Evolutionary and ecological aspects of early brain malnutrition in humans.

EVOLUTIONARY AND ECOLOGICAL ASPECTS OF EARLY BRAIN MALNUTRITION IN HUMANS William D. Lukas a n d B e n j a m i n C. C a m p b e l l Boston University

This article reviews the effects of malnutrition on early brain development using data generated from animal experiments and human clinical studies. Three related processes, each with their own functional consequences, are implicated in the alteration of brain development. (1) Maternal undernutrition at the start of pregnancy results in reduced transfer of nutrients across the placenta, allowing the conservation of effort for future reproductive episodes. (2) Differential allocation to growing organs by the fetus in response to nutritional stress spares the brain to a large though still limited degree, reflecting the organ's relative contribution to survival and reproductive success. (3) Prenatal malnutrition disrupts developing neurotransmitter systems, which results in the expression of specific cognitive and affective traits. It is argued that the increasing size and therefore cost of the brain, in conjunction with increasing ecological instability and marginality, reinforced selection for maternally controlled growth suppression of offspring, reallocation of organ growth rates by offspring, and behavioral changes related to development of neurotransmitter systems. KEYWORDS: ADHD; Brain sparing; Catecholamines; Cultural buffering; Growth programming; Intrauterine Growth Retardation; Plio-Pleistocene; Serotonin.

Worldwide, about one-third of children u n d e r five are malnourished (Grantham-McGregor 1995). SmaU-for-gestational-age infants and previ-

Received: December 18, 1998; accepted: May 24, 1999.

Address all correspondence to William Lukas, Department of Anthropology, Boston University, 232 Bay State Road, Boston, MA 02215. E-mail: [email protected] Copyright 2000by Walter de Gruyter, Inc., New York Human Nature, Vol. 11, No. 1, pp. 1-26.

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Human Nature, Vol. 11, No. 1, 2000

ously malnourished children with stunted school performance are common problems in both the developing world and among the poor of industrial countries (Launer et al. 1991). The large number of individuals with impaired cognitive and social skills from this potentially preventable cause makes it an important area of research for intervention programs. Behavioral and cognitive anomalies, some of them long-lasting, indicate that there are significant functional consequences to these developmental disturbances (Strupp and Levitsky 1995). A great deal of scientific study has been devoted to understanding the impact of early malnutrition on brain development in infants (Frisancho 1993). The two main approaches have been to understand its physiological etiology by means of experimental animal studies (Zamenoff and Van Marthens 1978; Zhou et al. 1996) or to focus on its cognitive manifestation in humans using intelligence tests (Strupp and Levitsky 1995; Wachs 1995). Less attention has been given to the evolutionary implications of the effects of malnutrition on the developing brain. We will employ the theory of parent-offspring conflict (Haig 1993; Trivers 1974), growth programming (Barker 1996, 1999; Desai and Hales 1997; Lucas 1991), links between neurotransmitter systems and behavior (Almeida et al. 1996; Coscina 1997; Kaplan, Klein, and Manuck 1997), and hypotheses about the socioecology and evolution of the human brain (Dunbar 1993; Kaplan et al. 1999; Leonard and Robertson 1994) in order to understand the alteration of brain development during fetal development resulting from maternal malnutrition. We propose that three major physiological mechanisms which are of adaptive significance underlie changes in brain development and function owing to gestational malnutrition: 1. The reduction of maternal nutrient transfer to the fetus in response to signals of energy availability in the environment around the time of conception. 2. The reallocation by the fetus of energy to developing organs based on their contribution to current survival and future fitness, resulting in brain sparing. 3. Permanent alterations in neurotransmitter systems which promote impulsivity and other behavioral traits that may enhance survival during periods of low environmental quality and social disruption.

MATERNAL MALNUTRITION DURING PREGNANCY Parental Effort and Parent-Offspring Conflict during Gestation Iteroparous organisms must weigh the costs and benefits of investing in current versus future offspring during each reproductive episode. This

Evolutionary and Ecological Aspects of Early Brain Malnutrition

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leads to a parent-offspring conflict, in which offspring will prefer more parental effort than does the parent at any given point in time. This conflict exists throughout the period of offspring dependency, including the prenatal period (Trivers 1974). During fetal development this conflict of interest is centered around the transfer of energy from mother to fetus. Pregnancy imposes a heavy energetic cost on the mother; the resting metabolic weight of an adequately nourished woman is elevated about 13% during pregnancy (Frisancho 1993). Typically, a woman needs to gain about 20% of her pre-pregnant weight to ensure a healthy birth weight (Rosso and Salas 1994). These energetic costs have consequences beyond the current reproductive episode. The depletion of maternal stores through successive reproductive episodes has been demonstrated in human females (Wood 1994); for example, parity is negatively correlated with second semester weight gain in Turkana women (Pike 1999). Under conditions of energetic limitation, mothers limit the flow of energy to the fetus in favor of maintaining reserves for future reproductive effort, even at the risk of reduced offspring survival. In fact, in the majority of human populations studied, optimal birth weight in terms of neonate survival is slightly greater than the actual mean birth weight (Frisancho 1993). The implications of parent-offspring conflict for mother-fetal interaction were developed by Haig (1993). The degree of placental infiltration of the maternal host places an upper limit on the amount of energy that the fetus can receive from the mother, while an interplay of maternal and fetal hormones influences the rate of energy transfer from the mother to the fetus (Haig 1993, 1999). Maternal Influence o n Prenatal G r o w t h

Despite maternal physiological adjustments to undernutrition during pregnancy, experimental data on mammals and clinical studies suggest that current maternal nutritional intake is not directly coupled to current fetal growth rate (Rosso 1990; Rosso and Salas 1994). This means that fetal growth rate potential is established before the fetus is large enough for its growth to be nutrient-limited (Harding and Johnston 1995), consistent with the importance of early placental development for fetal growth. In the case of brain growth, protein malnutrition in rats leads to reduced brain volume and DNA content in their offspring even when it occurs prior to or early in gestation (Harding and Johnston 1995). Supplementation studies of pregnant women demonstrate the difficulty, though not impossibility, of raising fetal growth rates once they have been established by the mother's nutritional state at conception (Ulijaszek 1995). If the mother is already malnourished and has poor weight gain during pregnancy, the newborn will be severely underweight (Neufeld et

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al. 1999; Rosso and Salas 1994); even if she has high energy intake during pregnancy, the outcome will usually be a nearly normal, but still low birth weight, infant (Rosso 1990). A woman who is in good physical condition prior to conception but experiences malnutrition during the first half of her pregnancy and then recovers can still produce a normal birth weight offspring. If a woman experiences severe malnutrition during the second half of pregnancy, however, her offspring's birth weight will be affected since by this time growth rate is more directly energy-limited (Rosso 1990). In the case of very obese females, however, even significant weight loss is compatible with normal birth outcome. Modulation of uteroplacental blood flow by changes in maternal plasma blood volume is the primary means through which fetal growth rate is matemally influenced (Figure 1). Human studies show that underweight (height-for-weight) women have lower plasma volume and cardiac output (Rosso and Salas 1994), and in undernourished rats, as food consumption decreases, so does plasma volume and uterine blood flow (Rosso 1990). Accordingly, there is a strong correlation between plasma volume and the weight of the neonate in both human and animal studies (Rosso 1990; Rosso and Salas 1994). The reduction of intrauterine growth rate also affects postnatal growth. Individuals small for gestational age at birth are smaller than normal throughout infancy and childhood (Gruenwald 1975; Hadders-Algra and Touwen 1990; Lucas 1991), and have reduced head circumference (Hadders-Algra and Touwen 1990). Animal studies that control for postnatal nutrition produce similar outcomes (Gruenwald 1975). In humans, the effects of intrauterine growth retardation extend to the next generation

