Book - Brain and behavioural development 3

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Dickerson JWT. and McGurk H. Brain And Behavioural Development. (1982) Blackie & Son Ltd., Glasgow.

Brain and Behavioural Development - 1982: 1 Neural Development | 2 Comparative Neural | 3 Malnutrition | 4 Hormones and Growth Factors | 5 Cortical Activity | 6 Functional Asymmetry | 7 Plasticity | 8 Sex Differences

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Chapter Three - Effects of Mafnutrition on Brain Growth and Development

John W. T. Dickerson, A. Merat And H. K. M. Yusuf


Introduction

Intelligence, a manifestation of brain function, is in part genetically determined. The extent to which this genetic potential is achieved is influenced by both the internal and the external environment. Thus, nutrition, hormonal status, infection, sensory stimulation, parental care, and many other factors are so closely intertwined in their effects on the brain that it is often difficult to distinguish the major factor(s) involved in a given situation. This is certainly so when we consider the brain development of children in malnourished communities. So complex is the problem (Cravioto et ai, 1966) that it might be considered to be purely of academic interest to discuss it at all. This is further emphasized by the paucity of our information about man, the species with which this book is mostly concerned. Fortunately, there is now sufficient evidence from animal experiments to make it possible to consider certain basic principles and to make reasonably confident extrapolations to man where the human data itself is inadequate. An understanding of the differences and similarities in the growth and development of the human brain and that of other species is of paramount importance in making any extrapolations (see Chapter 2).

It used to be thought that the brain was in some way ‘spared’ the consequences of malnutrition, and indeed its growth is always affected less by deprivation than that of the body weight. However, it is now clear from studies in experimental animals that the brain is particularly vulnerable to nutritional deprivation during the period of its growth spurt. Moreover, in the rat (Dobbing and Sands, 1971), and probably also in the human (Davies and Davis, 1970), the brain only has this single growth spurt which is strictly age-related. Consequently, a deficit in growth which occurs during this time may well not be compensated by subsequent catch-up growth.

Dobbing (1974) has emphasized three important points in connection with the extrapolation from animal studies to man which are often overlooked. The first of these is the actual length of the growth spurts. When considering a graph of these (see Fig. 2.7) it is easy to miss the fact that the spurt in the rat is a matter of days, whereas that in the pig is measured in weeks and that in the human in months. Thus, undernourishing a rat from birth for three weeks eclipses the entire growth spurt whilst the same period of time in the human would eclipse only a small fraction of the spurt. The second fact which Dobbing mentions is the irrelevance of birth, for this occurs at different times in relation to the spurt in different species. As far as we know at present, birth does not affect the growth curve of the brain except insofar as the metabolism of the brain may be affected by hypoglycaemia or hypoxia. Finally, it is of importance to emphasize that the various cellular systems in the brain develop in a definite order and relationship to the growth spurt of the whole brain. In the human foetus the neuroblasts, which develop into neurones, have completed most of their development by the beginning of the growth spurt which is mainly the result of neuroglial proliferation, dendritic arborization and synaptic development and, later, myelination. Thus, the critical period is post-neuronal and during neuroglial proliferation. The early completion of the main neuronal spurt by about 18 weeks (Dobbing and Sands, 1973) means that neuronal proliferation in the human is largely ‘protected’ for it is very difficult to malnourish an embryo. In contrast, the rat with its postnatal growth spurt may be particularly vulnerable to neuronal damage as it is relatively easy to malnourish the animal during the phase of neuronal development. Nutritional deprivation for varying periods of time at different ages will therefore expose different structure-types of cells, dendrites, synapses, and myelin, as well as different functions to the effects of malnutrition in different species.

Valuable as animal experiments are, they cannot replace, only complement, studies in man, even though these have to be much more limited in their scope. Broadly speaking, three kinds of human investigations are possible—measurements of the growth of the brain and its chemical development, and an assessment of some of its functions.

Brain size

Brown (1966) reported the weights of brains taken from autopsies of over 1000 children in Uganda. The mean body weight and mean brain weight were significantly lower at various ages in ‘malnourished’ than in ‘non-malnourished’ children and both were lower than a published reference standard. The brain : body weight ratios of the malnourished children were slightly higher than those of the non-malnourished children. The extent to which this may have been accounted for by oedema in the brains of children with kwashiorkor could not be ascertained. Oedema of the brain may account for the increased translucency of the head found in acute PEM, which disappeared after 6. months’ rehabilitation (Ergsner et al, 1974). Figure 3.1 shows that the weights of the brains of children dying from PEM in Jamaica tended to be too heavy for their body weight when compared with those for non-malnourished ‘controls’ (Dickerson, Merat and Waterlow, unpublished). The highest ratios tended to be in the more severely malnourished children.


Figure 3.1 The brain weights of malnourished (X) and ‘control’ (#) Jamaican children, plotted (a) against age, and (b) against body weight (from Merat, 1971).


In clinical practice the growth of the brain must be measured indirectly, and head circumference is on the whole accepted to correlate with brain size (Stock and Smythe, 1963; Ergsner, 1974: Cooke et al ., 1977). Ergsner has reported that marasmic infants, possibly because of the earlier occurrence of the malnutrition, have a greater reduction in head circumference than those with kwashiorkor. Catch-up of head circumference occurs during rehabilitation (Ergsner et al ., 1974) and tends to be more rapid and complete in children with kwashiorkor than in those with marasmus (Pearl et al ., 1972).

Malnutrition may also occur in utero resulting in the birth of babies who are underweight for their gestational age, called ‘light-for-dates’ or LFD’s. The head circumference and brain weight of such children have been found to be small for their gestational age (Gruenwald, 1963) though normal for body weight (McLean and Usher, 1970). Head circumference less than the tenth percentile at birth has been found to be associated with poor growth, later microcephaly and neurological deficit in a group of American children whose growth and development were evaluated at 5 years of age and who had weighed 2000 g or less at birth (Gross et al ., 1978). In a longitudinal study (Davies, 1980) it was found that head circumference growth was faster during the first 6 months after birth in LFD than in ‘appropriate-for-dates’ (AFD) babies. Presently available evidence suggests that even severe intra-uterine undernutrition may not necessarily permanently hinder catch-up (Davies, 1980).

Appropriate formulae have been worked out from the limited analytical data available in the human, relating head circumference to brain weight and to protein and DNA content during the first year of life (Winick and Rosso, 1969). Correlations have also been calculated between neonatal body weight and adolescent brain development in rats (Zamenhof et al ., 1979).


Brain composition

Cellular growth

In the whole rat brain, Winick and Noble (1965) produced evidence to show that DNA synthesis, and hence cell replication, stops at about 20 days of age, whereas deposition of protein continues until the brain reaches its adult weight at about


Figure 3.2 Schematic representation of an earlier view (Winick and Noble, 1966) of tissue growth. Phase I, cell division or ‘hyperplasia’. Phase II, cell division mixed with start of increase in cell size. Phase III, increase in cell size, or ‘hypertrophy’. (Redrawn from Sands et al, 1979, with permission).


90 days of age. It is then possible to distinguish three phases of growth- hyperplasia alone, hyperplasia and hypertrophy, and hypertrophy alone (Fig. 3.2, from Sands et al, 1979). From these results, Winick and Noble (1966) deduced that the control of catch-up growth following a period of growth retardation due, for instance, to malnutrition, depended on the nature of the growth process which was taking place at the time of the insult. Thus, interference with hyperplastic growth would permanently affect cell number and lead to true microcephaly, whereas complete recovery would be possible when only hypertrophic growth was reduced. This suggestion is attractive, seems to fit the findings, and had not been seriously challenged until recently when Dobbing and his colleagues (Sands et al, 1979) showed that a re-examination of the growth events in a number of organs does not show the expected sequence and does not support the previous suggestion that the period of hyperplastic growth constitutes a vulnerable period.

