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Enduring cognitive effects of early malnutrition: a theoretical reappraisal1

Enduring effects of early malnutrition in animals5
Cognitive effects, independent of altered motivation and/or emotion?
Literature cited


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 Nestle 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 Division of Nutritional Sciences, 109 Savage Hall, Cornell University, Ithaca NY 14853-630 1

Division of Nutritional Sciences and Department of Psychology, 109 Savage Hall, Cornell University, Ithaca, NY 14853-6301

ABSTRACT This article presents a reappraisal of the literature on the enduring cognitive effects of early malnutrition. In addition to summarizing the existing empirical literature, we present a theoretical framework for determining whether the processes likely to be most vulnerable to early malnutrition were adequately assessed. The two types of information used to make this determination are clinical and experimental behavioral data as well as reported neural changes. One point of clear consensus is that animals exposed to early malnutrition exhibit lasting changes in the realm of emotionality, motivation, and/or anxiety. Because these alterations profoundly affect all aspects of behavioral functioning, including cognition, it is suggested that future research focus on these changes, rather than control for them as many past studies have done. The functional integrity of specific cognitive processes is less clear. The only cognitive processes for which enduring cognitive changes were demonstrated in rehabilitated animals - outside of effects mediated by these affective changes - are cognitive flexibility and, possibly, susceptibility to proactive interference. However, the inference that these are the only processes affected does not appear to be warranted on the basis of the evidence that several cognitive processes likely to be affected have not been fully assessed. Examples include executive functions linked to the prefrontal cortex (for example, attention), transfer of learning, procedural learning and long-term memory. Future research focusing on these specific cognitive functions as well as on these unequivocal affective changes should allow a more definitive conclusion regarding the enduring functional consequences of early malnutrition. J. Nutr. 125: 2221S-2232S, 1995.


• malnutrition • learning e memory • behavioral-teratology • prenatal-exposure-delayed-effects

Despite extensive research efforts, there continues to be uncertainty about whether cognitive impairment is an inevitable consequence of severe early malnutrition. The purpose of this paper, in accordance with the charge,3 i. not to provide another exhaustive review of the literature,4 but, rather, to delineate the types of cognitive

3This paper is based on a presentation made by Barbara J Strupp at a Task Force meeting convened by the Intenational Dietary Energy Consultative Group (IDECG), held in Davis, CA, from December 6-10, 1993 The assignment for this presentation was to evaluate the available evidence concerning the enduring cognitive effects of malnutrition, drawing on relevant findings from cognitive neuroscience and developmental psychobiology

4For more detailed reviews, the reader is referred to Crnic 1976 Katz 1980, Levitsky and Strupp, 1995a, Levitsky and Strupp 1995b Smart 1977, Smart 1986, Smart 1993, Tonkiss et al 1993

A American Institute of Nutrition changes that were consistently observed as well as to suggest future research to answer the questions that remain. To guide this appraisal, we present a theoretical framework for identifying those cognitive processes most likely to be affected, drawing upon relevant findings from cognitive neuroscience and developmental psychobiology. The focus is on the animal research due to both the experimental perspective of the authors and the fact that the studies of previously malnourished humans remain more difficult to interpret because of the thorny issue of confounding factors. However, some human studies are discussed in relation to the animal work and when discussing the selection of cognitive tests for future studies.

Enduring effects of early malnutrition in animals5

5Unless otherwise indicated, this review deals exclusively with studies in which behavior was assessed after a sufficient period of nutritional rehabilitation to draw conclusions about enduring, as opposed to concurrent, effects of the nutritional insult

Historically, the prevailing view has been that early malnutrition permanently reduces brain size and cell number, resulting in irreversible cognitive impairment.

More recent research, however, requires a revamping of this view with respect to both the neuroanatomical and behavioral conclusions. Many of the dramatic anatomical alterations, so evident during or immediately after a period of malnutrition, were found to be reversible, but other, more subtle neural changes were uncovered that do not respond to nutritional rehabilitation (see Levitsky and Strupp 1995b). These changes, although likely to be functionally significant, are much more subtle. Examples include alterations in evoked neurotransmitter release and receptor sensitivity. A parallel transition is taking place in appraisals of the putative cognitive dysfunction. Although learning deficits and mental retardation were anticipated, the accumulating evidence indicates more subtle deficits, apparent only under certain circumstances or testing conditions. Although less blatant than initially predicted, these behavioral/cognitive changes are likely to significantly alter the lives of affected individuals.

