnormality in surviving premature infants is associated with an enormous amount of neurodevelopmental disability, manifested principally by cognitive, behavioral, attentional, and socialization deficits, most commonly with only relatively modest motor deficits. The most recognized contributing neuropathology is cerebral white matter injury. The thesis of this review is that acquired cerebellar abnormality is a relatively less recognized but likely important cause of neurodevelopmental disability in small premature infants. The cerebellar disease may be primarily destructive (eg, hemorrhage, infarction) or primarily underdevelopment. The latter appears to be especially common and relates to a particular vulnerability of the cerebellum of the small premature infant. Central to this vulnerability are the extraordinarily rapid and complex developmental events occurring in the cerebellum. The disturbance of development can be caused either by direct adverse effects on the cerebellum, especially the distinctive transient external granular layer, or by indirect remote trans-synaptic effects. This review describes the fascinating details of cerebellar development, with an emphasis on events in the premature period, the major types of cerebellar abnormality acquired during the premature period, their likely mechanisms of occurrence, and new insights into the relation of cerebellar disease in early life to subsequent cognitive/behavioral/attentional/socialization deficits.

/pdf/cerebellum-of-the-premature-infant-rapidly-developing-34ycoz0n9k.pdf

Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important.

Reductions in size and total DNA of cerebrum and cerebellum in adult mice after corticosterone treatment in infancy

DNA, ganglioside and sulfatide in brains of rats given corticosterone in infancy, with an estimate of cell loss during development.

GLUCOCORTICOIDS in large doses are known to interfere with body growth and bone maturation (WELLS and KENDALL, 1940; HOWARD, 1962; and others). Although there have been occasional reports of cerebral atrophy in Cushing’s syndrome (TRETHOWAN and COBB, 1952; SOFFER, DORFMAN and GABRILOVE, 1961) there seems to have been no systematic study of possible effects of corticoids on brain growth. In the course of observations on the effects of steroids on bone maturation, it was noticed that corticosterone given to infant mice produced a considerable reduction in brain weight, which will be described in this paper. The effects of restriction of body growth by corticosterone were compared with the effects of a similar degree of body growth restriction produced by limitation of food intake. To evaluate the significance of the decreases in brain weight, in terms of numbers of cells (BLOCH, 1958), the DNA content of the forebrain was determined. The results to be reported show that corticosterone exerted a significant interference with the normal increase in the DNA of the infant forebrain. The Nissl substance, long known to undergo a characteristic increase in relation to neuronal maturation, has been shown to contain RNA (EDSTROM and HYDI~N, 1954). In the present work, measurements of the RNA content of the forebrain were made as an approach to an evaluation of cellular maturation. Finally, cholesterol was measured as a representative of the lipids that are known to increase in amount with the progress of myelination (FOLCH-PI, 1955). Liver was studied also, since it provides an interesting comparison to the brain.

Evelyn Howard

Papers

Reductions in size and total DNA of cerebrum and cerebellum in adult mice after corticosterone treatment in infancy

DNA, ganglioside and sulfatide in brains of rats given corticosterone in infancy, with an estimate of cell loss during development.

Effects of corticosterone and food restriction on growth and on dna, rna and cholesterol contents of the brain and liver in infant mice.

Increased voluntary running and decreased motor coordination in mice after neonatal corticosterone implantation

Effect of neonatal food restriction in mice on brain growth, DNA and cholesterol, and on adult delayed response learning.