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Figure 1. Mechanisms of fetal growth retardation due to maternal malnutrition. (Adapted from Rosso 1990)


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(Weinstein 1978); for example, although gestation length is an important determinant of birth weight, the birth weight of the mother is a more reliable predictor (Klebanoff 1984). The mother's influence on growth rate can be considered an adjustment of parental effort. In unpredictable environments, parents should reduce reproductive effort if the survival of juveniles is more sensitive to environmental quality than is adult survival (Lindstrom 1999). Instead of regarding pregnancy as a dichotomous on/off event, it may be more useful to consider a range of effort in response to environmental conditions at each stage in the production of offspring (Peacock 1991). Even mildly negative energetic balance can depress ovarian function in humans, decreasing the probability of conception and implantation (Ellison 1994). Similarly, midand late gestational adjustments involve incremental tradeoffs between current and future reproduction by modulating energy transfer from mother to fetus. Intrauterine growth retardation appears to be the compromise between producing a normal-sized infant and abortion or stillbirth when energy intake is externally constrained (Peacock 1991). The bodily state of the mother at the time of conception is presumably crucial to fetal growth because it is a reliable indicator of recent past, and hence near future, environmental conditions. Changes in nutritional intake during pregnancy reflect acute and temporary fluctuations in food availability, but somatic stores manifest a chronic, long-term record of environmental quality. Since malnutrition can be caused by parasites and other pathogens, nutritional status also can signify any of several unfavorable conditions being imposed on the organism. A gestational system that constantly readjusted the rates of energy transfer might be easily misled by "noise," environmental microfluctuations, and produce lessadaptive outcomes. Therefore, the deterministic relationship between energy storage at conception and fetal growth rate should be considered informational as well as energetic in nature.

MALNUTRITION AND FETAL BRAIN DEVELOPMENT Energy Allocation and Differential Organ Growth According to Sibly and Calow (1987), the growth rate of organs in relation to each other is a function of their relative contributions to the survival of the individual. The size and functioning of individual organs can only be sacrificed so much until individual survival is threatened. Proximately, organ growth is determined by two major factors: central hormonal axes and intrinsic control mechanisms which are influenced by interactions with other organs (Bryant and Simpson 1984), including competition between organs over limited nutrients (Klingenberg and Nijhout 1998).

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The h u m a n brain is both critical to survival and an expensive and relatively metabolically invariant organ, responsible for 20% of adult human basal metabolism despite constituting only 2.5% of body weight (Elia 1992). During the first postnatal year, the brain is responsible for more than half of metabolic costs (Haig 1999). At birth the brain is 300-400 grams, one-fourth of its adult size (Morgan and Gibson 1991). The human brain is significantly larger and more costly than the chimpanzee's at birth in both relative and absolute terms. By the fifth year a typical human will have spent three times as much on brain maintenance costs than will a chimp (Bogin and Smith 1996; Foley 1992). Despite prolonged growth after birth, prenatal brain growth is still a major determinant of postnatal brain size potential, as demonstrated by studies of catch-up growth (Morgan and Gibson 1991). The organismic logic of brain growth under adverse conditions may be informed both by the brain's crucial role in survival and reproduction as well as its future metabolic costs in an "anticipated" environment of low energy availability. Brain sparing is believed to underlie the phenomenon of nutritional or growth programming (Barker 1999), in which prenatal malnutrition has consequences in adulthood of increased risk of diabetes, hypertension, and other diseases. This syndrome is thought to be caused by insulin resistance and vascular dilation, which redirects nutrients from viscera and muscles to the brain. Further, reduction in liver growth and development to spare the brain results in permanent changes to liver function, including impaired ability to modulate cholesterol metabolism, resulting in elevated serum cholesterol. Barker (1999:249) states that "Genes which allow the fetus to adapt successfully to undernutrition are likely to be favored by natural selection even if they may lead to disease and premature death in postreproductive life." The association of a relatively large head (but actually smaller than normal in absolute terms) with a small body, or asymmetric growth retardation, is typically seen when undernutrition occurs in the latter half of pregnancy (Barker 1996), but it can be also the result of severe and chronic growth retardation caused, for example, by placental insufficiency (Gruenwald 1975). The contrast in organ weights between small-for-term (minus two standard deviations) and preterm infants of similar weight is especially striking, with the former having significantly reduced livers and thymuses, slightly enlarged hearts, and much larger brains (Figure 2). Presumably, visceral mass is reduced to allow for brain growth, and cardiac capacity is maintained in order to supply nutrients to the brain.

Brain-Sparing Mechanisms The mammalian fetus adjusts to starvation by breaking down amino acids and, later, by utilizing fat as a metabolic fuel (Rosso and Salas 1994).

Evolutionary and EcologicalAspects of Early Brain Malnutrition

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Figure 2. The effects of growth retardation on organ weight. Organ weights of small-for-gestational age (-2 s.d.) neonates are shown relative to weights for normal-for-gestational-age preterm infants of similar weight. Numbers are percents. (Adapted from Gruenwald 1975)

The nature of the adjustments in glucose metabolism caused by starvation are modified by early programming. The fetuses of ewes who were malnourished prior to conception had slow growth in late gestation but were better able to maintain growth rates during an acute episode of maternal malnutrition (Harding and Johnston 1995) owing to the modulation of growth hormone in the fetus (Gallaher et al. 1998). This robustness of growth rates resulting from nutritional programming reinforces the central importance of periconceptual maternal body condition in determining pregnancy outcomes. The brain is partially protected from the effects of reduced transfer of

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glucose and other nutrients by an increase in circulation of blood to the fetal brain at the expense of other organs (Bradley and Nicolaides 1989). This is achieved by cerebral vasodilafion accompanied by increased vascular resistance elsewhere in the fetus (Kurjak et al. 1993). In addition to cerebral vascular volume, overall brain growth is also related to the activity of insulin and insulinlike growth factors (IGF) I and II and their receptors in facilitating the growth-promoting effects of glucose (de Pablo and de la Rosa 1995). The brain and the rest of the central nervous system have high levels of insulin-family receptors. Insulin and related growth hormones do not cross the placenta in significant amounts; instead, they are produced in the fetal brain and liver (Masters and Raizada 1993; Sara 1989). Within the fetus, insulin, like glucose, crosses the blood-brain barrier, which prevents the passage of many proteins and other large molecules (Kalat 1988).