The effects most consistently observed after either gestational or lactational malnutrition may be subsumed under two broad headings: an alteration in motivation and/or emotional reactivity and a decrease in cognitive flexibility. Certain other effects appear to be caused only by postnatal malnutrition. For example, enduring changes in cognitive functioning may be produced as a result of the experience of being malnourished for a protracted period of time. The changes referred to here are experiential effects, rather than ones directly mediated by the enduring effects of developmental malnutrition on brain structure. In addition, there is some evidence that susceptibility to proactive interference may be increased after postnatal, but not prenatal, malnutrition, but the paucity of relevant data render this conclusion tentative. Each of these effects is discussed below.

Motivational and emotional effects. In contrast to the controversy that persists concerning the existence of cognitive deficits after early malnutrition, there is a strong consensus that early malnutrition - either prenatal or postnatal - produces enduring changes in emotional reactivity and/or motivation (specific studies are reviewed in Crnic 1976, Katz 1980, Levitsky and Strupp 1995a, Smart 1977, Smart 1993, Tonkiss et al. 1993). Previously malnourished animals are more highly motivated than controls in both appetitively (Katz et al. 1979, Levitsky 1979, Smart et al. 1973, Smart and Dobbing 1977) and aversively motivated situations (de Oliviera and de Sousa Almeida 1985, Levitsky and Barnes 1970, Lynch 1976, Smart 1981, Smart et al. 1975). They also exhibit increased emotionality and/or anxiety, as evidenced by increased spilling in response to food restriction Levitsky and Barnes 1970), changes in locomotor behavior in unfamiliar environments (Levitsky and Barnes 1970, Wolf et al. 1986) and increased sensitivity to aversive reinforcement, such as shock or escape from cold water (de Oliveira and de Sousa Almeida 1985, Levitsky and Barnes 1970, Lynch 1976, Smart 1981, Smart et al. 1975) es well as increased aggression (Tonkiss et al. l 993). In addition, they appear to be more affected than controls when altered task contingencies produce a loss of reward (Tonkiss et al. 1990, Tonkiss et al. 1993). It is unknown whether this last effect should be subsumed under evidence for increased food motivation, emotional reactivity or decreased cognitive flexibility (this last putative effect is discussed below). In fact, as may be evident, very little is known about the nature of these effects or the mechanismls) by which they result from early malnutrition. For example, the finding that fond motivation is increased seemed intuitively obvious and therefore uninteresting. Yet the fact that such effects are evident even in animals having sustained only prenatal malnutrition indicates that the basis of this effect may not be as straightforward as often assumed.

In the quest to identify deficits that are purely cognitive, the potential importance of these alterations in motivation and/or emotional reactivity has been overlooked. They were generally dismissed as annoyance factors that significantly complicate the interpretation of observed performance differences in learning tasks. As a result, researchers employed manipulations and testing conditions to eliminate or control for these differences rather than study them. Although it may be instructive to determine if performance differences disappear under these conditions, the dismissal of these effects as unimportant is surely misguided. It would unquestionably affect an individual's life if, for example, she/he is more easily frustrated, more anxious, or adapts less well to stressful situations. It is our view that future research should focus on clarifying the nature of these changes rather than trying to control for them.

These motivational/emotional effects would be expected to have a substantial impact on problem-solving ability. For example, impaired performance in a variety of learning tasks was attributed to altered motivation or emotionality of the previously malnourished animals (reviewed in Katz 1980, Levin and Weiner 1976, Levitsky and Strupp 1995a, Smart 1977, Smart and Tonkiss 1985, Tonkiss et al. 1993). The findings of Celedon and Colombo (1979) concerning the Hebb-Williams maze provide particularly compelling evidence for this mechanism. Chlordiazepoxide, an anxiolytic, impaired the performance of the control group but improved the performance of the previously malnourished group. This pattern suggests that excessive anxiety may be a significant factor underlying the impaired performance of the previously undernourished animals.

Although these studies provide evidence of performance differences in previously malnourished animals mediated by alterations in anxiety, emotionality and/or motivation, they do not shed light on the mechanism underlying the behavioral change. However, research specifically focusing on the cognitive effects of these affective alterations provides hypotheses concerning the manner in which information processing may be altered in previously malnourished individuals. Two examples of experimental approaches likely to reveal such effects are: 1) Tests of Selective Attention and/or integration of information and 2) Analyses of: Response Style. Each of these is discussed below.

Selective attention. One very likely cognitive effect of early malnutrition is a narrowed focus of attention, regardless of whether these behavioral changes reflect increased emotionality, motivation and/or anxiety. All three have been shown to produce this type of cognitive alteration (Bahrick et al. 1952, Bruner et al. 1955, Cohen et al. 1969, Easterbrook 19.59, Eysenck 1982). This framework suggests that tests of attentional selectivity should be included in future studies of previously malnourished subjects. Although this aspect of cognition has not been explicitly tapped in studies of nutritionally rehabilitated subjects, the finding that incidental, but not intentional, learning is impaired in concurrently malnourished animals (Strupp 1982) provides evidence for a narrowed focus of attention at least during the period of malnutrition. Tests designed to assess the integration of information would, however, be superior for future studies of this hypothesized effect. Such tasks, unlike incidental/intentional paradigms, do not require assumptions about the subjects' central focus of attention.