Effects of intra-uterine under nutrition. Intra-uterine undernutrition is usually the result of placental insufficiency and the consequent decrease in the flow of nutrients to the foetus. Intra-uterine growth retardation (IUGR) can also be the result of maternal malnutrition if the mother’s body is depleted due to a poor dietary intake before and during pregnancy, severe illness or frequent close pregnancies. Information about the effects of this kind of malnutrition on the human brain is scanty.


Figure 3.3 The effect of protein-energy malnutrition on the DNA content of the human cerebellum, cerebrum, and brain stem. Values for malnourished children shown O and those for ‘normal’ children shown • (Winick et al ., 1970, and redrawn from Winick, 1976, with permission).


The amount of DNA in the brain depends on the size of the LFD infant (Chase et al , 1972; Sarma and Rao, 1974). Thus in the smaller infant studied by Chase et al the DNA content of the cerebellum was more severely depleted than that of the cerebrum-brain stem. In the latter study differences in depletion between the different parts of the brain were smaller. It is, of course, as pointed out, not known whether such a depletion in cell number could be made up by postnatal rehabilitation nor, indeed, if they are made up, whether the kind of cells formed will be in the same ratio as they would have been had they been formed prenatally (Chase, 1976).

In the human brain it is likely that the number of neurones will only be reduced by undernutrition early in gestation and that even late in gestation it will mainly be glial cell replication which will be reduced. Chase (1976) has suggested that loss of glial cells would not be likely to be as detrimental to intelligence as loss of neurones, and similarly that loss of cells from the cerebellum would not be as detrimental as loss of cells from the cerebrum. Impaired replication of glial cells would be expected to be associated with a decrease in the amount of myelin in the brain since this is formed from the membranes of oligodendroglial cells. Chase pointed out that complete removal of the cerebellum in a number of species results in disorder of movement while no recognizable function relating to intellect, perception or the sensory functions of touch, sight or hearing seemed disturbed by its removal (Dow, 1970).

In the rat, maternal undernutrition during gestation alone has been said to have only a small transient effect on the brain (Barnes and Altman, 1973), and perhaps this is to be expected since the growth spurt of the rat brain is entirely postnatal. However Dobbing (1981) has pointed out that in the rat birth falls between the two consecutive periods of neuronal and glial multiplication, a stage which occurs in mid-gestation in the human. Thus in the rat maternal undernutrition during the last one-third of pregnancy would be expected to reduce neuroblast replication.

Effects of postnatal malnutrition. Our knowledge of the effects of protein-energy malnutrition (PEM) on the number of cells in the human brain is scanty. It seems reasonably certain, however, that the brains of children severely malnourished early in life are small for their chronological age, though they contribute a larger than normal proportion to the body weight (Fig. 3.1). The different parts of the brain of such children contain a smaller amount of DNA than those of more normally nourished children when compared on the basis of chronological age (Fig. 3.3), but probably not when compared on the basis of weight (Fig. 3.4). In the same way the supine length or height of a child is affected by chronic, in contrast to acute, malnutrition, so it would be expected that the brain growth of children suffering only a transient period of acute dietary deprivation would be affected less than that of those for whom the deprivation was prolonged.

A problem arises in human populations of identifying with any accuracy the period of malnutrition. Thus it is not unlikely that children who die of PEM were also small at birth due to maternal malnutrition, but it is impossible to get this information in countries like Chile, Uganda or Jamaica from which most of the human material has been taken. However, the effect of malnutrition on brain cellularity has been studied in malnourished infants aged one to two years who were initially breast fed and of whom some were known to have had a normal birth weight (Chase et al , 1974). In these children, the amount of DNA in the cerebrum-brain stem, although lower than control samples for age, was not significantly different. Cerebellum DNA was similar in the malnourished and control children. Chase (1976) suggested that since these children represent the most frequent form of PEM (marasmus and marasmic kwashiorkor) affecting the world’s children, the differences between their study and those of Winick and colleagues may be due to the initial period of breast feeding and thus emphasize the importance of encouraging breast feeding in pre-industrial societies.

The information that is available about the effects of malnutrition on the human brain does not enable us to conclude anything about the permanency of the effects on brain growth or any aspect of its development although, as already pointed out, catch-up of head circumference does occur. In the rat the results of experiments too numerous to review in detail have clearly shown that if the growth of a rat is retarded up to 21 days of age its brain will remain permanently small and contain a smaller than normal amount of DNA. Thus, brain growth and cell replication is determined by chronological age rather than by stage of development. Furthermore, once the process has stopped it cannot be restarted and undernutrition does not alter the timing of its peak velocity, but merely the height of the peak which fails to return to its normal level on rehabilitation (Dobbing and Sands, 1973).

In the rat, relatively mild undernutrition produced by increasing the number of pups in a litter suckled by one mother to weaning (Kennedy, 1957-58; Widdowson and McCance, 1960) can produce a permanent reduction in brain DNA because the nutritional deprivation coincides with the entire growth spurt of the brain. In the pig where the growth spurt is perinatal (Davison and Dobbing, 1966) more severe undernutrition starting towards the end of the spurt is necessary to produce a similar effect (Dickerson et al , 1967). Earlier experiments in the rat (Dickerson and Walmsley, 1967) suggested that the DNA content of the brain of the weanling rat was not affected by undernutrition, and this result would agree with the view that there is a rather clear cut-off point at about 21 days for the cessation of cell replication in rat brain (Winick and Noble, 1966). However, an experiment in which growth was retarded more severely from weaning by feeding a low protein diet (Dickerson et al , 1972) showed that cell number in some areas was permanently reduced. This finding would lend some support to the more recent doubts as to the validity of the idea of a sharp cessation of hyperplastic growth (Sands et al , 1979).


Figure 3.4 The DNA content of the human brain plotted against the brain weight. Values for malnourished children shown +, and those for ‘controls’ shown #. Age of foetuses in weeks (W), others in months. (From Dickerson, 1981).


In the rat there are regional differences in the way in which cell multiplication is modified by undernutrition during the nursing period (Fish and Winick, 1969). The cerebellum, where the rate of cell division is most rapid, is affected earliest (that is by 8 days of age) and most markedly. An effect on the cerebrum with its lower rate of cell division appears later (that is by 14 days of age) and is less marked. In the hippocampus, the movement of cells from under the lateral ventricle is delayed and perhaps even partially prevented. Radioautographic studies with labelled precursors have shown that in neonatal rats undernourished for the first 10 days after birth only glial cell multiplication is inhibited in the cerebrum since, as we have seen, neuronal multiplication stops before birth. A reduction in the rate of cell division of neurones under the lateral ventricle accounts, at least in part, for the reduction in the DNA content of the hippocampus at 15 days of age.

Few studies have been carried out in which a biochemical approach to the problem of the effects of malnutrition on the brain have been supported by histological investigation. That histological changes do occur at any rate in animals reared from weaning on low protein diets was shown in rats by Platt (1962) and in pigs and dogs by Platt et al (1964). These workers described degeneration of both neurones and glia in the spinal cord and medulla and found that the changes persisted for as long as 3 months after rehabilitation on a high protein diet. The changes were exacerbated by beginning the malnutrition at an earlier age or by continuing it for a longer period. Neurones in grey matter were reduced in number, appeared swollen and were surrounded by a greater than normal number of ‘satellite cells’. Histochemical changes have been described in the brains of rats malnourished early in life (Zeman and Stanbrough, 1969). By means of special staining techniques it was demonstrated that the enzyme development of the brain was delayed. In some ways the effects of thyroid deficiency and corticosteroid administration are similar to those of undernutrition (Balazs, 1973) and these are discussed in Chapter 4.


Myelin lipids and myelination

Effects of intra-uterine undernutrition. Information is sparse about the effects of intra-uterine growth retardation on the composition of the brain. Such reports as there are usually relate to the analysis of the brains of very few infants.