The Sequence of Brain Development and Malnutrition The expression of brain malnutrition is dependent on the stage of maturation in which malnutrition is experienced; the specific cause of the deficiency is less important (Morgan and Gibson 1991). Severe malnutrition in the first month causes neural tube defects; in the second trimester, neuronal-deficit-producing gross microcephaly is the result. Malnutrition in the third trimester reduces neuroglia, dendritic arborization, and synaptic connections (Zamenoff and Van Marthens 1978). Up to the first year of postnatal life, these effects, especially inadequate myelination, will be found in conditions of low nutrition (Morgan and Gibson 1991). These latter instances of brain damage are more subtle and grade into fully normal brain development. During neuronal proliferation, more cells are produced than will survive in the mature brain. The level of cellular redundancy differs from one region of the brain to another; in some regions 75% of neurons undergo cell death (Shepherd 1994). This is achieved through competition for innervation of targets. Neurons that make successful connections receive trophic factors from their targets (Shepherd 1994). The human brain growth spurt begins in the latter part of the second trimester, at the termination of neuroblast proliferation, by which time the adult level of neurons has nearly been reached. Neuroblasts migrate to their mature positions and differentiate into their respective classes (Dobbing 1972). During the brain growth spurt, the neuroglia multiplies and there is rapid lipogenesis and myelination of neurons. Water content declines and protein and lipid quantities in the cells rise, increasing cell size, and dendritic arborization is underway (Dobbing 1972). The human brain, in contrast to that of other mammals, continues its


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prolific growth rate for a year after birth (Martin 1990). During the first year of postnatal life, its volume doubles, reaching 60% of its adult size (Konner 1991). The DNA content of the forebrain and brainstem is at 70% of its adult level by two years, peaking at six years of age (Morgan and Gibson 1991). The ratio of protein to DNA, indicating translational activity, is at its highest at two years of age, which is the end of the period of rapid growth (and highest vulnerability). Infants who died from marasmus (protein-calorie malnutrition) were found to have low brain weight as well as low levels of brain DNA and protein (Luke 1972). Myelination of the brain, as a central component of brain maturation and a particularly vulnerable process, warrants special consideration. One-fourth of the dry weight of the brain is lipid, half of which is in the form of myelin (Morgan and Gibson 1991). Myelin provides insulation to neural processes, allowing for the rapid and efficient conduction of electrical impulses, and makes possible the elaborate synaptic connections of the cortex (Konner 1991). Insulin, which stimulates glial cell differentiation, is essential to myelination (Sena and Ferret-Sena 1995). After the seventh gestational month, lipid content increases to three or four times its original levels. The progress of myelination is associated with landmark events of brain development, including those that are expressed behaviorally (Gibson 1991; Konner 1991). Interference with normal lipid deposition and myelination from malnutrition can have severe detrimental effects. Deficiency in linoleic acid, essential for lipogenesis, results in low brain weight (Zamenoff and Van Marthens 1978), and underweight babies often have poor myelination (Morgan and Gibson 1991).

SEQUELAE OF EARLY MALNUTRITION Animal Studies

Animals that have experienced early nutritional stress have persistently higher reactivity, anxiety, aggressiveness, and food-seeking behavior. They are also more sensitive to both negative reinforcement, such as shock, or deprivation of reward, such as withdrawal of food (Morgane et al. 1993; Strupp and Levitsky 1995; Tonkiss et al. 1993). Previously malnourished animals also show increased selective attention, which facilitates performance of tasks that require ignoring irrelevant stimuli and is a handicap on tasks that require attention to peripheral cues (Strupp and Levitsky 1995). Another characteristic of these animals is cognitive inflexibility, displayed by preseveration of behaviors even after reward contingencies change. In cases where there is measurable brain size reduction resulting from prenatal malnutrition, much of it is localized in the cerebral cortex and

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cerebellum (Strupp and Levitsky 1995). Though this is not usually associated with reduction in cell number, it does often involve abnormally dense packing of the cells, reduced arborization, reduced synapses, and low levels of neuroglia (Strupp and Levitsky 1995). Most of these aberrations can be corrected with early nutritional rehabilitation, but other changes, especially those that affect temperament rather than intelligence, appear to be less amenable to rehabilitation (Levitsky and Strupp 1995). Human Studies

Children who have been previously malnourished tend to have reduced emotional control, high impulsivity, difficulty interacting with peers, and attention disorders (Bengelloun 1990; Grantham-McGregor 1995; Robson and Cline 1998; Strupp and Levitsky 1995). A study of Barbados children found that those who had experienced malnourishment in the first year of life had more behavioral problems at home than their non-malnourished siblings at ages 5-11 and were more likely to have attention disorders than controls at ages 9-15 (Galler et al. 1985). Malnutrition during early development also is associated with impaired language development (Galler et al. 1985; Gorman and Pollitt 1992) and vulnerability to schizophrenia and depression later in life (Almeida et al. 1996). In contrast to the studies which found conduct disorders and attention deficit, several other studies report passivity and inactivity in children who experienced early malnutrition (Fleming 1994). This seeming contradiction might be due to differences in the degree, timing, and persistence of malnutrition (Fleming 1994), the behavioral effects of which are little understood. For example, there is little research on whether different patterns of behavioral expression are associated with early, chronic, and late prenatal malnutrition. In a study of Zulu newborns, infants with a low ponderal index (PI: weight to length), usually associated with malnutrition in the latter half of pregnancy, were more responsive, easily startled, and displayed greater object orientation than normal PI-low birth weight and high PI infants (Niestroj 1991). In addition to nutrition, other important influences on cognitive function include environmental stimulation and family relationships (GranthamMcGregor 1995; Morgan and Gibson 1991; Strupp and Levitsky 1995). Undernutrition can affect cognition indirectly as well as directly. Children whose energy level is depressed in the exploratory stage will engage their environments less, exacerbating the effects of the prenatal insult (Grantham-McGregor 1995). No amount of rehabilitation will generate new neurons, nor will it enhance myelination after this process has been completed (Morgan 1991). However, light-for-date infants sometimes display catch-up growth in terms of head circumference (faster than that of normal weight babies), and


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the first two years of postnatal life, while the brain growth rate is still high, is a period in which intervention can be highly effective (Dobbing 1972), as shown in the case of infants born during the Dutch famine of the winter of 1944--45 (Stein 1972). Even older children can have their IQs raised after suffering early malnutrition (Grantham-McGregor 1995), though subtle cognitive dysfunction often persists. Studies of children who recover in middle-class settings reveal normal IQ coexisting with memory and attention deficits (Morgan and Gibson 1991).

ALTERATION OF NEUROTRANSMII"rER SYSTEMS Serotonin and Catecholamines

Neurotransmitter metabolism is critical to brain function, and any alter~ ations of these systems will likely have far-reaching effects in terms of both cognition and affect. Of particular importance in this regard are the serotonin and catecholamine systems. In both the adult and developing brain, there is no saturation of the rate-limiting step for monamine synthesis, which means that the production of serotonin and catecholamines is influenced by dietary availability (Huether 1990). Malnutrition reduces competition of the serotonin and catecholamine precursors with other amino acids for transport across the blood-brain barrier, resulting in elevated synthesis of these monoamines (Figure 3). Huether (1990:147) states that "the earlier and the longer a developing system is confronted with an altered substrate supply the greater is the number of metabolic pathways affected downstream from its metabolism and the more unlikely is a rapid and complete restoration of the original balance when the dietary intake is normalized." One role of the neurotransmitter serotonin in the brain is to enhance the "capacity to plan and inhibit immediate responses to stimuli" (Higley and Linnoila 1997:49), an ability which is especially pronounced in primates. In rats, serotonin inhibits motor activity, reactivity to stimuli, feeding, and sexual behavior (Chaftez 1990). In humans, subnormal serotonin functioning is associated with suicide, alcohol and drug abuse, violent aggression, and sexual offenses (Coscina 1997). Protein restriction increases levels of monoamines in the rat brain (Almeida et al. 1996; Chen et al. 1992; Zhou et al. 1996) by reducing levels of both albumin, which binds with the serotonin precursor tryptophan, and large neutral amino acids (LNAA), which compete with tryptophan for brain uptake (Heuther 1990). In a review of studies of the effects of drugs on animals (mainly rats) that had experienced early malnutrition, Almeida and colleagues (1996) conclude that they are usually less behaviorally responsive to serotonin agonists and antagonists, which is consistent with