It should be noted that a narrowed focus of attention would be expected to improve performance in some tasks but impair it in others, depending on the extent to which integration of information is required. For example, increased food restriction improved learning rate in a multiple cue task in which a narrowed focus of attention facilitates performance (that is, irrelevant cues had to be disregarded; Strupp et al. 1989), whereas it impaired learning in a task involving the same apparatus but in which the two sets of cues had to be integrated to determine the correct response (Strupp, B. J., Levitsky, D. A., Beal, M., unpublished observations).

Analysis of response style. The enduring motivational/emotional effects of early malnutrition are also likely to manifest as alterations in response style, which may be detected by detailed analyses of responses exhibited during the process of solving discrimination problems. For example, one likely manifestation is increased frustration in response to failure. An analysis of the responses made on a given trial as a function of the outcome of the previous trial (correct or incorrect) would provide a test of this putative effect. We employed this type of analysis in our research with animal models of fetal alcohol syndrome (Strupp et al. 1989), phenylketonuria (Strupp et al. 1990) and low level lead exposure (Strupp and Alber 1995). In the former two cases, the experimental group differed more from controls on trials after incorrect responses than on trials after correct responses. We found that logistic regression provides a powerful technique for detecting subtle treatment differences in response patterns (Strupp and Alber 1995).

Cognitive inflexibility A second effect consistently reported after early malnutrition is a reduction in cognitive flexibility. It is not clear if this effect should be viewed as another manifestation of the emotional/motivational changes described above or interpreted as a distinct type of cognitive alteration. Regardless of etiology, quite consistent evidence from a variety of behavioral paradigms points to this type of cognitive change (see Smart and Tonkiss 1985, Tonkiss et al. 1993). For example, impaired reversal learning was demonstrated after both prenatal (Jaiswal et al. l 991, Tonkiss and Galler 1990, Villescas et al. 1981) and grandmaternal (Bresler et al. 1975) malnutrition. Particularly compelling evidence is provided by the recent observation that animals malnourished prenatally exhibit impaired performance during rule reversal in a spatial alternation task administered in a T-maze, but not in an operant chamber (Tonkiss and Galler 1990). Although this apparent inconsistency may seem to question the reliability of this effect, it actually provides an opportunity to more precisely specify the underlying basis of the performance difference observed in the T-maze task. One difference between these two versions of the task is that spatial alternation is the prepotent response in the T-maze task but not in the operant version. Consequently, the demand for cognitive flexibility after the switch to the spatial matching rule is greater in the T-maze version. In contrast, the two tasks are similar in the extent to which the rule change produces a drop in reward, thereby ruling out an alternative interpretation of the performance impairment: increased frustration due to a reduction in reward density. This pattern of findings, therefore, suggests that reduced cognitive flexibility is the likely basis of the impaired reversal performance of the prenatally malnourished animals in the T-maze reversal task. Because inflexibility is associated with damage to the frontal lobes (reviewed in Fuster 1989), this type of cognitive change is consistent with the evidence, presented below, that prefrontal dysfunction may be a likely effect of early malnutrition.

Possible areas of dysfunction due to experiential factors. Cognitive changes also result from the experience of living in the malnourished state for a protracted period of time. This type of effect is clearly in a different category than the enduring cognitive and/or emotional alterations that are the product of irreversible changes in brain structure and/or chemistry. Two examples of such experiential effects, for which there are data, are discussed here: 1) decreased intrinsically motivated, or advantageous, learning and 2) effects of maternal depression on cognitive development. Before discussing these effects, it should be acknowledged that they obviously represent only a small subset of the many complex effects that are produced when malnutrition occurs within the context of poverty, poor sanitation and low socioeconomic conditions. Under these circumstances, not only is cognitive development affected but also, very likely, numerous aspects of the individual's personality and perspective, such as self-esteem and sense of control over life events. These effects would have far-reaching and enduring effects on the individual but are beyond the scope of this paper.