The accumulation of the myelin lipids, cerebroside sulphatide (Chase et al , 1972) and galactose cerebroside (Sarma and Rao, 1974) and the activity of the rate-limiting enzyme of sulphatide synthesis, galactolipid sulphotransferase (Chase et a/., 1972) have been found to be low in the brains of LFD babies with respect to their chronological age. As with the DNA content,-we know nothing about the permanency of such changes.

The rat is in some ways not the best model for the human LFD baby. The young animal, and therefore its brain, is small so that the number of analyses that can be performed on a single brain is limited. Moreover, as we have seen, the timing of the growth-spurt of the rat brain is entirely different with respect to birth to that of the human. The newborn piglet, on the other hand, more nearly approximates in weight to that of a newborn baby and the growth spurt of its brain, like that of the human, is perinatal. A litter of piglets may number twelve or more and the body weight of the individual foetuses may vary by a factor of two. A study in which the brains of runt newborn piglets were compared with those of their large littermates and also with normal foetuses of 93-95 days gestation but the same body weight (Dickerson et al , 1971) showed that myelination, as judged by the concentration of cholesterol, was delayed in the growth retarded newborn piglets, but was further advanced than in the normal foetuses of similar body weight. Cellular replication was also retarded in the runts but the mean size of the cells, as judged by the protein/DNA ratio, was similar in each part of the brain to that in the large piglet.

Effects of postnatal malnutrition. There is abundant evidence from biochemical (Dobbing, 1964; Benton et al , 1966; Chase et al , 1967; Dickerson et al , 1967) and histological studies (Benton et al, 1966; Fishman et al, 1969; Stewart et al, 1974) that nutritional deprivation during the period of most rapid growth of the brain retards myelination. More recent studies (Wiggins and Fuller, 1979) using a double isotope technique, have shown that early postnatal undernutrition in the rat depresses myelin synthesis to about the same extent in all major brain regions (cerebral cortex, medulla oblongata, midbrain, hippocampus, striatum and hypothalamus) at 18 and 21 days of age. Furthermore, full recovery in terms of the total amount of myelin in the brain is not possible on subsequent rehabilitation. In the rat, deposition of cholesterol, a commonly used marker for myelin, continues for some time after the normal weaning age of 21 days. In the experiment to which reference has already been made (Dickerson et al, 1972) in which the body weight of weanling rats was held constant for 4 weeks by feeding a low protein diet, deposition of cholesterol in the forebrain and brain stem continued to be below control values after rehabilitation. The period of growth retardation in these animals was after the spurt in myelination is normally considered to be complete. One explanation of this finding is that, as in the human brain (p. 56), myelination occurs in cycles and that there are areas in the brain in which it starts and finishes during the early post-weaning period.

We do not know whether myelination will achieve the normally expected levels on rehabilitation of malnourished children, or indeed whether a smaller than normal amount of myelin has any functional significance. Evidence from determinations of cerebroside-sulphatide (Chase et al ., 1974) and cholesterol (Rosso et al, 1970) suggest that the brains of malnourished children contain too little myelin for their chronological age. However, examination of a larger number of brains from children in whom the malnutrition was evidently of differing severity (Dickerson, Merat and Waterlow, unpublished) suggested that myelination may be reduced only when the children have been chronically malnourished. Moreover, the amounts of cholesterol in the forebrains of malnourished children are probably appropriate for the weight of the forebrains even when these are severely reduced for age (Dickerson, 1975).


Figure 3.5 Effect of development and malnutrition in early life on the cholesterol ester ratio (cholesterol ester as percentage of total cholesterol) of the human forebrain, cerebellum and brain stem. Forebrain: controls O, malnourished #; cerebellum: controls A, malnourished A; brain stem: controls □, malnourished ■.


In the rat, it seems clear that chronic undernutrition delays the maturation of myelin and hence results in a difference, when compared with that of normal animals of the same age, in the qualitative nature of the membrane. Earlier studies (Fishman et al , 1971) in which the composition of the myelin was reported to be normal were not supported by morphometric investigations (Krigman and Hagan, 1976) which showed a 15-fold preponderance relative to control of promyelinating fibres in 30-day-old undernourished rats. Wiggins et al (1976) also found the pattern of myelin-specific proteins in undernourished rats to be characteristic of younger controls. Furthermore, the high preponderance of cholesterol esters in the brain of malnourished children (Fig. 3.5; Yusuf, 1976) and mice (Yusuf and Mozaffar, 1979) has also been interpreted as indicating immaturity of myelin.

Nervous tissue contains a number of species of lipids called gangliosides (Table 2.1) which are primarily located, as the name implies, in neurones and their associated processes. A small amount of ganglioside, accounting for 0.8-1.2% of the total ganglioside of the rat forebrain (Yusuf, 1976), can be recovered from myelin. The total concentration of ganglioside NeuNAC in myelin remains more or less constant, irrespective of age, at about 50 jug per 100 mg (Suzuki et al, 1967). It follows therefore that the increase in the amount of NeuNAC recovered from myelin with increasing age (Table 3.1) represents


Table 3.1 The effect of age on the ganglioside composition of myelin from the rat forebrain


Ganglioside NeuNAC Mole percentage distribution


Age

(days)

in myelin (jig/brain)

Gmi

fjDla

^Dlb

G T i

21-22

7.3

42 (2.8)*

19(1.2)

23 (1.5)

15(1.0)

31

9.5

57(5.5)

19(1.7)

19(1.7)

5 (0.5)

51

13

68 (8.8)

15 (2.0)

13(1.6)

4 (0.5)

81

16.4

75(12.4)

10(1.6)

12 (2.0)

3 (0.5)

121

21

85(17.8)

6 (1.3)

6(1.3)

2 (0.5)


Values in parentheses are the total amounts of ganglioside NeuNAC in jig in each fraction the increased deposition of myelin itself. Maturation of the membrane was accompanied by a change in the pattern of the major gangliosides with the mole percentage of the monosialoganglioside, G M1 , increasing with age. These changes are a useful basis for the study of the effects of undernutrition on myelin development.

Pregnant rats were given 50 % of the amount of food consumed by control pregnant animals on the same day of gestation and food restriction was continued through lactation and in the offspring through 121 days of age (Yusuf and Dickerson, 1979). Purified myelin prepared from the forebrains of these animals contained a greater than normal proportion of the multisialo- gangliosides, G Dla , G mb and G T1 (Svennerholm, 1963) from day 31 and a lower than normal proportion of the monosialoganglioside, G M1 , the major ganglioside of mature myelin (Table 3.2). The absolute amount, in /tg, of G M1 did not, however, differ from the control value so the difference in composition brought about by undernutrition was entirely due to retention of the multisialo- gangliosides. The cause of the retention of these compounds is not at presen> known, but one explanation is that immature myelin may be a mixture of ‘mature’ myelin and glial cell membranes and that the immature matrix of ‘premyelin’ is gradually converted to the adult membrane during brain development (Smith, 1967; Cuzner and Davison, 1968).

The ganglioside molecule contains glucosamine and measurements of the incorporation of tritiated glucosamine (d-[1 — 3 H]glucosamine) into myelin G M1 showed that the rate of incorporation in the undernourished animals was higher and so too was the rate of decay (Yusuf and Dickerson, 1979). The differences between these animals and their controls was brought out more clearly when the calculated half-life of G M1 was considered. During the 30-60


Table 3.2 The effect of chronic undernutrition on the ganglioside composition of myelin from the rat forebrain


Age

{days)

Ganglioside NeuNAC in myelin (gg/brain)

Gmi

Mole percentage distribution

t^Dla ^Dlb

G T1

21-22

6.6

45 (2.8)*

22(1.3)

18(1.1)

15(1.0)

31

10

48 (4.7)

26 (2.6)

16(1.6)

10(1.0)

51

17

57 (9.7)

18(2.1)

18 (3.0)

6(1.0)

81

27.3

47(12.8)

26 (7.1)

23 (6.3)

3 (0.8)

121

30.9

49(15.3)

35 (7.9)

21 (6.6)

3(1.0)


Values in parentheses are the total amounts of ganglioside NeuNAC in gg in each fraction

day interval this was 42 days as compared to 109 days in the controls. Similarly, during the 60-100 day interval the values in the two groups were 37 and 992 days respectively. The long period in the control animals (probably at least equal to the life-span of the animal) is in accord with earlier studies which showed that when 14 C labelled cholesterol or 32 P labelled phosphate were injected into growing animals the label could be recovered from the brain at least 12 months later.

