What is meant by sensitive period in brain development?

Critical or sensitive periods in the life of an organism during which certain experiences or conditions may exert disproportionate influence (either for harm or benefit) on long-term developmental outcomes have been the subject of investigation for over a century. This chapter reviews research in the context of the development of social preferences and sensory systems, with a summary of the criteria for defining such a period and the evidence necessary to establish its existence. The notion of nutritional programming, central to the Barker/Developmental Origins hypotheses of health and disease, represents a variant of the critical/sensitive period concept. It is implicit in these hypotheses that the fetal period is a time during which metabolic and physiological systems are malleable and thus susceptible to either insult or enhancement by nutrient intake. Evidence for critical/sensitive periods or nutritional programming requires a systematic manipulation of the age at which nutritional conditions or supplements are implemented. While common in research using animal models, the approach is difficult to establish in epidemiological studies and virtually nonexistent in human clinical trials. Future work seeking to establish definitive evidence for critical/sensitive periods or programming may be advanced by harmonized outcome measures in experimental trials across which the timing, duration, and dose of nutrients is varied.

© 2020 S. Karger AG, Basel

• The concept of critical periodis often invoked with reference to phenomena in the field of nutrition. The history and evolution of the critical period concept in development is briefly reviewed.

• A critical period (or its less restrictive form, a sensitive period) carries with it a number of methodological criteria that are typically not met in the literature on early nutrition.

• The phenomenon of programming is placed within this developmental concept.

• Implications of these developmental phenomena for the design of preclinical research and clinical trials that seek to demonstrate true programming or critical/sensitive period effects are described.

The idea that early nutritional status is critical to lifelong health is pervasive in the scientific literature [1]. Although much of the writing on this topic has been focused on the potential early-life determinants of adult obesity [2-5], much has also been written about the importance of nutrition in the first 1,000 days following conception [6] and the potential impact of nutrition and nutritional status on both biological [7] and behavioral [8] systems later in life.

In many of these papers, authors make direct reference to critical periods as a developmental basis for these proposals [9, 10]. While the critical period phenomenon has been a topic of extensive discussion in the biobehavioral and developmental sciences, there have been few detailed expositions of the concept and its implications within the nutrition literature. One objective of this chapter is to provide a background on the history of and criteria for critical periods for nutrition researchers. A second objective is to integrate the notion of fetal/neonatal programming – a common concept within the nutrition field – within the framework of critical periods and developmental science. Finally, the chapter seeks to delineate the implications of critical/sensitive periods for the design of future preclinical research and clinical trials.

History of the Concept of Critical Periods

As noted above, the concept of critical periods has a long history in the field of developmental psychology [11-13]. The basic phenomenon was first identified from research in embryology [14], where the effect of exposures to toxic substances on developing embryos was observed to vary systematically with the timing of the exposure. Toxic exposures occurring in the embryonic period produced pervasive and severe effects across multiple biological systems; however, the same exposure or dose later in development resulted in somewhat milder effects, which were constrained more narrowly to particular or specific systems. Indeed, the same exposure applied even later in development might have no demonstrable effects or result in effects evident only upon systemic challenges or stressors. These common sequelae led investigators to the logical conclusion that the biological systems were broadly malleable very early in life, and that as the organism matured and those systems became settled in form and function, they became less vulnerable to environmental insult.

Imprinting and Critical Periods

The extension of this work to the behavioral sciences came with Lorenz’s [15] exposition of imprinting in birds. In this phenomenon, precocial bird species developed strong social preferences for objects to which they were exposed immediately after hatching; young birds would then attach emotionally and maintain proximity to such objects until fledging. The evolutionary adaptiveness of this phenomenon is obvious, as hatchlings are typically exposed immediately after hatching to their own mother (or at least, a conspecific from the same species), and a neural mechanism that promoted hatchlings’ emotional and physical affiliation with their mother very likely increased the probability of their survival. Indeed, this framework was adapted for use in the early evolutionary-based accounts for explaining human infants’ attachment to their own mothers [16].