During the period of malnutrition, there is a significant decrease in the animal's propensity to acquire information under conditions in which the learning is not required to meet a biological need (see Levitsky and Strupp 1995a, Strupp 1982). Learning under these conditions has been referred to as intrinsically motivated, or advantageous, learning (see Strupp and Levitsky 1983, Strupp et al. 1984). The apathy that is so apparent in the malnourished child provides a vivid illustration of this effect. The available animal literature indicates that the propensity to engage in this type of learning recovers after nutritional rehabilitation (for example, Rogers and Smart 1986, Strupp and Levitsky 1983, Strupp et al. 1984). Nonetheless, the suppression of this mode of information processing during the period of malnutrition is likely to produce lasting cognitive deficits through two mechanisms. First, developmental delays would be expected because of the decreased propensity to actively acquire information during the period of malnutrition, particularly if the episode is protracted. To the extent that there are critical periods for certain types of learning, such delays would be of particular concern. Second, if the period of malnutrition is prolonged, there may be lasting deficits in the extent to which the individual engages in this type of learning, not because of irreversible damage to the relevant underlying neural systems but because of a learned mode of interacting with the environment. If so, the tendency to engage in such learning would need to be explicitly taught. This area could be a potentially important focus of intervention strategies.

A related indirect mechanism by which malnutrition may affect child development is maternal depression. In cases where both the child and the mother are malnourished, as is common in the developing world, it is likely that the mother is depressed because of both the direct effects of semistarvation (Keyes et al. 1950a, Keyes et al. 1950b) and the emotional toll of being powerless to feed one's child. In light of the evidence that maternal depression is negatively associated with intellectual development in infancy (Lyons-Ruth et al. 1986), this appears to be a very likely mechanism, albeit indirect, by which malnutrition may curtail cognitive development of malnourished children.

Increased susceptibility to proactive interference. There is some evidence, albeit inferential, of greater susceptibility to proactive interference in rats exposed to lactational malnutrition.6 This evidence derives from the pattern of results obtained in tasks designed to tap working memory function. There is a clear consensus that lactationally malnourished rats exhibit intact learning and memory in the Morris water maze when tested as adults [Bedi 1992, Campbell and Bedi 1989, Castro and Rudy 1987). In addition, such animals exhibit normal short-term memory abilities in both 8- and 12-arm radial mazes, even when extramaze cues have been reduced (Hall 1983),7 a procedure that increased the sensitivity of this task to hippocampal lesions (Winocur 1982). In light of these latter findings, the profound delay-dependent impairment of lactationally malnourished rats in an aquatic delayed spatial alternation task (Castro et al. 1989) may appear spurious. However, there is one important difference in these spatial memory tasks that may allow reconciliation of these apparently discrepant findings: the degree of proactive interference involved. In delayed alternation tasks, the correct response on a given trial is the side (left or right) opposite to the one chosen by the animal on the previous trial. Because numerous trials are generally presented each day the animal must not only remember which side it chose on the previous trial but also discriminate the previous response (the critical memory from the many similar responses made earlier in the session. Consequently, the decline in performance generally seen with increasing retention intervals reflects not only decay of the memory trace but also proactive interference. Radial maze tasks entail much less; proactive interference because only one set of to-be-remembered information is generally presented each day. The critical information does not have to be supplanted within the course of a testing session as in delayed spatial alternation (DSA) tasks. The very different forgetting curves in these two tasks very likely reflect this difference in proactive interference: In 8-arm radial mazes, delays of 8 12 h must be inserted halfway through the test session to observe any forgetting (Beatty and Shavalia 1980, Strupp 1989), whereas in DSA tasks, performance falls substantially if delays of > 20 s are imposed (for example, Kasprow 1987, Strupp and Alber 1994, van Haaren et al. 1985). The Morris maze tasks used in these malnutrition studies also entailed much less proactive interference than the DSA task of Castro et al. (1989) because only one set of to-be-remembered information was presented per testing session. The fact that these three tasks all assess spatial working memory but differ in the extent to which they tap proactive interference raises) the interesting possibility that the pronounced impairment observed in the study by Castro et al. 1989) reflects a greater susceptibility to proactive interference in the previously undernourished animals rather than an anomalous deficit in working memory. This putative alteration in proactive interference is consistent with the proposal, presented below, that functions related to the prefrontal cortex may be particularly vulnerable to early malnutrition (Fusser 1989).

6The available evidence suggests that susceptibility to PI is normal in animals exposed to prenatal malnutrition. This conclusion is based on the fact that no differences between prenatally malnourished rats and controls were seen in a delayed alternation task (Tonkiss and Galler 1990), despite the strong influence of PI on performance in this task (for example, Fuster 1989, Strupp and Alber 1995). Consistent with this conclusion, Tonkiss and Galler (1990) also reported that the degree of disruption produced when PI was explicitly increased did not differ between groups. However, the implications of this latter finding are limited by the fact that the performance of both groups was near chance levels under the high PI condition, raising the possibility that a floor effect may have obscured a difference between the two groups.

7Although Jordan and colleagues 91981) reported radial maze deficits in previously malnourished animals, the deficient performance does not appear to reflect an impairment in spatial memory but rather alterations in motivation and/or anxiety in traversing the maze. The fact that the previously malnourished animals did not always consume the rewards precludes attributing the increased errors to deficient memory processes.

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