These experiments suggest that chronic undernutrition in the rat, at least, not only retards the deposition of myelin and its maturation, but the membrane formed is metabolically unstable. Destruction of myelin is characteristic of demyelinating diseases, such as multiple sclerosis (MS). White matter from the brain of an individual with MS contains a greater than normal proportion of cholesterol esters and consequently has a high cholesterol ester: cholesterol ratio. A similarly elevated ratio has been found in the brains of children dying of PEM (Fig. 3.5). Could it be that it is the result of the instability of the myelin and consequent demyelination rather than simply myelin immaturity as suggested earlier?


Malnutrition and synaptic development

Each of the 10 11 neurones in the adult human brain consists of a cell body surrounded by a network of delicate tube-like extensions, the dendrites, which provide the main physical surface on which the neurone receives incoming signals. The axon, usually thinner and longer than the dendrites, extends away from the cell body and provides the pathway over which signals can travel from the cell body to other parts of the brain. Information is transferred from one cell to another at specialized points of contact, the synapses (Fig. 3.6). A typical neurone may have from 1000 to 10000 synapses and receive information from something like 1000 more (Stevens, 1979).

The transfer of information across the synapses is accomplished by a chemical transmitter which is synthesized and stored in vesicles within the synaptosome (Fig. 3.6). Passage of an impulse involves the release of the transmitter at the presynaptic membrane into the synaptic cleft and its subsequent inactivation at the postsynaptic membrane. A number of substances have been identified as transmitters. These include acetylcholine (Ach), serotonin (5-HT) and norepinephrine (NE). Histamine and certain amino acids (e.g. glutamic acid and y-aminobutyric acid (GABA)) also function as transmitters. Certain parts of the brain are rich in synapses containing particular transmitters.

It is clear that the development of the information system within the brain involves not only the structural basis for the retention and transfer of information—neurones, dendrites and axons, but also the enzyme systems involved in the synthesis and degradation of the chemical transmitters.



When we consider the growth of the structural components—the dendrites, axons and associated synapses—it must be said that we know very little of a quantitative nature about the timing of these processes. Such information as there is in man has been gained by the use of staining techniques, the Golgi method or a variant of it, which are in themselves fickle and make possible little more than a crude comparison. Probably all that can be said at present is that the process of dendritic arborization is predominantly postnatal (Dobbing, 1981).

The best hope presently available, as pointed out by Dobbing, seems to be in the application of the more modern technique of stereology and this is being exploited in studies of the effects of undernutrition in experimental animals (see below). However, application of this technique to the human brain is made difficult by the unavailability of acceptable material and by the sheer bulk of the organ. At present therefore it would seem that a chemical marker would offer certain advantages. Gangliosides seem to have some merit as markers since they are located in high concentration in grey matter; the changes in ganglioside patterns with development in different parts of the brain in different species have been discussed above (p. 59).

Unreliable as the normal staining procedures are, they have suggested that undernutrition from birth in the rat results in substantial reduction in synaptic development (Cragg, 1972; Salas et al ., 1974). By means of stereology, Dobbing and colleagues (Thomas et al ., 1979) have shown that a period of moderate undernutrition from birth results in a deficit of about 37% in the average number of synapses per neurone in the cortex. The important question is, of course, whether this deficit persists on rehabilitation, and adult rehabilitated animals did, in fact, provide no evidence of permanent deficiency (Thomas et al , 1980).

In an attempt to study the effect of the severity and timing of malnutrition on dendritic development using the total ganglioside NeuNAC content as a marker, rat pups were malnourished in three different ways (Merat and Dickerson, 1974). They were (a) undernourished from birth by increasing the litter size, (b) malnourished by feeding future mothers a 12% protein diet from weaning and maintaining them on this diet through pregnancy and lactation, and (c) by giving mothers a 7 % protein diet during gestation and lactation. In view of the fact that many human mothers in poor countries may have a marginally adequate protein intake throughout their lives, it is of interest that the brains of the offspring of rat mothers in group (b) were of normal weight and contained normal amounts of gangliosides. Pups in the other two groups were small for their age at weaning, and had smaller brains which contained smaller than normal amounts of gangliosides. The reduction in gangliosides in the animals whose growth was retarded only from birth was proportional to the reduction in brain weight, but in the brain stem of the more severely retarded animals of group (c) there was evidence of a specific effect of malnutrition on ganglioside deposition so that the amount present was too little for the weight (Fig. 3.7).

Similar results have also been obtained from forebrain tissue of children dying from malnutrition in Jamaica. Fractionation of the gangliosides in these brains showed that the deficit in the total ganglioside NeuNAC in the forebrain was entirely accounted for by the smaller amount of the disialoganglioside, G Dla


Figure 3.7 The effect of the severity of malnutrition in the rat on the relationship of the amount of A-acetylneuraminic acid (NeuNAC) in the brain stem to brain stem weight. Numerals indicate ages of rats in days reared, • 3 pups to one mother, O 8 pups to one mother, ■ 15 pups to one mother, □ 15 pups to one mother that had been reared on a 12 % protein diet since 24 days of age, A 8 pups to one mother that had been fed a 7 % protein diet from the 5th day of gestation. (From Merat and Dickerson, 1974).


(Fig. 3.8; Merat, 1971; Dickerson, 1980). On the assumption that the distribution of the different gangliosides between the different structural components of the human brain is similar to those in rat brain, it seems that the deficiency in the amount of G Dla might indicate that malnutrition in the human, as in the rat, retards the development of dendritic arborization. Moreover, the retardation in this aspect of brain development would appear to be of a relatively greater magnitude than that which occurred in cell replication or myelination in the same brains, since the amounts of G Dla , but not of DNA or cholesterol, were too small for the weight of the forebrains. It would seem therefore that this feature of developmental retardation might be more serious from a functional viewpoint, for the transmission of information throughout the brain might be less efficient. However, suggestions of this sort, though tempting, are at present a matter only of conjecture.

It may be, however, that gangliosides are related to behaviour and brain function in other ways than simply as structural components of membranes. Theories of learning have been suggested which involve the NeuNAC component of the ganglioside molecule acting as a specific binding site for positively charged neurotransmitters (Schengrund and Nelson, 1975). In support of this link between gangliosides and brain function, small changes in ganglioside metabolism have been reported to occur in the whole brain of rats after shortterm environmental stimulation (Dunn and Hogan, 1975; Irwin and Samson, 1971). More recently, increase in the content of certain ganglioside fractions in particular areas of the rat brain after long-term active avoidance conditioning has been shown to be associated with permanent functional connection of the neurones involved (Savaki and Levis, 1977).