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VAL

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Figure 3. A model of the effects of malnutrition on serotonin and dopamine synthesis. The circulating monoamine precursors tryptophan (TRP) and tyrosine (TYR) compete with other amino acids for active transport at the blood brain barrier. Malnutrition leads to relatively higher levels of tryptophan and tyosine, resulting in elevated synthesis of serotonin (5HT) and dopamine (DA) in the brain. (Adapted from Huether 1990) reduced postsynaptic serotonin sensitivity following high serotonin levels and turnover. Rats that experience malnutrition in utero have a reduced number of serotonin receptors in the hippocampus (Almeida et al. 1996; Morgane et al. 1993), although other studies show increased brain serotonin receptors following prenatal malnutrition (Huether 1990). A study of postnatally malnourished rats found retarded development of serotonergic inhibition of spontaneous activity (Nagy 1979). The catecholamines dopamine and norepinephrine have major roles in the central nervous system. Dopamine is crucial in reward systems and memory, while the functions of norepinephrine include enhancing arousal and coordination of the SAM (sympathetic-adrenal medulla) stress response (Chaftez 1990). It is not surprising that differences in catecholamine function have been associated with behavioral outcomes in humans and animals. For example, high dopaminergic activity promotes extroversion in humans (Depue and Collins 1999), and both hypo- and hypersecretion of norepinephrine are associated with distractibility in rats and monkeys (Strupp and Levitsky 1995). Dopamine is synthesized from the protein tyrosine and is the precursor of norepinephrine. Lower tyrosine intake results in reduced catecholamine


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production; administration of tyrosine has been shown to be effective in treating depression in humans (Chaftez 1990). Early malnutrition leads to enhanced norepinephrine secretion and down-regulation of beta adrenoreceptors (Almeida et al. 1996; Strupp and Levitsky 1995). Consistent with this, most rodent models of early malnutrition show reduced sensitivity to drugs affecting the catecholamine system (Almeida et al. 1996). Peripheral as well as central down-regulation of catecholamine receptors are found in these animals (Almeida et al. 1996). The behavioral traits of impulsivity and attention disorders often presented by children who suffered early malnutrition bear some resemblance to the symptoms of attention deficit hyperactivity disorder (ADHD) (Strupp and Levitsky 1995). ADHD is often of genetic etiology but can be induced by a wide range of neurological insults (Wender 1995), including early malnutrition. Studies with dopamine transporter knockout mice suggest that inadequate serotonin activity relative to dopamine signaling is responsible for ADHD by impairing the ability of serotonin to inhibit the hyperkinetic and attention-disrupting effects of dopamine (Gainetdinov et al. 1999). It is possible that the serotonin-dopamine imbalance hypothesis may be applicable to the ADHD-like symptoms found in some children who have suffered early malnutrition, though much more research is required for a firm statement to be made. Implications of Neurotransmitter Disturbance The socioecological implications of nutritional influences on neurotransmitter function have been explored by investigators. Kaplan and colleagues (1997; Kaplan, Mulcldon et al. 1997) propose that during periods of poor dietary quality, particularly low fat intake, low serum serotonin results in increased impulsivity and aggression, facilitating food acquisition and competitive behaviors. Ernandes et al. (1996) present a similar hypothesis relating the effects of diets high in maize on serotonin levels and social behavior, including human sacrifice and cannibalism among the Aztecs (Emandes and Giammanco 1992). The hypotheses of Kaplan and Ernandes and their colleagues differ from the one offered here in that theirs concern current, rather than developmental, responses to ecological conditions. In addition, both hypotheses posit a relationship between low serotonergic activity and behavior, instead of early high serotonin activity resulting in reduced sensitivity. However, all of these hypotheses are mutually compatible; disturbances during neurotransmitter system development could reset the psychophysiological response to reduced monoamine precursor availability later in life. The sensitivity of monoaminergic systems to nutritional intake during development may be an anticipatory response to future environmental conditions. A nutrient-deprived prenatal environment provides an indica-

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tor of low resource availability in the future; the organizational alteration of neurotransmitter systems would serve to establish affective and behavioral patterns appropriate to that environment. In addition to effects on catecholamines and serotonin, the metabolism of other neurotransmitters and neuropeptides is altered by early malnutrition; a consistent result from rat studies is reduced sensitivity to drugs acting on the opoid system (Almeida et al. 1996). Huether (1996) has suggested that many organizational effects of stressors and insults on brain development are part of an adaptive response to changing environmental conditions.

H U M A N EVOLUTION A N D BRAIN DEVELOPMENTAL ALTERATION Socioecological Context of Brain Function

Although costly both to the parent in terms of reproductive effort and to their individual owners in terms of maintenance, large brains can serve to enhance survivorship and success in sexual selection (Pagel and Harvey 1988). Both social intelligence and foraging ability are likely to have played a role in the evolution of large brain size in the human lineage, especially the expansion of the neocortex (Dunbar 1993). Field studies demonstrate that the size and complexity of primate social groups increases with resource predictability (Foley 1992). This inference is consistent with the finding that group size in primates is highly correlated with the size of the neocortex (Dunbar 1993). These advantages, however, are not intrinsic properties of large brains, but are dependent on the socioecological context in which individuals live. In a reduced and disrupted social environment, there will be less opportunity for triadic manipulation, displays of verbal sophistication, and other hallmarks of social intelligence that aid in sexual selection. Social groups will tend to be more widely dispersed and less likely to coalesce, reducing the iteration of encounters between a large number of social actors. The benefits of long-term planning are reduced as the environment, including food resources, becomes more unpredictable, lessening the probability that decisions based on past experience will be rewarded in the future. The inhibition of emotionally driven behaviors such as attack and escape is less likely to be expedient in a disrupted social milieu. Instead, the expression of the suite of cognitive traits found in prenatally malnourished animals, including higher food-seeking motivation, enhanced selective attention, and heightened impulsivity and aggression, may be more advantageous. Jensen et al. (1997) and Shelly-Tremblay and Rosen (1996) propose evo-


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lutionary hypotheses for the adaptive basis of attention deficit hyperactivity disorder (ADHD) which are similar to our model. According to Jensen and colleagues, the syndrome's features of impulsivity, inattention, and hyperactivity would have promoted survival and food acquisition in threatening and low-resource environments during the Pleistocene by facilitating rapid scan of surroundings and decisions in time-critical situations. However, while Jensen and coworkers appeal to an evolutionary scenario to explain the persistence of ADHD as a condition with a strong genetic component that no longer appears beneficial, we argue that the developmentaUy induced expression of a syndrome with some features that are similar to ADHD may be beneficial to survival under marginal ecological circumstances.

