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Malnutrition and the brain: changing concepts, changing concerns¹

Historic reasons for suspecting neonatal malnutrition should permanently disrupt cognitive functioning: effects on total size of the cerebrum
Enduring effects of early malnutrition on total brain and cerbral cortex
Functional estimates of changes in brain structure
Further substantiation of enduring changes in neurotransmitter metabolism caused by early malnutrition
Other enduring functional effects of early malnutrition on brain: the hippocampus
Early malnutrition and cerebellar changes
Literature cited

DAVID A. LEVITSKY² AND BARBARA J. STRUPP

Division of Nutritional Sciences and Department of Psychology, Cornell University, Ithaca, NY 14853-6301

¹Prepared for the International Dietary Energy Consultative Group (IDECG) Task Force workshop on malnutrition and behavior at the University of California, Davis, CA, December 6-10, 1993 This workshop was supported by IDECG, the Nestlé Foundation Kraft Foods and the International Union for Nutritional Science Guest editor for this supplement publication was Ernesto Pollitt Department of Pediatrics, University of California, Davis, CA, 95616

²To whom correspondence should be addressed: I 12 Savage Hall, Cornell University, Ithaca, NY 14S53-6301

On the basis of a recent Medline search, at least 1100 studies on the effects of early malnutrition on brain and brain function (behavior) have been published since 1966; the vast majority of the studies involved experimental animals. The study of animals is essential for estimating the potentially harmful effects of malnutrition to humans because only through experiments with animals can causal relationships between early malnutrition, alterations in brain structures and resulting behavioral and cognitive consequences be established. Unfortunately, the major disadvantage of using animals is a greater dependence on interpretation and extrapolation to infer events in humans than if humans could be studied directly. As a result of this great dependence on animal research to answer questions concerning the potentially harmful effects of malnutrition to humans, a large literature on this subject has accumulated. It is with the wisdom of hindsight, that much of the research relating malnutrition to brain structure will be reviewed to view it within a historical perspective and provide an estimation of our current state of understanding.

Historic reasons for suspecting neonatal malnutrition should permanently disrupt cognitive functioning: effects on total size of the cerebrum

During the mid- 1960s, a small group of dedicated and well-respected researchers turned their attention to the frightening realization that half the world's children were suffering from various degrees of malnutrition and that such a condition might permanently limit their intellectual capacity to function in an technologically advancing world (for example, Scrimshaw and Gordon 1968). Clearly, the most cogent argument supporting this terrifying possibility was that malnutrition imposed during early life not only reduces the growth of the brain but leaves it permanently smaller in size. The phenomenon was observed in rats (Chase et al. 1967, Culley and Lineberger 1968, Dobbing 1965, Smart et al. 1973, Winick and Nobel 1966, Zamenhov et al. 1971), mice (Randt and Derby 1973), guinea pigs (Chase et al. 1971) and pigs Dickerson and Dobbing 1966).

The discovery that a narrow window of vulnerability existed early in the life of mammals spurned a controversy over the identification of brain damage caused by malnutrition that might be responsible for potentially limiting the cognitive potential of children. The conventional view championed by the pioneering work using DNA as an indicator of brain growth by Winick and Noble (1966) and Dobbing (1964) was that the mammalian brain was most vulnerable to malnutrition during the period when the brain was growing most rapidly. For the rat (the most frequently used experimental model of malnutrition), this period of most rapid brain growth occurs postnatally. Consequently, those structures that develop postnatally such as the cerebrum, the hippocampus and the cerebellum would be most susceptible to permanent alteration by malnutrition. Alternatively, the position held by Morgane et al. (1993) was that the period of maximum vulnerability of early malnutrition was not the period when the brain was growing most rapidly, but rather when the organization of specific neurons during ontogenesis occurred. According to this latter view, the prenatal period in the rat should be more susceptible to the deleterious effects of malnutrition than the postnatal period. As with most controversies, the truth lies somewhere between the extremes. The evidence is quite clear that malnutrition limited to the prenatal period of the rat is not only sufficient to produce permanent alterations in brain structure but also causes enduring changes in behavior that are at least as powerful as those produced by postnatal malnutrition |Smart 1986).