These observations are relevant to a possible link between biochemistry and function in the brains of nutritionally deprived animals and children. Further support for such a link has been provided by experiments in which undernourished rat pups were subjected to early stimulation (Morgan and Winick, 1980a). Stimulation of the pups during the first 21 days of life reduced the change


Figure 3.8 The effect of protein-energy malnutrition on the amount of the disialo-ganglioside, G Dla , in the human forebrain. Values for malnourished children shown +, and those for ‘controls’ shown £. Age of children given in months. (From Dickerson, 1980).


in open-field behaviour induced by the malnutrition. This improvement in behaviour was associated with a significantly higher ganglioside and glycoprotein NeuNAC content in both the cerebrum and cerebellum. Of particular interest was the fact that at age 6 months after the animals had been rehabilitated on a standard laboratory diet, the effects of the early stimulation were shown in an improved ability to learn a Y-maze. The increased levels of gangliosides and glycoprotein NeuNAC also persisted in the adults. The same workers tried another approach to the problem (Morgan and Winick, 1980b). NeuNAC administered intraperitoneally was found to result in raised cerebral and cerebellar ganglioside and glycoprotein NeuNAC. Treatment from 14 to 21 days after birth of rat pups malnourished for the first 21 days of life was found to bring about these changes without affecting brain weight, cell size or number. Changes in behaviour similar to those resulting from early stimulation were described.

The fact that both environmental stimulation and administration of NeuNAC caused the same changes in brain NeuNAC may well suggest that brain NeuNAC plays a role in determining behaviour. An additional link in the biochemical explanation for this role is provided by earlier reports of the close association between NeuNAC and serotonin-containing vesicles (Weseman, 1969). The liberation of NeuNAC from these vesicles by sialidase treatment seems to facilitate the release of serotonin from the vesicles. As we shall see, malnutrition in the growing rat reduces the concentration of serotonin in the brain (Dickerson and Pao, 1975).

The enzyme Na + K + -ATPase plays an important role in the maintenance of sodium and potassium in tissues. Moreover, in nervous tissue the activity of this enzyme is necessary for the polarization of neurones after transmission of the nerve impulses. The activity of the enzyme is extremely low in the brain of the newborn rat and increases rapidly during the brain growth spurt which also coincides with the spurt in myelination (Samson and Quinn, 1967). It is also of interest that the enzyme requires lipids such as cholesterol (Noguchi and Freed, 1971) for its activity.

Undernutrition of rat pups by removing them from the mother for 12 h each day from the 6th 11th day or 6th-17th day resulted in a significant reduction in Na + K + -ATPase activity in cortex homogenates which was partially recovered after 4 weeks’ rehabilitation (Mishra and Shankar, 1980). Again, these changes may have relevance to brain function, for a change in the activity may affect the proliferation ol nerve cells (Samson and Quinn, 1967). The ouabain-sensitive fraction of the enzyme, which was also reduced in this experiment, may also be related to neurotransmitter release (Gilbert et al., 1975). Mishra and Shankar postulated that since inhibition of ATPase may be the physiological mechanism of neurotransmitter release, an analogous situation could occur during undernutrition. Greater release of neurotransmitter in undernourished animals may bring about disturbances in the functioning of nervous tissue.


In these rats the concentrations of sodium and potassium in the brain were normal. However, the concentration of potassium has been reported to be low in the brains of malnourished children (Alleyne et al , 1969), particularly when the children had gastroenteritis and were presumably losing excessive amounts of potassium in the faeces.


Malnutrition and energy metabolism

For obvious reasons most of our knowledge of brain metabolism has been derived from studies on experimental animals.

Glucose is the main energy substrate utilized by the brain under normal circumstances and is almost completely metabolized to carbon dioxide and lactate. The first convincing evidence that glucose could be replaced in part by other substrates came with the discovery that there was a considerable uptake of acetoacetate and 3-hydroxybutyrate, as measured by arterio-venous differences, by the brains of patients undergoing prolonged therapeutic starvation for obesity (Owen et al , 1967).

In the adult rat the uptake of ketone bodies by the brain is dependent on their circulating concentrations and when these are increased by starvation in the pregnant animal the activities in foetal brain of the enzymes involved in ketone utilization are increased. These enzymes are therefore substrate-induced in foetal brain in contrast to those in adult brain where starvation or fat-feeding has no effect on the activities of the 3 enzymes involved—3-hydroxybutyrate dehydrogenase, acetoacetyl-CoA thiolase and 3-oxoacid CoA transferase (Williamson and Buckley, 1973).

The newborn mammalian brain, including the human brain, is more resistant to anoxia than is the adult organ. However, it is important to note that even short periods of anoxia reduce the rate of cell division in neonatal rat brain as measured both by DNA content and by thymidine incorporation (Baum et al , 1976). As Winick (1976) has pointed out, this difference between the neonatal ability to withstand anoxia and its effect on cell multiplication is important because foetal malnutrition, resulting in intra-uterine growth retardation (IUGR), so often involves vascular insufficiency. Moreover, anoxia at birth in the human full-term baby occurs at a time when brain growth and cell replication is taking place at a rapid rate and it clearly may have an effect on this process.


Fatty acids and brain development

The brain differs from most other organs in that it contains practically no neutral fat, that is triglyceride. Its appreciable content of fatty acids is due to their presence in the various complex phospho-, glyco- and sphingolipids which are important membrane components. Fatty acids can be broadly classified as ‘saturated’ or ‘unsaturated’ and the latter may contain one or more double bonds in different positions along the carbon chain. The unsaturated fatty acids in the brain are derived from two parent short-chain polyunsaturated fatty acids (SCP)—-namely linoleic (18 : 2 co6) and linolenic (18 : 3co3) acids, which are not synthesized de novo in the mammal (Alfin-Slater and Aftergood, 1968; Holman, 1973) although a dietary requirement for linoleic acid only has been shown in man (Collins et al, 1971; Holman, 1973). These parent fatty acids are converted by chain elongation and desaturation into the long-chain polyunsaturated fatty acids (LCP) necessary for brain growth and development. Crawford and his colleagues (Hassam et al ., 1975) have suggested that LCP may not be readily synthesized from SCP because the rate of desaturation is low or because the necessary desaturating enzymes are absent (Cowey et al , 1976).

The overall spectrum of polyunsaturated fatty acids in the human brain changes with age and interest in the LCP is related to the fact that they are associated with the grey matter, growth of which occurs primarily in utero. Since LCP may not be readily synthesized from SCP during the period of rapid brain growth and also since they are not present in vegetable foods, it might appear that animal fat would be necessary in the diet for the normal development of the human brain (Crawford et al ., 1973). This is clearly of considerable importance for those masses of the world population whose diet does, in fact, consist wholly or mostly of vegetable foods.

Presently available evidence suggests that the mother can desaturate and elongate SCP to LCP in her liver, and the foetus obtains its supply of both types of fatty acids from the maternal blood that passes through the placenta (Sanders et al , 1977). Foetal plasma choline phosphoglycerides contain more LCP and less SCP than those of maternal plasma so it seems that the placenta modifies the maternal supply of polyunsaturated fatty acids by preferential absorption or by the desaturation and elongation of SCP. Furthermore, additional modification can be accomplished in the foetal liver and it seems that all these processes are likely to have the result that the supply of fatty acids for the foetal brain is independent of the maternal diet. This conclusion is supported by work in rats (Eddy and Harman, 1975) in which it was shown that varying the degree of unsaturation, or the content of maternal dietary fat, with the exception of lard, did not influence the fatty acid composition of whole brain lipid or of the two major phospholipids, phosphatidyl ethanolamine and phosphatidyl choline in their offspring. The lard used in these experiments contained a small amount of docosahexaenoic acid (22 : 6co3) and the level of this fatty acid was raised in the brains of the offspring of mothers given the lard diet.

It is of interest that the few vegan mothers who have been studied in Britain have produced quite normal infants who have developed into normal children (T. B. Sanders, personal communication).


