Cognitive impairment as a mediator in the developmental pathway from infant malnutrition to adolescent depressive symptoms in Barbadian youth

Severe malnutrition early in life has well known neurodevelopmental sequelae, with potentially lifelong functional consequences. Adverse clinical outcomes can involve cognition, behavior and affect1,2. Pre-clinical studies have established an impact of pre- and post-natal malnutrition on neurochemistry and brain structure, affecting glial and dendritic development in a regionally specific fashion 3,4, 5. Prefrontal cortical and hippocampal structures are especially vulnerable, with permanent changes detectable into adulthood, even in animals rehabilitated after the neonatal exposure 6, 7. The potential for regionally specific impact of malnutrition on the prefrontal cortex and hippocampus in the developing brain is of particular interest because of their pivotal role in human learning and memory 8,9 as well as emerging links to depressive disorders 10, 11. The Barbados Nutrition Study (BNS) is a now 40-year longitudinal study that has evaluated children who had been hospitalized for moderate to severe malnutrition in the first year of life and a comparison group from the same classrooms and social milieu12. Because the malnourished children were successfully rehabilitated nutritionally and followed until 12 years of age to assure adequate nutrition and normal growth and development, the episode was restricted to the first year of life, without ongoing undernutrition 13. Participants were evaluated three times in a 7-year period between 1977 and 1984, spanning grammar school age to late adolescence. Data are currently being collected on these same individuals, now entering their fifth decade. At the first evaluation, when the children were 5 to 11 years of age, the previously malnourished group exhibited lower IQ, more attention problems and poorer grades in school12, 14, 15. Performance on the Common Entrance Examination (CEE), a standard academic achievement test administered to all Barbadian children at 11 years of age to determine high school placement, was also lower in the previously malnourished children, referable largely to their lower IQ and problems with attention and self-regulation as measured in the primary grades by a teacher questionnaire designed for the study 16. Maternal depression can also adversely affect child development, including cognition and mood17 and may in fact contribute to the initial episode of malnutrition18, 19. Significantly, in the BNS, mothers of previously malnourished children reported more depressive symptoms when the children were school age and adolescent. These symptoms were associated with negative child outcomes, including poorer school grades and teacher reported hygiene. These previously malnourished children themselves also reported more symptoms of depression than their adequately nourished peers as adolescents. Although maternal depressive symptoms predicted adolescent depressive symptoms, their effect was independent of the effects of malnutrition and standard of living 20. Depressive symptoms in adolescence have similarly been reported in other long-term follow-up studies of children malnourished early in life21. Developmental psychopathologists have advanced the core concept of the developmental cascade. According to Masten and colleagues, a developmental cascade occurs when “functioning in one domain of adaptive behavior spills over to influence functioning in other domains in a lasting way (p. 735).” 22 Thus, importantly, a deviation or early insult having a direct effect on one functional domain may indirectly impair functioning in other domains, ultimately affecting development and adaptive success far more broadly. The relevance of this developmental framework to the problem of early nutrition has been previously discussed by Wachs, who observed that “Models based exclusively on nutrition and CNS pathways do not provide sufficient explanations of how nutritional deficiencies translate into maternal and child mental health problems (p. 937S).”23 Thus, although some neurodevelopmental consequences are likely the direct result of the nutritional insult to the immature brain, a developmental perspective argues that such consequences are not necessarily direct sequelae, but may be epiphenomena arising indirectly in the course of the child’s developmental adaptation to and interaction with the environment. Along these lines, it is well established that children with learning impairment are vulnerable to internalizing symptoms as they become aware of their struggles. Ackerman et al.24, for example, found that poor readers from disadvantaged environments exhibited an increase in internalizing symptoms between the 3rd and 5th grades as a consequence of their reading problems. These symptoms were thought to be triggered by normative developmental advances in self-awareness as the children approached adolescence and became more cognizant of their struggles. In the present context, academic struggles resulting from cognitive compromise related to the malnutrition could lead to depressive symptoms in the setting of academic and other adaptive challenges, potentially mediating the relationship between malnutrition and the depressive symptoms detected in adolescence. The goal of the present report is to integrate findings from the BNS within the framework of a developmental cascade, extending from infancy, when the episode of malnutrition and thus the original presumptive neurological insult occurred, to adolescence, when the elevated level of depressive symptoms was observed. The primary hypothesis is that the association between early malnutrition and adolescent depressive symptoms is mediated by the cognitive impairment that ensues from the malnutrition. Figure 1a shows the simple, direct effect model; that is, early malnutrition leads directly to depressive symptoms in adolescence. Figure 1b shows the more elaborated developmental model to be evaluated. Here, the episode of early malnutrition has a presumed direct neurological impact, manifest in lowered IQ and increased attention problems. These cognitive sequelae serve to impair school achievement, measured by performance on the CEE. Poor school functioning in childhood then leads to depressive symptoms in adolescence. In the model, academic performance is included as a proximal mediator between the cognitive impairment and depressive symptoms because it is presumably the more salient experiential indicator of the impairment for the child. The model also includes a potential direct effect of early malnutrition on depressive symptoms since the cognitive symptoms may not fully mediate the association. Because of the known association between maternal and child depression, and also because of the known associations of both maternal depression and socioeconomic conditions with malnutrition in our sample, we controlled for the household standard of living in all analyses and include maternal depressive symptoms as a predictor in the final model. Figure 1 (a) Simple model showing early malnutrition leads to depressive symptoms in adolescence. (b). Hypothetical model showing that malnutrition affects IQ and school behavior (attention) which in turn affects performance on the CEE which then affects depressive ...