Ecological Uncertainty and Hominid Socioecology A period of significant global cooling and drying about 2.5 million years ago roughly coincides with the emergence of H. habilis (Potts 1996). Brain expansion presumably started in early Homo and continued in Homo erectus because it enabled behaviors that effectively imposed stability and predictability on otherwise unpredictable environments and selected for individuals who are capable of a wide range of facultative responses to ecological changes, which Potts (1996, 1998) calls variability selection. Because the duration of environmental fluctuations must be commensurate with an organism's life history for obligate plastic responses to be adaptive, Potts (1998) discounts the significance of phenotypic plasticity in human evolution, which would include our arguments about malnutrition and brain development. However, Potts does mention ecological fluctuations during hominid evolution which are in the range of decades and centuries, on the scale of one or several human generations. Further, there is evidence for adaptive phenotypic plasticity in terms of body size (Stini 1975; Stinson 1992) as well as physiological and morphological developmental adjustments to high altitude (Frisancho 1993; Greksa and Beall 1989) and hot dry climates (Frisancho 1993). We propose that while cultural buffering is indeed the primary human response to environmental adversity, other responses, including phenotypic plasticity, come into play when its capacity is exceeded. Modern hunter-gatherers have four basic responses to dealing with ecological uncertainty: mobility, diversification of subsistence behaviors, storage of resources, and exchange of resources with other groups (Halstead and O'Shea 1989). However, such strategies are not always successful in preventing malnutrition. Episodic nutritional stress is well-known among prehistoric human hunter-gatherers (see reports in Cohen and Armelagos 1984), though its severity is difficult to assess (Wood et al. 1992). Short

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periods of environmental stress would result in temporary changes in reproductive function, including ovarian function, that lead to delays in reproduction and the lengthening of birth intervals. However, when the capacity of cultural buffering was exceeded for very long periods, those who reproduced, even if they had to sacrifice some offspring quality, would have had greater fitness than those who deferred reproduction indefinitely (Peacock 1991). Both storage and exchange can only occur if there is a previous surplus of some resources, and storage is limited by mobility (Mandryk 1993). In addition, diversification of subsistence in impoverished environments can take the form of utilizing decidedly suboptimal resources. Among huntergatherers and other subsistence populations, periods of environmental scarcity lead to the consumption of famine foods which are not normally eaten at other times (Turner and Davis 1993). These foods are often unpalatable roots and other plant materials and tend to have high levels of toxins. With greater scarcity and unpredictability of resources there will be a tendency for groups of foragers to become increasingly dispersed within a region and for larger kin networks to be more unstable (Mandryk 1993).

Provisioning by Males and Offspring Survival Hypotheses of the evolution of h u m a n intelligence have related increased brain size to the increasing contribution of males to subsistence (Kaplan et al. 1999; Lancaster 1997; Lancaster and Lancaster 1987; see Bird 1999 for a contrary view). In a survey of hunter-gatherers by Kaplan et al. (1999), the mean percentage of calories from vertebrate meat was over 60%. Following Martin's (1990) argument that maternal metabolic output during pregnancy and lactation determines brain size, Leonard and Robertson (1994) reason that improved maternal nutrition was needed to support increased brain volume. The inclusion of male provisioning in the family unit (Lovejoy 1981) allowed the energetic demands of large brains among early Homo to be met (Leonard and Robertson 1994). Males should be more likely to bond with mates and provide parental care as a function of the degree to which male provisioning enhances child survivorship (Draper and Harpending 1982; Hurtado and Hill 1992). However, the potential for males to increase their fertility through multiple matings is a countervailing factor in paternal investment, which is exacerbated by resource unpredictability and scarcity. The low probability of offspring survivorship, regardless of attempts to provision, means that mate desertion and avoiding a wasted investment will be a more desirable option for males (Borgerhoff Mulder 1992; Draper and Harpending 1982; Weinrich 1977). Also, because resource unpredictability leads to increased variance in male success at obtaining resources, it is better for a female to


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desert a high-investing but unsuccessful male for short-term mating with a low-investing male who currently has more resources to offer (Weinrich 1977), further promoting dissolution of pair bonds. The importance of sociality and the possibility of paternal investment coupled with long-term environmental unpredictability would have led to fluctuation between relatively low and stable mortality regimes that are selective for high investment and those with high and capricious mortality regimes that favor organisms that temporarily reduce reproductive effort, which includes delivering less energy to their offspring during early development. Under such conditions, it would be advantageous for a mother to reduce energy transfer to the fetus. Consequent energy allocation decisions made by the offspring and changes in brain development result in changes in brain function, including altered neurotransmitter metabolism leading to a set of cognitive and affective traits. While increasing efficient acquisition of high-quality resources (Kaplan et al. 1999; Milton 1999) and increased group size and complexity (Dunbar 1993) would have provided a relatively stable environment favoring large brains, downturns in environmental quality may have been sufficiently common and severe to fragment large social groups into bands in an unstable and widely dispersed network. Low resource availability and reduced mate provisioning by males would have resulted in less nutrients being available to mothers, as well as their prenatal and infant offspring. Fluctuations between environments that allow for high sociality and parental provisioning and those where such behaviors are sharply reduced would favor selection for large brains whose ultimate size and functioning is dependent on the level of maternal allocation during early development.

SUMMARY A N D CONCLUSION

Each of the three processes discussed, (1) maternal reduction of energy transfer during pregnancy, (2) fetal organ growth reallocation, and (3) altered neurotransmitter function and its behavioral outcomes, may actually be nonadaptive side effects instead of adaptations. Further, although there are substantial reviews of the adaptive aspects of maternal-fetal interaction (Haig 1993, 1999; Peacock 1991) and brain-sparing mechanisms (Barker 1999; Desai and Hales 1997), the case for the adaptive value of neurotransmitter alteration from early malnutrition is less substantiated. The development of the brain is a highly complex, largely irreversible, and temporally constrained process; it cannot be indefinitely fine-tuned. Nevertheless, we have attempted to show that the processes of maternal energy transfer, differential organ growth, and neurotransmitter system disturbance caused by gestational undernutrition have features that are

18


not expected from a purely constraint-based perspective. First, that fetal growth rates appear to be more influenced by maternal body condition at conception (when gestational costs are lowest) rather than by day-to-day maternal nutritional intake implies an information-based and long-term basis of fetal growth instead of a solely energy-based and short-term one. Second, the phenomenon of brain sparing, including its coordination with other organs and even its incompleteness, supports the hypothesis that organ growth rates within the fetus are modulated to promote survival under adverse conditions. Finally, the appearance of behavioral and cognitive traits associated with reduced cortical inhibition is at least consistent with a developmentally primed set of appropriate tendencies in marginal and socially disrupted environments. However, instead of the term adaptation to describe the significance of these phenomena, a better word may be accommodation, which according to Frisancho (1993:7) refers to "responses that are not wholly successful because even though they favor survival of the individual they also result in significant losses in some important functions." The physiological and behavioral consequences of malnutrition during early development might facilitate survival in low-resource environments, but they would be detrimental to fitness in resource-rich environments. Fetal growth retardation, the effects of brain sparing, and altered neurotransmitter function are unattractive options compared with the developmental outcomes resulting from an optimal environment, but stated bluntly, it is better to be sickly than dead in terms of natural selection. In proposing that some of the characteristics of early brain malnutrition have origins in selection for the environmentally contingent expression of traits that aid survival and reproduction, by no means do we wish to suggest that such outcomes are in any w a y "good" or desirable in a moral sense. It would be most desirable, of course, for the individual never to have experienced malnutrition in the first place. The possibility that a physiological outcome to an environmental stressor may have a selective advantage does not relieve society from attempting to prevent such insults and of treating their effects (Haig 1999). The tragedy of disturbed brain development resulting from early malnutrition is a phenomenon whose expression may be best understood through the tools of evolutionary biology. We thank Nanette Barkey, Jane Lancaster, Laura MacLatchy, Mark Turner, and three anonymous reviewers for their helpful comments and criticisms. Of course, they should be held blameless for any errors found in this paper. William D. Lukas is a graduate student in the Department of Anthropology at Boston University. He is currently studying the relationship of hormones to immune function and body composition in different populations of African men.