Anatomical examination of specific brain areas not only confirmed the suspicions of Winick and Dobbings and others but also yielded additional evidence of pronounced structural alterations resulting from early exposure to malnutrition. The cerebral cortex, the brain region most: closely linked to cognitive and intellectual functioning, exhibits a reduction in volume (Bedi and Bhide 1988, Leuba and Rabinowicz 1979a, Leuba and Rabinowicz 1979b, Morgane et al. 1978, Thomas et al. 1979, West and Kemper 1976) and width (Cragg 1972, Clark-et al. 1973, Dobbing et al. 1971, Noback and Eisenman 1981, Saissi and Saissi 1973, West and Kemper 1976) after neonatal malnutrition. The number of cortical neurons, however, is not affected Leuba and Rabinowicz 1979a, Sugita 1918). Although this sparing of cortical neuron numbers may be interpreted as evidence of a remarkable case of neural resiliency in the face of severe malnutrition, it is generally described in pathologic terms as cell packing (Bedi et al. 1980b, Bedi and Warren 1983, Callison and Spencer 1968, Cordero et al. 1976, Cragg 1972, Leuba and Rabinowicz 1979a, Saissi and Saissi 1973, Sugita 1918, Thomas et al. 1979, Thomas et al. 1980).

Despite the sparing of the total number of cortical neurons from the ravages of malnutrition, more sophisticated analyses of cortical structures continued to reinforce the idea that malnutrition caused permanent structural damage to the brain. Studies using Golgi staining techniques show that malnutrition causes a significant disruption in pyramidal cells of the cerebral cortex (Angulo-Colmenares et al. 1979, Cordero et al. 1985, Leuba end Robinowicz 1979b, Noback and Eisenman 1981, Salas et al. 1974, Schonheit 1981, Schonheit and Haensel 1989, West and Kemper 1976), reduction in the density of cortical dendritic spines (Angulo-Colmenares et al. 1979, Leuba and Rabinowicz 1979b, Noback and Eisenman 1981, Salas et al. 1974, Sarkar et al. 1990, Schonheit 1982, Schonheit and Haensel 1989, West and Kemper 1976), a decrease in the width of cortical cells (Angulo-Colmenares et al. 1979, Leuba and Rabinowicz 1979b, Salas et al. 1974) and the complexity of the dendritic branching of the cortex (Leuba and Rabinowicz 1979a, Leuba and Rabinowicz 1979b, Schonheit 1982, Yoshida 1985). In addition, the total number of cortical glial cells is significantly reduced by early malnutrition (Leuba and Robinowicz 1979a). Although the density of cortical synapses appeared to be unaffected by malnutrition Cragg 1972, Gambetti et al. 1974, Warren and Bedi 1984), the total number of synapses in visual cortex is clearly reduced by malnutrition (Warren and Bedi 1984). The length and the width of synaptic reactive zones are also reduced, and the number of cisterns embedded within the spinous apparatus is also significantly altered by malnutrition (Medvedev and Babichenko 1988).

These studies leave little doubt that although the total number of cerebral neurons (brain cells) did not appear to be reduced by malnutrition, other cortical structures were dramatically altered by malnutrition. The crucial political and humanitarian question, however, was whether this damage to the microstructures was permanent or could they be reversed with nutrition rehabilitation.

Enduring effects of early malnutrition on total brain and cerbral cortex

Given these rather profound anatomical effects of early malnutrition observed during or immediately after the period when brain was growing at its maximum or near maximum rate, it is not surprising that neuroscientists predicted that enduring alterations in cognitive function would persist. More recent evidence, however, suggests that the term irreversibly may have been premature and that many of the earlier animal studies may not have allowed sufficient time for recovery of various structures to occur. Studies of the recovery of the brain after the period of malnutrition revealed that the period of mitotic activity of the cortex of the rat is prolonged after early malnutrition (Gopinath et al. 1976), allowing the period of maximal brain protein synthesis to continue (Hamberger and Sourander 1978). Moreover, although the size of the brain of normally nourished rats diminishes later in life, this reduction occurs much later in previously malnourished rats (Jones and Dyson 1981). Although there is little indication that total recovery of cortical size occurs, it is clear that the concept that a narrow critical period for growth of brain exists beyond which irreversible damage occurs is less tenable than once believed.

Remarkable recovery of other brain parameters from early malnutrition were also demonstrated. The increase in cell packing observed in the cortex during early malnutrition is reversed by subsequent nutritional rehabilitation (Bedi et al. 1980a, Leuba and Rabinowicz 1979a, Saissi and Saissi 1973, Thomas et al. 1979, Thomas et al. 1980, Warren and Bedi 1988) primarily due to the recovery of cortical width (Angulo-Colmenares et al. l 979, Bass et al. 1970, Diaz-Cintra et al. 1990). Other cortical parameters that appear to recover from early malnutrition are the change in cortical glial cell density (Leuba and Rabinowicz 1979a) and cortical synapse:neuron ratio (Diaz-Cintra et al. 1990). The only neural aberration in the cortex that fails to recover with nutritional rehabilitation is the reduced number of cortical dendrites in synaptic spines (Leuba and Rabinowicz 1979b).