The developing brain is affected by a dietary deficiency of essential fatty acids (EFA). The results of studies on the offspring of females fed a virtually fat-free diet who were continued on the same diet after weaning showed that the brain is less sensitive than other organs to this deficiency (Galli, 1973). This is also true when the animals are exposed to the effects of a low maternal intake of EFA prenatally (Ailing et al , 1973). In the former study the fatty acids of ethanol- amine phosphoglyceride isolated from the myelin of 180-day-old male rats contained a lower than normal proportion of n-6 acids and a higher than normal proportion of n-9 acids. The triene : tetraene ratio was 1.79 in the EFA deficient animals compared with 0.18 in the controls. These changes were, however, reversible, thus demonstrating that the fatty acids of brain lipids, even those of myelin, undergo continuous replacement. At ages earlier than 180 days it becomes progressively unlikely, the younger the animal, that changes in the fatty acid composition of the brain will be found due to the mobilization of EFA from maternal depots. Changes were, however, pronounced at 18 days of age in the experiments where the maternal organism was depleted prior to mating (Ailing et al , 1973).

Karlsson and Svennerholm (1978) compared the effects of feeding pregnant rats diets low in protein or EFA. Pups were weaned at 30d and continued on the same diet as their mothers. Measurement of DNA, gangliosides and cerebroside led to the conclusion that nutritional deficiencies only delay the development of neuronal membranes but irreversibly reduce the formation of myelin.


Malnutrition and brain protein

Discussion of the mechanisms of mammalian protein synthesis is outside the scope of this book. A brief review of this subject in relation to the brain has been written by Nowak and Munro (1977).

Studies in experimental animals have been aimed at examining the effects of malnutrition on the processes of transcription (RNA synthesis and turnover) and translation (cytoplasmic protein synthesis) in the brain. Underfeeding rats from birth by increasing the litter size has been shown to significantly reduce the synthesis of RNA at lOd of age (Ramirez de Guglielmone et al , 1974). The metabolic transformation of 3 H-orotic acids to nucleotides was also reduced.

Rehabilitation from days 21 to 30 produced an increase towards control values but a reduced incorporation of radioactive label into microsomal RNA still persisted at 30 days. Further studies on a similar animal model by the same group of workers (Duvilanski et al , 1980) has suggested that impaired nucleocytoplasmic transport of both messenger RNA (mRNA) and ribosomal RNA (rRNA) and their effect on protein synthesis could be factors underlying the decreased membrane formation in rats undernourished early in life.

If we consider the process of translation, Patel et al (1975) have shown that incorporation of leucine into protein in the forebrain was reduced in 15- and 21- day-old rats whose mothers had been malnourished from the first week of pregnancy. Adequate feeding for 2 weeks restored the incorporation to control levels.

In the inborn error of metabolism, phenylketonuria (PKU), there is a deficiency of the enzyme phenylalanine hydroxylase and the metabolism of phenylalanine (PhAl) is impaired. If the condition is not detected early in life and the child given a low phenylalanine diet, the growth and development of the brain is impaired due to the accumulation in the blood and brain of high levels of PhAl. It is not surprising therefore that this has been one of the most extensively studied examples of how an excess of one amino acid can disturb the levels of other amino acids and protein synthesis in the brain. There is now considerable evidence (Nowak and Munro, 1977) that hyperphenylalaninaemia in infant rats causes a reduction in DNA synthesis, reduces total brain protein and lipid (Davison, 1973), and especially galactolipids and proteolipids. Furthermore there is a reduction in the uptake of 14 C-galactose into brain lipids. Where they have been studied in different parts of the brain the changes are greater in the cerebellum than in the cerebrum.

As Nowak and Munro point out, these changes are comparable to those produced in the suckling rat by malnutrition and are in agreement with the suggestion of a common mechanism dependent on the inadequacy of free amino acid pools in the brain that result from inadequate dietary intake in one case and from competition for entry into the brain in the other.


Amino acids and neurotransmitters

The intracellular free amino acids in the brain, as in other tissues, may be assumed to provide the substrates for protein synthesis. These amino acids are derived from the plasma or, in some cases, produced locally from appropriate precursors. The interpretation of changes in the concentration of individual


Table 3.3 Neurotransmitters in mammalian central nervous systems (Wurtman and Growdon, 1980)


Group

Source

I

Serotonin, acetylcholine,

From a circulating


histamine, dopamine, norepinephrine

precursor

II

Various peptides found in brain neurones

By polyribosomes

III

Glycine, glutamate, aspartate

From glucose or other energy sources


y-aminobutyric acid (GABA)

From glutamate

amino acids in the amino acid pool of any tissue is a complex problem, for they are the result of differences in the relative rates of influx, efflux, incorporation into and release from proteins, degradative metabolism and synthesis. Interpretation is further complicated by the existence of functional compartments within cells so that in an organ as complex as the brain there are different pools in different types of cells. In addition to this fact, and perhaps even responsible for it, it must be considered that certain amino acids are either themselves neurotransmitters or are the precursors of neurotransmitters.

Some 15-20 compounds that probably function as neurotransmitters have been identified in mammalian central nervous systems. A suggested classification is shown in Table 3.3. Wurtman and Growdon (1980) suggest that the rate of synthesis of transmitters in Group I only will normally be coupled to plasma composition and food consumption.

In adult human brain four amino acids are each present at concentrations in excess of 1 pinole per g. These are taurine (1.25 /imole/g), glutamic acid (7.19 /rmole/g), aspartic acid (1.10 /rmole/g), and glutamine (5.55 /an role/g). The other non-essential amino acid thought to function as a transmitter, glycine, is present at a rather lower concentration (0.45) (Hansen et al , 1973). In most species so far studied the concentrations of individual free amino acids are lower in adult than in neonate brain. Exceptions are glutamic and aspartic acids and glutamine, whose concentrations tend to increase with age (Nowak and Munro, 1977). Miller (1969) has identified peaks of free amino acid concentration around the 7th and 20th days, and related them to increased protein synthesis at these times.

It is difficult to find a simple explanation for the fall in concentration of most of the amino acids between birth and maturity. The change in water concentration is inadequate, but increase in lipid concentration could be a contributing factor. However, it seems possible that a major contributing factor is the high level of amino acids in foetal plasma relative to maternal plasma, for these rapidly fall after birth to adult levels (Christensen, 1972).

It is not surprising that there are pronounced regional differences in the concentrations of some amino acids. Thus the concentration of glutamic acid is higher in the cerebral cortex, and GABA in the hypothalamus and midbrain.

For practical reasons, it is difficult to obtain reliable analyses of free amino acids in the human brain because of intervening post-mortem changes. Thus, in the case of these constituents the results obtained on experimental animals, principally the rat, are of considerable importance even though, as with the other aspects considered, results must be extrapolated with caution.

Plasma concentrations of amino acids are influenced by diet and these in turn may affect the passage of amino acids into the brain. It is therefore very important in considering experiments designed to study the effects of malnutrition on brain amino acids to carefully note the nature of the dietary manipulation as well as its timing and duration. In rat pups undernourished from birth to 21d by removing them from the mother for different periods of time, Rajalakshmi et al. (1967) reported no change in the cerebrum in the concentrations of aspartic acid, alanine, glutamic acid, glutamine and GABA. Feeding pregnant rats a 7 % casein diet (Pao and Dickerson, 1975), though reducing the body and brain weight at birth, had no significant effect on the concentrations of amino acids or amines (Table 3.4). However, in contrast to the effects of undernutrition, the low protein diet did result in lower levels of glutamic acid. The concentration of aspartic acid was higher in the malnourished pups, as also was that of tyrosine. Higher levels of aspartic acid were also found in the cerebellum but not in the brain stem. In agreement with these observations, incorporation of U- 14 C-glucose into aspartic acid was enhanced in the forebrain and cerebellum. We suggested that these findings could be explained by the effects of the low-protein diet on the activity of the Krebs (tricarboxylic acid) cycle. The activity of this cycle is reduced by a decreased entry of glucose into the brain such as occurred in these animals. This would probably decrease the level of acetyl-CoA and the rate of its condensation with oxaloacetate to form isocitrate. In effect, this would then increase the rate of transamination of glutamate and oxaloacetate, thus resulting in higher concentrations of aspartate and a-oxoglutarate in the brain.