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Benjamin C. Campbell is Assistant Professor of Anthropology at Boston University. He studies human reproductive ecology, the endocrinology of male fertility and health over the life span, and biocultural interactions in African populations.

REFERENCES Almeida, S. S., J. Tonkiss, and J. Galler 1996 Malnutrition and Reactivity to Drugs Acting in the Central Nervous System. Neuroscience and Biobehavioral Reviews 20:389-402. Barker, D. J. P. 1996 The Origins of Coronary Heart Disease in Early Life. In Long-term Conse-

quences of Early Environment: Growth, Development, and the Lifespan Developmental Perspective, C. J. K. Henry and S. J. Ulijaszek, eds. Pp. 155--162. Cambridge: Cambridge University Press. 1999 The Fetal Origins of Coronary Heart Disease and Stroke: Evolutionary Implications. In Evolution in Health and Disease, S. C. Stearns, ed. Pp. 246-250. New York: Oxford University Press. Bengelloun, W. A. 1990 Kwashiorkor: Behavioral Indices of Neurological Sequelae. In (Mal)nutrition and the Developing Brain, N. M. van Gelder, R. E Butterworth, and B. D. Drujan, eds. Pp. 65-82. New York: Wiley-Liss. Bird, R. 1999 Cooperation and Conflict: The Behavioral Ecology of the Sexual Division of Labor. Evolutionary Anthropology 8:65-75. Bogin, B., and B. H. Smith 1996 Evolution of the Human Life Cycle. American Journal of Human Biology 8:703-716. Borgerhoff Mulder, M. 1992 Reproductive Decisions. In Evolutionary Ecology and Human Behavior, E. A. Smith and B. Winterhalder, eds. Pp. 339-374. New York: Aldine de Gruyter. Bradley, R. J., and K. H. Nicolaides 1989 Ultrasound Guided Procedures in Small-for-gestation Fetuses. In Fetal Growth Retardation: Diagnosis and Treatment, A. Kurjak and J. M. Beazley, eds. Pp. 109-118. Boca Raton, Florida: CRC Press. Bryant, P. J., and P. Simpson 1984 Intrinsic and Extrinsic Control of Growth in Developing Organs. Quarterly Review of Biology 59:387-415. Chaftez, M. D. 1990 Nutrition and Neurotransmitters: The Nutrient Bases of Behavior. Engelwood Cliffs, New Jersey: Prentice Hall. Chen, J. C., J. Tonkiss, J. R. Galler and L. Volicer 1992 Prenatal Protein Malnutrition in Rats Enhances Serotonin Release from Hippocampus. Journal of Nutrition 122:2138-2143. Cohen, M. N., and G. J. Armelagos, eds. 1984 Paleopathology at the Origins of Agriculture. New York: Academic Press.

20


Coscina, D. V. 1997 The Biopsychology of Impulsivity: Focus on Brain Serotonin. In Impulsivity: Theory, Assessment, and Treatment, C. D. Webster and M. A. Jackson, eds. Pp. 95-115. New York: Guilford Press. de Pablo, E, and E. J. de la Rosa 1995 The Developing CNS: A Scenario for the Action of Proinsulin, Insulin, and Insulin-like Growth Factors. Trends in Neurosciences 18:143-150. Depue, R. A., and P. F. Collins 1999 Neurobiology of the Structure of Personality: Dopamine, Facilitation of Intentive Motivation, and Extraversion. Behavioral and Brain Sciences 22:491569. Desai, M., and C. N. Hales 1997 Role of Fetal and Infant Growth in Programming Metabolism in Later Life. BiologicalReviews 72:329-348. Dobbing, J. 1972 Vulnerable Periods of Brain Development. In Lipids, Malnutrition and the Developing Brain, K. Elliot and J. Knight, eds. Pp. 20-30. CIBA Foundation Symposium. Amsterdam: Elsevier. Draper, P., and H. Harpending 1982 Father Absence and Evolutionary Strategy in Ecological Perspective. Journal of Anthropological Research 38:255--273. Dunbar, R. I. M. 1993 Coevolution of Neocortical Size, Group Size, and Language in Humans. Behavioral and Brain Sciences 16:681-735. Elia, M. 1992 Organ and Tissue Contribution to Metabolic Rate. In Energy Metabolism: Tissue Determinants and Cellular Corollaries,J. M. Kinney and H. N. Tucker, eds. Pp. 61-79. New York: Raven Press. Ellison, P. T.

1994 Advances in Human Reproductive Ecology. Annual Review of Anthropology 23:255-275. Ernandes, M., and S. Giammanco 1992 Serotonin Deficiency Hypothesis Explaining the Aztec Human Sacririce/Cannibalism Complex. Antroplogia Contemporanea 15:65-73. Ernandes, M., M. La Guardia, and S. Giammanco 1996 Maize-Based Diets and Possible Neuro-behavioural After-Effects among Some Populations in the World. Human Evolution 11:67-77. Fleming, S. A. 1994 Effects of Fetal and Early Malnutrition on Brain and Behavioral Development. Unpublished Master's thesis, School of Public Health, Boston University. Foley, R. 1992 Evolutionary Ecology of Fossil Hominids. In Evolutionary Ecology and Human Behavior, E. A. Smith and B. Winterhalder, eds. Pp. 131-166. New York: Aldine de Gruyter. Frisancho, A. R. 1993 Human Adaptation and Accommodation. Ann Arbor: University of Michigan Press.


