PANTALLA DE CONTROL DE CARGA MODIFICADA.

OUTLINE: This section will begin with a brief description of normal neurological development during the prenatal and early postnatal period. This will be followed by a review of the effects of reduced thyroid hormone levels on neuro­ logical development during this period. Finally, evidence from human studies of neuropsychological functioning on the effects of thyroxine deficiency in endemic cretinism, premature neonates and adults with acquired hypothyroidism will be considered.

Two questions will be addressed. Firstly, what type of neurological impairment results from thyroid hormone defi­ cit? Secondly, what is the evidence that the psychological deficits are a consequence of neurological impairments which occur at a specific time period of fetal or early postnatal life?

1. NORMAL NEUROLOGICAL DEVELOPMENT IN EARLY LIFE

Prenatal development of the nervous system can be divided into three periods, namely the germinal period (0- 14 days), the embryonic period which is characterised by cell proliferation and migration (2-9 weeks), and the fetal period where cell growth and differentiation are the predominant processes (9-40 weeks). In addition, the basic sequence of developmental events for each neuron is simi­ lar. This is well summarised by Stein et al (1991). "In a population of specific neurons, neurogenesis is followed by migration. Migration is followed by axonal outgrowth and

elongation and by dendritic outgrowth, elongation and branching. These events are followed by synaptogenesis and subsequently, myelination." However, such descriptions do not reflect the full complexity of brain development. The timing of the processes of cell proliferation, migration and differentiation vary according to the area of the developing brain and are dependent on the successful completion of previous neurological events. Bass et al (1977) wrote, "it is not possible to speak of a single maturational profile for the developing brain or cerebral hemispheres, unless we completely neglect the fact that the brain is exquisitely partitioned into a variety of systems whose rates of morphological and functional maturation are entirely different."

The beginnings of the nervous system can be observed at the third week of gestation with the neural groove which gradually deepens and eventually folds over on itself resulting in a fluid filled central canal called the neural tube (4 weeks). Cells in the wall of the tube begin to proliferate and growth increases at the cranial end where three outpouchings appear which rapidly differentiate into the rudiments of the forebrain, midbrain and hindbrain structures. By the end of the seventh week the cerebral hemispheres, the thalamus, pons and cerebellum can be readily identified.

At the beginning of the fetal period (9 weeks) the head constitutes at least half the mass of the fetus. At 8-10 weeks the early cortical plate (precursor of the

cerebral cortex) forms from the first major wave of migrat­ ing cells so that four layers of the cortex are visible at this time. As the cortical plate thickens due to migrating neurons, more layers are formed giving the cortex its final six layered composition by approximately 28 weeks.

At the beginning of the fifth month the increasing number of cortical cells causes the smooth surface of the developing brain to develop the typical pattern of convolu­ tions and sulci. Much of this growth is a consequence of glial cell proliferation and axonal and dendritic differen­ tiation. The weight of the brain continues to increase but the rate of increase is not constant. Dobbing and his colleagues (Dobbing 1977; Dobbing and Smart 1974) have found that there are two periods of development when brain growth is particularly rapid. The first of these "growth spurts" occurs between 15-28 weeks when there is very rapid neuroblast (immature neuron) proliferation. When the number of neurons in the developing brain has reached approximate­ ly adult levels the second growth spurt begins at about 30 weeks and involves an enormous proliferation of glial cells. This period continues into the second year of post­ natal life. It should be emphasised that in humans the main part of the brain growth spurt is postnatal and that the number of brain cells (predominantly glial cells) doubles between birth and the sixth postnatal month (Morreale de Escobar 1983). At birth, the brain is approximately 25% of the adult brain weight and by 30 months this has increased to approximately 75% (Rose 1976).

As well as the replication of glial cells, postnatal development also involves rapid myelination which continues well into the third and fourth years. There is also in­ creased synaptic connectivity brought about by further axonal and dendritic growth and elaboration. This is un­ doubtedly in part a response to environmental stimulation which promotes increasing functional organisation of the nervous system.

As emphasised at the beginning of this section, dif­ ferent structures in the brain follow different timetables. The development of the cerebellum clearly illustrates this diversity of process and timing. Cell proliferation is predominantly postnatal with only 17% of the final number of granule cells being present at birth. Cell migration, in contrast to the cortex, occurs in an "outside-in" direction so that the external granule cells finally form a layer beneath the Purkinje cells.

Dobbing (1977) has suggested that specific brain structures are more vulnerable to long term dysfunction during the earlier stages of cell proliferation and migra­ tion. The time period during which the fetus or neonate lacks thyroid hormone may be critical in understanding its differential effects on separate brain functions. As already described, the fetus obtains thyroid hormone from both the mother and, after about twenty weeks gestation, from its own thyroid system. As there is no evidence for maternal thyroid deficiency in CH, it is more probable that the insult to brain development due to thyroid dysfunction

occurs in the second half of gestation during the period of cell differentiation and growth. Evidence from animal studies does lend support to this hypothesis (see below). The timing of the neurological insult would also have different effects on parts of the brain depending on its relative maturity. For example, in the second half of gestation, the cerebellum is still in the process of cell proliferation and migration so that these earlier processes may be disturbed by thyroid deficits after twenty weeks gestation.