The forebrains of the malnourished pups at 21 days contained normal concentrations of the two neurotransmitters, 5-hydroxytryptamine and norepinephrine (Table 3.4). Since, however, the forebrain weights were lower than in the controls, the absolute amounts of the neurotransmitters were low, a result in agreement with Shoemaker and Wurtman (1971).


Table 3.4 Effect of feeding rats a 7 % protein diet during gestation and lactation on body weight, brain weight, DNA amino acids and amines


Birth

21

days


Control

Malnourished

Control

Malnourished

Body weight (g)

6.2

5.0***

59.7


Brain weight (g)

0.2

0.22***

1.49

1.06***

DNA (^g/brain)

540

501*

2700

1810***

Concentration expressed per g brain tissue

Glutamic acid (/rmole)

5.22

4.59

9.01 1

8.23 1 *

Aspartic acid (gmole)

0.88

0.92

1.50 1

1.90 1 *

GABA (/rniole)

1.19

0.96

2.72 1

2.63 1

5-Hydroxytryptamine {pg)

0.19

0.17

0.32 1

0.35 1

Norepinephrine {pg)

0.20

0.21

0.31 1

0.33 1

1 Values are for forebrain only. Values significantly different

from control

values shown:

when P < 0.05, and *** when

P < 0.001.


Many pre-school children amongst the world’s poorer nations suffer from malnutrition. It is therefore of considerable interest to know what effect this is likely to have upon the amino acids in the brain since such effects might well be involved in impaired protein and transmitter synthesis in brain function. Giving weanling rats a 3 % casein diet for 56 days (Pao and Dickerson, 1975) produced changes in the plasma levels of some amino acids similar to those found in children with kwashiorkor. Higher concentrations of glycine and histidine were found in both plasma and brain. The concentration of methionine was not changed in the plasma but was raised in the brain. The plasma level of tryptophan was severely reduced by the low protein diet (Dickerson and Pao, 1975) and this was reflected in reduced concentration of tryptophan in forebrain, cerebellum and brain stem and of 5-hydroxytryptamine in the forebrain and brain stem. In agreement with the suggestion by Fernstrom and Wurtman (1971) of a mechanism of control of tryptophan entry into the brain which is affected not only by a supply of protein but also of carbohydrate (Fig. 3.9), it was found that exogenous insulin increased tryptophan intake into the brain of the malnourished animals. Brain and plasma tryptophan levels returned to normal after 7 days on a diet adequate in protein.


Figure 3.9 Proposed sequence describing diet-induced changes in the concentration of serotonin in the brain. Ratio of tryptophan to tyrosine (T) +phenylalanine (P) +leucine (L) +isoleucine (I) + valine (V) in plasma thought to control tryptophan entry into the brain (adapted from Fernstrom and Wurtman, 1972).


Thus, it would appear that these effects were only transient. However, their potential importance may lie in the fact that reduced serotonin synthesis was produced in the brain after the recognized vulnerable period of the growth spurt. Such changes may, in fact, partly explain why behavioural changes in undernourished animals may be less dependent on vulnerable periods of growth (Smart, 1977).

There is evidence that the concentration of ‘free’, in contrast to ‘total’ tryptophan, affects the entry of tryptophan into the brain. The proportion of tryptophan which is bound to albumin depends on the concentrations of albumin and of non-esterified fatty acids (NEFA). The influence of these factors seems not to have been examined in malnourished animals.

A number of experiments on the effects of malnutrition on brain amino acids have been done on other species including miniature swine (Badger and Tumbleson, 1974a, b) and monkeys (Enwonwu and Worthington, 1973, 1974). The results of all these studies as well as those in rats may briefly be summarized (Nowak and Munro, 1977) as showing that in young animals (a) the plasma levels of certain amino acids, particularly the branched chain amino acids and tryptophan are reduced by PEM, and particularly in kwashiorkor or experimental protein deficiency; (b) these changes are reflected in the amino acid pools in the brain; (c) in older animals subjected to PEM the changes in the plasma and brain amino acids are much less severe.


Brain function—behaviour and intelligence

From the preceding discussion it may be concluded that malnutrition in early life distorts the chemical composition of the brain and that effects on certain structural components—cell number and myelination—may not disappear on rehabilitation. It is tempting to ask whether such distortions damage the central nervous system sufficiently to lead to permanent intellectual impairment. On the face of it, this seems unlikely because of the immense functional reserve (Dobbing and Smart, 1974). However, there are numerous studies both in experimental animals and in man which show that undernutrition, which in animals can be quite mild, is associated with alterations in behaviour and intelligence. These may not be closely linked with ‘vulnerable periods’ (Smart, 1977) such as we have described (Chapter 2). It is becoming abundantly clear that there are many factors which are inseparably linked with malnutrition so that it is difficult, even in an animal experiment, to isolate malnutrition completely as a single factor. As an example, we may consider the large and small litter experiment in which rats are undernourished from birth by rearing them in large litters, or alternatively that in which pups are undernourished by removing them from their mothers for varying periods of time. They are certainly deprived of food but they are also deprived of mother-infant interactions. In the impoverished circumstances in which so many children in poor countries are raised, there is a complex interreaction of multiple environmental factors which cannot be ignored (Pollitt and Thomson, 1977; Cravioto and Delicardie, 1979).

Some of the difficulties in making and interpreting studies in children have been discussed by Richardson (1976). The problems apparent in animal experiments are compounded and the ‘controls’ on which the whole interpretation of the results are malnourished, or previously malnourished, children depend, may differ in many ways from the ‘experimental’ children. Richardson himself carried out a study on 74 severely malnourished boys who had been treated for malnutrition in a hospital during their first two years of life. They received an average of 8 weeks of in-patient care with good medical care and feeding. Follow-up visits were made by nurses to the boys’ homes for 2 years following discharge. At the time of the study they ranged in age from 6 to 10 years. A classmate or neighbour comparison was selected for each malnourished, or index, child. Aspects of behaviour and intelligence were assessed using the WCSC IQ test, a teacher’s evaluation of school performance, and parents’ reports of behaviour at home. The background histories of the index and comparison boys were determined on the basis of a composite score which was based on three social background variables (Table 3.5; Richardson, 1980). The results of this study suggest that severe malnutrition in the first two years of life has differing consequences for intellectual impairment, depending on the background history and characteristics of the child’s guardian, the economic conditions of the household and the child’s social environment. It was concluded that if severe malnutrition in infancy occurs in a context of a life history which is generally favourable for intellectual development, the early malnutrition appears to have a negligible effect on intellectual functioning. If the general circumstances are unfavourable then severe malnutrition is clearly related to later intellectual impairment.

These conclusions are in agreement with the results of a study of Korean orphans who were examined after being fostered at 2-3 years of age into middle- class American families (Winick et al ., 1975). By 7 years, differences in weight


Table 3.5 Background variables used in the measurement of the social background of malnourished children and their comparison children in Jamaica. (Richardson, 1980)


1. Mother’s or caretaker’s capabilities:

(a) Use of spare time.

(b) Level of ability in reading and writing.

(c) Is caretaker a source of help and advice to others?

(d) State of neatness and organization of the house.

(e) Understanding of questions at interview, responses and interviewer’s rating of her intelligence.

2. Socio-economic measure based on home furnishing and appliances:

(a) If electric power, the presence of a refrigerator.

(b) If electric power, the number of other electric appliances.

(c) If no electricity, the presence of a sewing machine.

(d) The type of fuel used for cooking.

(e) The presence of a transistor radio.

(f) Person/bed ratio.

3. Intellectual stimulation derived from:

(a) Whether child had any toys, books or magazines.

(b) Whether child listened to the radio or watched television.

(c) Whether child was taken on trips.

(d) Whether child was told stories or read to.