21

Gainetdinov, R. R., W. C. Wetsel, S. R. Jones, E. D. Levin, M. Jaber, and M. G. Caron 1999 Role of Serotonin in the Paradoxical Calming Effect of Psychostimulants on Hyperactivity. Science 283:397-306. Gallaher, B. W., B. H. Breier, C. L. Keven, J. E. Harding, and P. D. Gluckman 1998 Fetal Programming of Insulin-like Growth Factor (IGF)-I and IGF-Binding Protein-3: Evidenced for an Altered Response to Undemutrition in Late Gestation Following Exposure to Periconceptual Undemutrition in Sheep. Journal of Endocrinology 159:501-508. Galler, J. R., F. R. Ramsey, and G. Solimano 1985 Influence of Early Malnutrition on Subsequent Behavioral Development, V: Child's Behavior at Home. Journal of the American Academy of Child and Adolescent Psychiatry 24:58-64. Gibson, K. R. 1991 Myelination and Behavioral Development: A Comparative Perspective on Questions of Neoteny, Altriciality, and Intelligence. In Brain Maturation and Cognitive Development: Comparative and Cross-Cultural Perspectives, K. R. Gibson and A. C. Peterson, eds. Pp. 29-64. New York: Aldine de Gruyter. Gorman, K. S., and E. Pollitt 1992 Relationship between Weight and Body Proportionality at Birth, Growth during the First Year of Life, and Cognitive Development at 36, 48, and 60 Months. Infant Behavior and Development 15:279-296. Grantham-McGregor, S. 1995 A Review of Studies of the Effect of Severe Malnutrition on Mental Development. Journal of Nutrition 25:33s-38s. Greksa, L. M., and C. M. Beall 1989 Development of Chest Size and Lung Function at High Altitude. In Human Population Biology: A Transdisciplinary Science, M. A. Little and J. D. Hass, eds. Pp. 222-238. New York: Oxford University Press. Gruenwald, P. 1975 The Relation of Deprivation to Perinatal Pathology and Late Sequels. In The Placenta and its Maternal Supply Line, P. Gruenwald, ed. Pp. 335-355. Baltimore: University Park Press. Hadders-Algra, M., and B. C. L. Touwen 1990 Body Measurements, Neurological and Behavioural Development in SixYear-Old Children Born Preterm and/or Small-for-Gestational-Age. Early Human Development 22:1-13. Haig, D. 1993 Genetic Conflicts in Human Pregnancy. Quarterly Review of Biology 68: 495-532. 1999 Genetic Conflicts of Pregnancy and Childhood. In Evolution in Health and Disease, S. C. Stearns, ed. Pp. 77-89. New York: Oxford University Press. Halstead, P., and J. O'Shea 1989 Introduction: Cultural Responses to Risk and Uncertainty. In Bad YearEconomics: Cultural Responses to Risk and Uncertainty, P. Halstead and J. O'Shea, eds. Pp. 1-7. New York: Cambridge University Press. Harding, J. E., and B. M. Johnston 1995 Nutrition and Fetal Growth. Reproduction, Fertility, and Development 7: 539-547.

22


Higley, J. D., and M. Linnoila 1997 Low Central Nervous System Serotonergic Activity Is Traitlike and Correlates with Impulsive Behavior. In The Neurobiology of Suicide, D. M. Stoff and J. J. Mann, eds. Pp. 39-51. Annals of the New York Academy of Sciences 836. Huether, G. 1990 Malnutrition and Developing Synaptic Transmitter Systems: Lasting Effects, Functional Implications. In (Mal)nutrition and the Developing Brain, N. M. van Gelder, R. F. Butterworth, and B. D. Drujan, eds. Pp. 141-156. New York: Wiley-Liss. 1996 The Central Adaptation Syndrome: Psychosocial Stress as a Trigger for Adaptive Modifications of Brain Structure and Brain Function. Progress in Neurobiology 48:569-612. Hurtado, A. M., and K. R. Hill 1992 Paternal Effect on Offspring Survivorship among Ache and Hiwi Huntergatherers: Implications for Modeling Pair-bond Stability. In Father-Child Relations: Cultural and Biosocial Contexts, B. S. Hewlett, ed. Pp. 31-55. New York: Aldine de Gruyter. Jensen, P. S., D. Mrazek, P. K. Knapp, L. Steinberg, C. Pfeffer, J. Schowalter, and T. Shapiro 1997 Evolution and Revolution in Child Psychiatry: ADHD as a Disorder of Adaptation. Journal of the American Academy of Adolescent and Child Psychiatry 36:1672-1697.

Kalat, J. W. 1988 BiologicalPsychology, third ed. Belmont, California: Wadsworth. Kaplan, H., K. Hill, J. Lancaster, and A. M. Hurtado 1999 A Theory of Life History Evolution: Brains, Learning, and Longevity. Evolutionary Anthropology, in press. Kaplan, J. R., K. P. Klein, and S. B. Manuck 1997 Cholesterol meets Darwin: Public Health and Evolutionary Implications of the Cholesterol-Serotonin Hypothesis. Evolutionary Anthropology 6:28-37. Kaplan, J. R., M. F. Mulddon, S. B. Manuck, and J. J. Mann 1997 Assessing the Observed Relationship between Low Cholesterol and Violence-Related Mortality: Implications for Suicide Risk. In The Neurobiology of Suicide, D. M Stoff and J. J. Mann, eds. Pp. 57-80. Annals of the New York Academy of Sciences 836. Klebanoff, M. A. 1984 Low Birth Weight across Generations. Journal of the American Medical Association 252:2423-2427. Klingenberg, C. P., and H. F. Nijhout 1998 Competition among Growing Organs and Developmental Control of Morphological Asymmetry. Proceedings of the Royal Society of London (Biological Sciences) 265:1135-1139. Konner, M. 1991 Universals of Behavioral Development in Relation to Brain Myelination. In Brain Maturation and Cognitive Development: Comparative and Cross-Cultural


23

Perspectives, K. R. Gibson and A. C. Peterson, eds. Pp. 181-224. New York: A1dine de Gruyter. Kurjak, A., Z. Alifireviv, G. Rizzo, and D. Ardulni 1993 Utero-placental and Fetal Circulation in Intrauterine Growth Retardation. In Fetal Growth Retardation: Diagnosis and Treatment, A. Kurjack and J. M. Beazley, eds. Pp. 119-144. Boca Raton, Florida: CRC Press. Lancaster, J. B. 1997 The Evolutionary History of Human Parental Investment in Relation to Population Growth and Social Stratification. In Feminism and Evolutionary Biology: Boundaries, Intersections, and Frontiers, P. A. Gowaty, ed. Pp. 466-488. New York: Chapman and Hall. Lancaster, J. B., and C. S. Lancaster 1987 The Watershed: Changes in Parental-Investment and Family-Formation Strategies in the Course of Human Evolution. In Parenting across the Life Span: Biosocial Dimensions, J. B. Lancaster, J. Altmann, A. S. Rossi, and L. S. Sherrod, eds. Pp. 187-205. New York: Aldine de Gruyter. Launer, L. J., J. Villar, and E. Kesfler 1991 Epidemiological Differences among Birth Weight and Gestational Age Subgroups of Newborns. American Journal of Human Biology 3:425--433. Leonard, W. R., and M. L. Robertson 1994 Evolutionary Perspective on Human Nutrition: the Influence of Brain and Body Size on Diet and Metabolism. American Journal of Human Biology 6:77--88. Levitsky, D. A., and B. A. Strupp 1995 Malnutrition and the Brain: Changing Concepts, Changing Concerns. Journal of Nutrition 22:12s-20s. Lindstrom, J. 1999 Early Developments and Fitness in Birds and Mammals. Trends in Evolution and Ecology 14:343-348. Lovejoy, C. O. 1981 The Origin of Man. Science 211:341-350. Lucas, A. 1991 Programming by Early Nutrition. In The Childhood Environment and Adult Disease, J. Whelen, ed. Pp. 39-55. CIBA Foundation Symposium. New York: Wiley and Sons. Luke, B. 1972 Maternal Nutrition. Boston: Little, Brown. Mandryk, C. A. S. 1993 Hunter-gatherer Social Costs and the Nonviability of Submarginal Environments. Journal of Anthropological Research 49:39-71. Martin, R. D. 1990 Primate Origins and Evolution: A Phylogenetic Reconstruction. London: Chapman and Hall. Masters, B. A., and M. K. Raizada 1993 Insulin-like Growth Factor ! and IGF-II Actions in Neuronal Cultures from the Brain. In The Role of Insulin Growth Factors in the Nervous System,