In contrast, the alterations in nonneural structures have been consistently found to resist rehabilitation. One example is the reduction in brain myelin (Fuller and Wiggins 1984, Reddy et al. 1979, Royland et al. 1992, Wiggins et al. 1976, Wiggins et al. 1984), which may be indicative of a reduction in the number of myelinated axons in brain (Wiggins 1982). This reduction may be functionally important because myelinated axons transmit information at considerably higher speeds than nonmyelinated fibers. Another structural aberration that persists after rehabilitation is an increase in the number of neuronal mitochondria in cortical cells. This alteration was observed to withstand rehabilitation in the case of both prenatal (Herschkowitz and Rossi 1971, Muzzo et al. 1973) and lactational (Jones and Dyson 1981, Wiggins et al. 1986) malnutrition.

Analysis of specific cortical structures reveals a similar picture of recovery from malnutrition. With respect to the visual system, malnutrition initially produces a profound reduction in the number and size of optic fibers emanating from the eye and terminating in higher brain structures (Bedi and Warren 1983), a decreased number of synapses per neuron in visual cortex (Bedi et al. 1983, Bedi et al. 1989, Gundappa and Desiraju 1988) and changes in the structure of pyramidal cells enervating the visual cortex (Diaz-Cintra et al. 1990). Most of these changes were totally reversed with nutritional malnutrition (Diaz-Cintra 1990, Gundappa and Desiraju 1988, Warren and Bedi 1982). One inexplicable finding was obtained with respect to synaptic density. Early malnutrition followed by nutritional rehabilitation resulted in an increase in synaptic density when the malnutrition was induced via the dam, but a decrease in synaptic density when the animals were nurtured artificially (Bedi et al. 1989). The interpretation of this interaction between malnutrition and rearing condition is unclear.

Functional estimates of changes in brain structure

Historically, the predictions that children will be intellectually damaged by early malnutrition were based on anatomical perturbations. As indicated above, the results of long-term studies do not support the assertion that the anatomical changes observed in the cortical regions during or immediately after malnutrition are irreversible. Other approaches of estimating long-term alterations in brain function resulting from early malnutrition not only confirmed the suspicions of the early researchers but also helped focus the behavioral and cognitive analysis on the crucial aspects of brain function that are most affected.

One such approach analyzed the response characteristics of neural structures innervating cerebral cortex to ascertain whether or not early malnutrition affects the sensitivity of cortex to neural stimulation. Electrophysiological studies showed that during the period of malnutrition, young rats show a decreased excitability and a diminished ability of parietal and prefrontal cortical neurons to follow repetitive pulses produced by electrical stimulation [Perez et al. 1987, Ruiz et al. 1986, Soto-Moyano et al. 1981). Most importantly, this diminished cortical response to stimulation by the locus ceurulus persists despite nutritional recovery (Forbes et al. 1978, Ruiz et al. 1986, Soto-Moyano et al. 1981). This enduring diminished sensitivity of cortical structures to basal stimulation is abolished by the administration of propranolol, a drug that blocks, b-adrenergic receptors (Soto-Moyano et al. 1987). This phenomenon suggests that early malnutrition may produce long-term alterations in brain function by altering neurotransmitter metabolism perhaps at the receptor level.

Further substantiation of enduring changes in neurotransmitter metabolism caused by early malnutrition

There is little question that alterations in various neurotransmitter systems are evident during and immediately after early malnutrition.. However, the nature of these changes is not clear. Most investigators have demonstrated that either pre- or postnatal malnutrition causes an increase in brain concentration of the monoamines, serotonin and norepinephrine (for example, Benesova et al. 1972, Burns and Brown 1977, Miller et al. 1977, Sobotka et al. 1974, Stern et al. 1974, Stern et al. 1975). Others, however, have found a decrease in monoamines (Detering et al. 1980a, Detering et al. 1980b, Detering et al. 1980c, Hisatomi and Niiyama 1980, Lee and Dubos 1972, Ramanamurthy 1977, Seidler et al. 1990, Sereni et al. 1966). In most cases, however, brain levels of these amines are normalized after nutritional rehabilitation (Burns and Brown 1977, Detering et al. 1980a, Detering et al. 1980b, Detering et al. 1980c).