Table 3.6 Effects of adoption for 6 years or more of female Korean children (Winick et al, 1975). Number of children shown in parentheses


Initial condition

Initial percentiles | for height and weight

Percentiles | at 8+ years height weight

IQ

Malnourished (41)

< 3rd

71.3*

73.9

102*

Moderately nourished (50)

3rd to 24th

76.9

79.9

106

Well-nourished (47)

> 25th

82.8

82.1

112

t Korean standards.

Significantly lower than well-nourished. Others not significantly different.


and IQ due to malnutrition had disappeared (Table 3.6) and the previously severely and also the marginally malnourished children were achieving exactly the expected standard of American children of the same age and the same grade. These findings in malnourished children from poorer countries are in agreement with those in children in affluent societies who have been malnourished as a result of paediatric disease, where it has been difficult to demonstrate any residual effects on behaviour (Lloyd-Still, 1976). Furthermore, the older the child, the less likely it is that there will be any behavioural deficit.

However, in a recent study in India (Pereira et al, 1979) in which an attempt was made to control for environmental factors by comparing the scholastic performance of survivors of PEM with that of their siblings, the authors concluded that the poorer performance of the malnourished children argued for a direct effect of PEM on intellectual ability, the supposition being that other factors were controlled in the siblings.

The direct effects of sensory stimulation on brain development have been studied in the rat and other species. These experiments have shown that in young animals an enriched environment with visual and other stimulation results in more advanced brain development (see Dickerson, 1980), including an increase in dendrite arborization (Morgan and Winick, 1980 b).

Lloyd-Still concluded his discussion of the evidence for the effects of malnutrition on behaviour by saying

The evidence suggests that recovery may be related to a combination of adequate nutritional replacement in association with much emotional and psychological support and that this is not only a continuous process but these different parameters also reinforce one another. Thus efforts to alleviate this situation in less fortunate areas of the world require not only nutritional replacement, but more emphasis on improvement in the emotional well-being of the family.

Richardson (1980) concluded his discussion of the problem on a similar note.

As long as it was believed that malnutrition caused mental retardation, it was not unreasonable to try and solve the problem through the single approach of making food available. If our concern is providing children with the best opportunities for the development of their social and intellectual capabilities, then a far more complex net of action is needed.

Only in this way can so many of the world’s children hope to have better prospects than their parents and to stand any chance of breaking out of the vicious circle of the environment in which their lot has been cast.

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Ailing, C., Bruce, A., Karlsson, I. and Svennerholm, L. (1973) The effect of dietary lipids on the central nervous system’, in Dietary Lipids and Postnatal Development (eds. C. Galli, G. Tacini and A. Pecile), Raven Press, New York, 203-215.

Badger, T. M. and Tumbleson, M. E. (1974a) Protein-calorie malnutrition in young miniature swine: brain free amino acids. J. Nutr., 104, 1329-1338.

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Chase, H. P. (1976) ‘Undernutrition and growth and development of the human brain’, in Malnutrition and Intellectual Development (ed. J. D. Lloyd-Still), MTP, Lancaster, 13—38.

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Cragg, B. G. (1972) Development of cortical synapses during starvation in rats. Brain, 95, 143-150.

Cravioto, J. and Delicardie, E. R. (1979) ‘Nutrition, mental development and learning’, in Human Growth (eds. F. Falkner and J. M. Tanner), Plenum, New York, 481-511.

Cravioto, J., Delicardie, E. R. and Birch, H. G. (1966) Nutrition, growth and neurointegrative development: an experimental ecological study. Pediatrics, 38, 319-372.

Crawford, M. A., Sinclair, A. J., Msuya, P. M. and Munhambo, A. (1973) ‘Structural lipids and their polyenoic constituents in human milk’, in Dietary Lipids and Postnatal Development (eds. C. Galli, G. Jacini and A. Pecile), Raven Press, New York, 41-56.

Cuzner, M. L. and Davison, A. N. (1968) The lipid composition of rat brain myelin and subcellular fractions during development. Biochem. J ., 106, 29-34.

Davies, D. P. (1980) ‘Some aspects of “catch-up” growth in “light-for-dates babies’”, in Topics in Paediatrics. 2. Nutrition in Childhood (ed. B. Wharton), Pitman Medical, Tunbridge Wells, 72-80.

Davies, P. A. and Davis, J. P. (1970) Very low birth weight and subsequent head growth. Lancet, i, 1216-1219.

Davison, A. N. (1973) ‘Inborn errors of amino acid metabolism affecting myelination of the central nervous system’, in Inborn Errors of Metabolism (eds. F. A. Hommes and C. J. Van Den Berg), Academic Press, London and New York, 55-67.

Davison, A. N. and Dobbing, J. (1966) Myelination as a vulnerable period in brain development Brit. Med. Bull, 22, 40-44.

Dickerson, J. W. T. (1975) ‘Effect of growth and undernutrition on the chemical composition of the brain’, in Nutrition, Proc. 9th Int. Congr. Nutrition, Mexico 2 (eds. A. Chavez, H. Bourges and S. Basta), Karger, Basel, 132-138.

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Dickerson, J. W. T. and Pao, S.-K. (1975) The effect of a low protein diet and exogenous insulin on brain tryptophan and its metabolites in the weanling rat. J. Neurochem., 25, 559-564.

Dickerson, J. W. T. and Walmsley, A. L. (1967) The effect of undernutrition and subsequent rehabilitation on the growth and composition of the central nervous system of the rat. Brain, 90 897-906.

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Dickerson JWT. and McGurk H. Brain And Behavioural Development. (1982) Blackie & Son Ltd., Glasgow.

Brain and Behavioural Development - 1982: 1 Neural Development | 2 Comparative Neural | 3 Malnutrition | 4 Hormones and Growth Factors | 5 Cortical Activity | 6 Functional Asymmetry | 7 Plasticity | 8 Sex Differences


Cite this page: Hill, M.A. (2019, October 15) Embryology Book - Brain and behavioural development 3. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Brain_and_behavioural_development_3

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Davies, P. A. and Davis, J. P. (1970) Very low birth weight and subsequent head growth. Lancet, i, 1216-1219.

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Davison, A. N. and Dobbing, J. (1966) Myelination as a vulnerable period in brain development Brit. Med. Bull, 22, 40-44.

Dickerson, J. W. T. (1975) ‘Effect of growth and undernutrition on the chemical composition of the brain’, in Nutrition, Proc. 9th Int. Congr. Nutrition, Mexico 2 (eds. A. Chavez, H. Bourges and S. Basta), Karger, Basel, 132-138.

Dickerson, J. W. T. (1980) ‘Protein deficiency and the brain’, in Food and Health: Science and Technology (eds. G. G. Birch and K. J. Parker), Applied Science Publishers, London, 487-500.

Dickerson, J. W. T. (1981) ‘Nutrition, brain growth and environment’, in Maturation and Development (eds. K. J. Connolly and H. F. R. Prechtl). Spastics Int. Med. Publ., Heinemann, London, 110-130.

Dickerson, J. W. T., Dobbing, J. and McCance, R. A. (1967) The effect of undernutrition on the development of the brain and cord in pigs. Proc. Roy. Soc. B., 166, 396-407.

Dickerson, J. W. T., Hughes, P. C. R. and McAnulty, P. A. (1972) The growth and development of rats given a low-protein diet. Brit. J. Nutr., 27, 527-536.

Dickerson, J. W. T., Merat, A. and Widdowson, E. M. (1971) Intrauterine growth retardation in the pig. III. The chemical structure of the brain. Biol. Neonate , 19, 354-362.

Dickerson, J. W. T. and Pao, S.-K. (1975) The effect of a low protein diet and exogenous insulin on brain tryptophan and its metabolites in the weanling rat. J. Neurochem., 25, 559-564.

Dickerson, J. W. T. and Walmsley, A. L. (1967) The effect of undernutrition and subsequent rehabilitation on the growth and composition of the central nervous system of the rat. Brain, 90 897-906.

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