24


M. K. Raizada and D. LeRoith, eds. Pp. 89-101. Annals of the New York Academy of Sciences 692. Milton, K. M. 1999 A Hypothesis to Explain the Role of Meat-Eating in Human Evolution. Evolutionary Anthropology 8:11-21. Morgan, B., and K. R. Gibson 1991 Nutritional and Environmental Interactions in Brain Development. In

Brain Maturation and Cognitive Development: Comparative and Cross-Cultural Perspectives, K. R. Gibson and A. C. Peterson, eds. Pp. 91-106. New York: A1dine de Gruyter. Morgane, P. J., R. Austin-LaFrance, J. Bronzino, J. Tonkiss, S. Diaz-Cintra, T. Kernper, and J. R. Galler 1993 Prenatal Malnutrition and Development of the Brain. Neuroscience and Biobehavioral Reviews 17:91-128. Nagy, Z. M. 1979 Effects of Early Malnutrition on Brain and Behavior of Developing Mice. In Development and Evolution of Brain Size, M. E. Hahn, C. Jensen, and B. C. Dudek, eds. Pp. 321-344. New York: Academic Press. Neufeld, L., D. L. Pelletier, and J. D. Haas 1999 The Timing of Maternal Weight Gain During Pregnancy and Fetal Growth. American Journal of Human Biology 11:627-637. Niestroj, B. H. E. 1991 Fetal Nutrition: A Study of Its Effect on Behavior in Zulu Newborns. In

Multicultural and Interdisciplinary Approaches to Parent-Infant Relations. The Cultural Context of Infancy, vol. 2, J. K. Nugent, B. M. Lester, and T. B. Brazelton, eds. Pp. 321-354. Norwood, New Jersey: Ablex. Pagel, M. D., and P. H. Harvey 1988 How Mammals Produce Large-Brained Offspring. Evolution 42:948957. Peacock, N. 1991 An Evolutionary Perspective on the Patterning of Maternal Investment in Pregnancy. Human Nature 2:351-385. Pike, I. L. 1999 Age, Reproductive History, and Maternal Body Composition during Pregnancy for Nomadic Turkana of Kenya. American Journal of Human Biology 11:658--672. Potts, R. B. 1996 Humanity's Descent: The Consequences of Ecological Instability. New York: William Morrow. 1998 Variability Selection in Human Evolution. Evolutionary Anthropology 7: 81-96. Robson, A., and B. Cline 1998 Developmental Consequences of Intrauterine Growth Retardation. Infant Behavior and Development 21:331-344. Rosso, P. 1990 Nutrition and Metabolism in Pregnancy. New York: Oxford University Press.


25

Rosso, E, and S. P. Salas 1994 Mechanisms of Fetal Growth Retardation in the Underweight Mother. In Nutrient Regulation during Pregnancy, Lactation, and Infant Growth, L. Allen, J. King, and B. Lonnerdal, eds. Pp. 1-9. New York: Plenum Press. Sara, V. R. 1989 Insulin-like Growth Factors in the Nervous System: Characterization, Biosynthesis and Biological Role. In The Physiology of Human Growth, J. M. Tanner and M. A. Preece, eds. Pp. 167-182. New York: Cambridge University Press. Sena, A., and V. Ferret-Sena 1995 Insulin and Brain Development. Trends in Neurosciences 18:485. Shelly-Tremblay, J. F., and L. A. Rosen 1996 Attention Deficit Hyperactivity Disorder: An Evolutionary Perspective. Journal of Genetic Psychology 157:443453. Shepherd, G. M. 1994 Neurobiology, third ed. New York: Oxford University Press. Sibly, R. M., and P. Calow 1987 Growth and Resource Allocation. In Evolutionary Physiological Ecology, P. Calow, ed. Pp. 37-52. New York: Cambridge University Press. Stein, Z., M. Susser, G. Saenger, and M. Marolla 1972 Nutrition and Mental Performance. Science 178:708-713. Stini, W. A. 1975 Adaptive Strategies of Human Populations under Nutritional Stress. In Biosocial Interrelations in Population Adaptation, E. S. Watts, F. E. Johnson, and G. W. Lasker, eds. Pp. 19-41. The Hague: Mouton. Stinson, S. 1992 Nutritional Adaptation. Annual Review of Anthropology 21:143-170. Strupp, B. J., and D. A. Levitsky 1995 Enduring Cognitive Effects of Early Malnutrition: A Theoretical Reappraisal. Journal of Nutrition 22:21S-31S. Tonkiss, J., J. Galler, P. J. Morgane, J. D. Bronzino, and R. J. Austin-LaFrance 1993 Prenatal Protein Malnutrition and Postnatal Brain Function. In Maternal Nutrition and Pregnancy Outcome, C. L. Keen, A. Bendich, and C. C. Willhite, eds. Pp. 215-227. Annals of the New York Academy of Sciences 678. Trivers, R. L. 1974 Parent-Offspring Conflict. American Zoologist 11:249-264. Turner, N. J., and A. Davis 1993 "When Everything Was Scarce": The Role of Plants as Famine Foods in Northwestern North America. Journal of Ethnobiology 13:171-201. Ulijaszek, S. J. 1995 Human Energetics in Biological Anthropology. Cambridge: Cambridge University Press. Wachs, T. D. 1995 Relation of Mild-to-Moderate Malnutrition to Human Development: Correlational Studies. Journal of Human Nutrition. 25:45s. Weinrich, J. D. 1977 Human Sociobiology: Pair-bonding and Resource Predictability. Behavioral Ecology and Sociobiology 2:91-118.

26


Weinstein, R. S. 1978 Stress Factors during Growth and Development: Implications for Human Reproductive Performance. Yearbook of Physical Anthropology 21:201-214. Wender, P. H. 1995 Attention-Deficit Hyperactivity Disorder in Adults. New Order: Oxford University Press. Wood, J. W. 1994 Dynamics of Human Reproduction: Biology, Biometry, Demography. New York: Aldine de Gruyter. Wood, J. W., G. R. Milner, H. C. Harpending, and K. M. Weiss 1992 The Osteological Paradox: Problems of Inferring Prehistoric Health from Skeletal Samples. Current Anthropology 33:343-370. Zamenoff, S., and E. Van Marthens 1978 Nutritional Influences on Prenatal Brain Development. In Influences. Studies on the Development of Behavior and the Nervous System, vol. 4, G. Gottlieb, ed. Pp. 149-179. New York: Academic Press. Zhou, D., G. Huether, J. Wiltfang, and E. Ruther 1996 Serotonin Transporters in the Rat Frontal Cortex: Lack of Circadian Rythmicity but Down-Regulation by Food Restriction. Journal of Neurochemistry 67:656-661.

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