More sophisticated pharmacological and psychopharmacological studies than those based on measurement of neurotransmitter concentration strongly suggest, however, that the activity of these systems may be permanently altered. One such alteration observed in the recovered, previously malnourished rat, is a reduction of the number of norepinephrine receptors (Keller et al. 1982, Keller et al. 1990a, Keller et al. 1990b, Seidler et al. 1990, Wiggins et al. 1984). This enduring decrease in receptor number may be responsible for the decreased activation seen in these animals after administration of adrenergic drugs (Del Basso et al. 1983, Keller et al. 1984).

More recent studies suggested a related subtle, but potentially important, effect of early malnutrition on this system: a decreased ability of adrenergic receptors to exhibit down regulation. Down regulation refers to the compensatory reduction in receptor number that occurs as a result of direct stimulation of the receptor by the neurotransmitter or a related agonist. Previously malnourished rats were found to display normal up regulation of, b-adrenergic receptors in response to chronic treatment with the b-blocker, propranolol, but failed to exhibit down regulation of these receptors in response to chronic treatment with the antidepressant, desipramine (Keller et al. 1990a).

A functional consequence of this reduced down regulation may be a diminished ability to adapt to stressful situations. For example normally exhibit a reduction in activity level when injected with drugs that either activate postsynaptic dopamine receptors (for example, apomorphine) or that block noradrenergic autoreceptors (for example, clonidine). Although this response is normally attenuated after repeat d immobilization stress or chronic desipramine treatment, conditions that would be expected to produce a chronic increase in activity of central catecholaminergic systems, no such adaptation is evident in previously malnourished, but nutritionally rehabilitated rats (Keller et al. 1990a, Keller et al. 1990b).

Another indication of a long-term, alteration in central catecholaminergic system can be observed when previously malnourished animals are given repeated administrations of amphetamine. Where the ability of amphetamine to produce stereotypy was not affected by prior malnutrition, the concentration of striatal dopamine and its metabolites were significantly reduced in the previously malnourished animals, indicating an inability to adapt to the stress of repeated amphetamine administrations (Brioni et al. 1986). These studies suggest that although malnutrition leaves the brain sufficiently intact to function normally under stable conditions, enduring changes may be evident under stressful conditions that usually induce a neurochemical adaptation in normal animals. Although speculative, it is possible that this type of effect may alter an individual's susceptibility for affective disorders. Consistent with this hypothesis is the observation that adult rats subjected to early malnutrition, but nutritionally rehabilitated, were less responsive to desimprimine than, their well-nourished controls Molina et al. 1987).

A similar lack of responsiveness to psychopharmacological challenges was observed with other neurochemical systems. Hall et al. (1983) demonstrated that rats subjected to early malnutrition show a consistently blunted behavioral response to the serotonin agonist, dimethyl-tryptamine. In addition, a pattern of neuropharmacological responses almost identical to that described above for the adrenergic system was observed with the b-endorphins. Nutritionally rehabilitated adult rats failed to exhibit a significant reduction of hypothalamic, b-endorphin in response to active avoidance training, a characteristic reaction of animals with no history of malnutrition (Vendite et al. 1988). Further evidence of enduring alterations in the central endorphin system in previously malnourished rats is suggested by several other findings as follow: 1) the lack of an amnesic effect after b-endorphin administration, a phenomenon apparent in control rats (Souza et al. 1992); 2) a lack of novelty induced analgesia (Vendite et al. 1990); and 3) a milder withdrawal syndrome in response to naloxone administration in opiate treated, previously malnourished rats (Cohen et al. 1991).

The behavioral response to anxiolytic drugs is also blunted in previously malnourished but nutritionally rehabilitated animals. For example, these drugs are less effective in previously malnourished rats in antagonizing the aversiveness of high salt fluids (Almeida et al. 1990), increasing exploration in an elevated plus-maze (Almeida et al. 1991, Laino et al. 1993), affecting step-down latency in a passive avoidance paradigm (Almeida et al. 1992), improving DRL responding (Brioni and Orsingher 1988) and reducing anticonflict behavior (Brioni et al. 1989, Cordoba et al. 1992) than in control animals. It is notable that this depressed reaction to noradrenergic, serotonergic and GABA-ergic drugs is not a reflection of generalized decrease in responsiveness to all drugs. Previously malnourished animals show no change in their behavioral response to caffeine (Mello et al. 1992) or to amphetamine (Blanchard et al. 1987).

Other enduring functional effects of early malnutrition on brain: the hippocampus

Neuroanatomical studies for many years provided evidence that the hippocampus is adversely affected by early malnutrition. Observed effects include a significant reduction in the size of cells taken from the dentate gyrus as well as a reduction in the degree of dendritic branching (Cintra et al. 1990). Similarly, the number of granule cells is reduced by early malnutrition, an effect that is not reversed with nutritional rehabilitation (Bedi 1991a, Bedi 1991b).

However, a more functional measure of the hippocampus, the number of synapses per neuron, shows a completely different pattern. Although the number of synapses per neuron is not affected by early postnatal malnutrition, there are significantly fewer synapses per neuron after 75 d of nutritional rehabilitation (Ahmed et al. 1987). After ~ 130 d of rehabilitation the number of neurons per synapse decreased in the controls and continued to increase in the previously malnourished rats. Finally, by 250 d of age the previously malnourished animals had accumulated ~ one-third more synapses per neuron than the well-fed controls that continued to show a decrease in the number of synapses per neuron. Thus, like the study of cortex, traditional neuranatomical techniques failed to produce clear information about whether to expect lasting cognitive impairment from early malnutrition.

Electrophysiological data provided some evidence, although it too is difficult to interpret. Recording of electrical activity of the hippocampus of previously malnourished but rehabilitated rats showed a shift in the peak theta frequency during rapid eye movement sleep (Morgane et al. 1985). Further evidence that early malnutrition alters the function of the hippocampus comes from paired-pulse stimulation studies. The optimal interval between pairs of pulses to the hippocampus necessary to produce electrical activity during different phases of sleep and waking is significantly affected by previous malnutrition and resists nutritional rehabilitation (Austin et al. 1992). These effects, unfortunately, are difficult to interpret in terms of cognitive dysfunction.

One neurological phenomenon that is characteristic of the hippocampus is electrically stimulated convulsions. Contrary to expectations, early malnutrition followed by nutritional rehabilitation was found to increase the number of electrical stimuli necessary to produce convulsions (Austin et al. 1986, Austin et al. 1992, Bronzino et al. 1986, Bronzino et al. 1990), although the initial seizure was less intense than in well-nourished controls (Austin et al. 1992). However, the threshold for stimulating the afterdischarge after the seizure was found to be significantly reduced in the previously malnourished animals (Bronzino al. 1986, Bronzino et al. 1990, Bronzino et al. 1991a, Bronzino et al. 1991b). Despite knowing how to specifically interpret these findings, it is clear the firing pattern of hippocampal neurons is altered by early malnutrition.

The phenomenon of kindling refers to the fact that after electrically inducing a seizure in the hippocampus, less electrical stimulation is required to evoke a seizure to the same area when tested several days later. Like the phenomenon of down regulation, the previously malnourished animals fail to show long-term adaptation. Although well-nourished controls display a decrease in the susceptibility to seizure after the initial seizure, the previously malnourished animals maintain the same high resistance to electrically stimulated seizures (Austin et al. 1992, Bronzino et al. 1986, Bronzino et al. 1990).

A similar lack of adaptation in the hippocampus of previously malnourished rats is exhibited in the phenomenon of a long-term potentiation (LTP). Unlike kindling, which utilizes seizures, LTP refers to the effect of a subconvulsive threshold of electrical stimulation sufficient to cause a neural response that will cause lowering the threshold to cause the same response when tested later in time. The LTP of previously malnourished rats is significantly diminished (Austin et al. 1986, Jordan and Clark 1983).

Early malnutrition and cerebellar changes

Early in the study of malnutrition and the brain, the cerebellum was recognized as an area that is particularly sensitive to the effects of early malnutrition (Adlard et al. 1973, Chase et al. 1969, Cully and Lineberger 1968, Howard and Granoff 1968, Schain and Watanabe 1973, Sobotha et al. 1974, Winick 1969). In fact, it was generally held that when compared with other structures in the brain that were developing at about the same time such as the forebrain, the cerebellum was the most vulnerable structure to the effects of malnutrition imposed postnatally. This conclusion was reached by comparing the amount of DNA (used as an indication of number of cells) relative to age-matched controls. Peeling and Smart (1991) proposed that such comparisons may be inappropriate and that if more sophisticated techniques are used to measure growth of various brain structures to detect the impact of malnutrition, the forebrain is, indeed, just as vulnerable to grow retarding effects of poor diet as the cerebellum.

Nevertheless, the reputation of the cerebellum as being particularly sensitive to the effects of malnutrition stimulated a considerable amount of meticulous anatomical work directed at understanding what specific cells within the cerebellum are affected by malnutrition. Although the data are quite clear that malnutrition imposed postnatally increases the density of Purkinje cells within the cerebellum (Clos et al. 1976, McConnell and Berry 1978, Neville and Chase 1971), the effect on the development of granule cells is less clear: some researchers have observed an increase in the number of granule cells (McConnell and Berry 1978, Neville and Chase 1971), whereas others have failed to detect any effect (Bedi et al. 1980a, Bedi et al. 1980b, Clos et al. 1976).

Other evidence, however, completely supports the view that the cerebellum is severely affected by early malnutrition. Early malnutrition causes grossly abnormal electrophysiological activity of Purkinje cells (Sharma et al. 1987) and a suppression in the synapse:neuron ratio (Bedi et al. 1980a, Bedi et al. 1980b, Warren and Bedi 1990). Moreover, abundant evidence indicates that malnutrition early in life causes clear delays in psychomotor development in young, malnourished animals (Elias and Samonds 1977, Lynch et al. 1975, Massaro et al. 1977a, Massaro et al. 1977b, Nagy et: al. 1977, Oliverio et al. 1975, Sykes and Cheyne 1976, Wainwright and Russell 1983) as well as in children (Benefice 1992, Celedon and de Andraca 1979, Celedon et al. 1980, Joos et al. 1983, Reyes et al. 1990).

However, like many of the brain changes discussed above, the alterations so apparent in the cerebellum during the period of malnutrition appear to be reversible with nutritional rehabilitation. Several investigators found that nutritional rehabilitation normalizes the low density of cerebellar Purkinje cells (McConnell and Berry 1978, McConnel and Berry 1981), although others did not observe full recovery (Bedi et al. 1980a, Bedi et al. 1980b). More clearly established is the total recovery in both the density of granules cells (Altman and McCrady 1972, Barnes and Altman 1973a, Barnes and Altman 1973b, Bedi et al. 1980a, Bedi et al. 1980b, McConnell and Berry 1978, McConnell and Berry 1981) and in the synapse:neuron ratio (Bedi et al. 1980a, Bedi et al. 1980b, Warren and Bedi 1990, Yucel et al. 19941. Interestingly, the recovery of the ratio of synapse:neurons continues despite nutritional rehabilitation (Warren and Bedi 1990).

One parameter that appears nonreversible with adequate nutrition is the reduced ratio of granule:Purkinje cells. Dobbing et al. (1971) suggested the nonreversibility of this parameter on the basis of very few animals, but it has received considerable support from subsequent research (Bedi et al. 1980a, Bedi et al. 1980b, McConnell and Berry 1978, McConnell and Berry 1981, Warren and Bedi 1988). The functional significance of these findings is not clear. Standard batteries of psychomotor tests generally failed to reveal long-term effects of early malnutrition in either animals (Smart and Bedi 1982, Tonkiss and Smart 1983) or humans (Barter et al. 1978, Beardslee et al. 1982). On the other hand, more sensitive tests of psychomotor coordination demonstrated subtle motor differences in the gait of previously malnourished animals (Clarke et al. 1992, Gramsbergen and Westerga 1992) and in previously malnourished children (Galler et al. 1984, Galler et al. 1985, Caller et al. 1987, Hoorweg and Stanfield 1976, Stoch et al. 1982).

Our conceptions of how malnutrition endured early in life affects brain development have evolved considerably since the mid-1960s when it was feared that malnutrition endured during certain sensitive periods in early development would produce irreversible brain damage, possibly resulting in mental retardation and an impairment in brain function. We now know that much of the alterations in the growth of various brain structures caused by malnutrition that concerned early investigators eventually recover, although permanent alterations in the hippocampus and cerebellum remain. However, recent neuropharmacological research has revealed long-lasting, if not permanent, alterations in brain neural receptor function resulting from an early episode of malnutrition.

These more recent findings indicate that the kinds of behaviors and cognitive functions impaired by malnutrition may be more related to an emotional response to stressful events rather than to factors related to intelligence, the age range of vulnerability to these long-term effects of malnutrition may be much greater than we had suspected and the minimal amount of malnutrition (hunger) necessary to produce these long-term alterations is unknown.

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