Of critical importance to the current discussion, however, two points shaped future thinking about the nature of critical periods in development. First, the nature of the objects to which hatchlings could be imprinted was extremely general; during this period young birds could be manipulated to form social preferences for nearly any object, whether it was Lorenz [17] himself or a moving tennis ball [18]. The other points were derived from Lorenz’s claim that the development of these strong social affiliations could only be formed during a very brief period of time during the hatchlings’ develop­-ment – once imprinting had occurred, it could not be undone [19] – and that nonimprinted organisms were not able to imprint beyond the hatchling period [20]. Thus, the effects of exposure during this early period of life were claimed to be both irreversible and unrecoverable, thus bringing about the label of the period as critical. However, much of the literature that emerged immediately after these initial claims demonstrated substantial reversibility and flexibility [21] in imprinting. Thus, while the early period of life might represent heightened malleability or plasticity, the period might not be as rigidly bound or essential as it had originally been designated, making the term sensitive periodmore appropriate. The phenomenon was later generalized to the notion of food imprinting [22-25] in several species, where the food preferences typically exhibited by certain animals could be substantially altered by early exposure to alternate foods.

Critical Periods in the Development of the Visual System

The 1960s and 1970s produced the most comprehensive descriptions of critical periods in mammalian biology and behavior in Hubel and Wiesel’s program of research on the development of the visual system in the cat [26-28]. Briefly, these investigators used techniques for measuring the activity of single neurons in the cat visual cortex, mapped the responsiveness of these neurons to different visual stimuli, and then sought to map the maturation of this neuronal activity from birth to adulthood. While some neurons in the visual cortex were dedicated from birth to processing specific types of input (e.g., accepting from one or both eyes, or responding to horizontal vs. vertical bars), they also determined through careful experimentation that the fate of many cells in the cortex was determined by both the quantity and quality of postnatal input [29, 30] and that the period during which that input was received was limited to the first 4–7 weeks of life. Similar to imprinting, recovery of normal vision after deprivation of input during that period of life was initially reported to be limited [31], suggesting that this was another clear manifestation of a true “critical” period. These findings from the cat were largely confirmed in primates [32, 33], and observational studies of humans deprived of various visual input were found to be generally consistent with the principles outlined in this work [34-36].

Since the emergence of this seminal line of research in biobehavioral development, numerous refinements have been explored in isolating the specific mechanisms underlying the early plasticity of the system and the processes which bring that plasticity to an end [37]. For example, it is clear that this is a sensitive period, rather than a critical period, as some level of recovery of visual function can be attained after the end of the period [38, 39]. In addition, eye movements play a major role in the neural processing that contributes to the dedication of neurons to visual inputs [30], and both the onset and the eventual end of the sensitive period is triggered by the initiation of visual input [40]. In keeping with the general principles of early plasticity, early disruptions in the normal course of sensory exposure have been found to alter the order in which sensory systems develop and in which sensory preferences or priorities are expressed in postnatal life [41, 42].

Summary

The phenomenon of critical/sensitive periods in biobehavioral development has been explored in domains beyond that of imprinting and sensory systems; for example, there is also a substantial literature on a critical/sensitive period for language development [43-45]. Several generalities can be drawn from this brief and admittedly perfunctory review, however. First, the principles regarding early vulnerabilities of organisms to frank environmental insult or compromise appear to be reliable and robust; early damage will yield severe and widespread effects, while later damage will tend to be less severe and more specifically localized. Second, in the behavioral realm, wherever a “critical” period has initially been described, including claims of absolute irreversibility or inability to recover from deprivation, subsequent work has generally shown that some degree of recovery is possible under special conditions or with targeted remedial actions. Organisms may be both relatively more vulnerable to environmental deprivation and relatively better able to benefitfrom environmental enhancement early in life, but it is likely better to characterize these early periods of malleability as sensitive periodsrather than truly critical periods [13]. Figure 1 schematically represents the difference between “critical” and “sensitive” periods and their interaction with both positive (beneficial) and negative (harmful) events. That said, given that evidence suggests that early interventions will be relatively (rather than absolutely) more effective than later interventions, there is clear economic value in understanding these developmental principles.

Schematic representation of the difference between a critical period (a, b) and a sensitive period (c, d). Time/age moves from left to right. Note that, in a critical period, the period of malleability or plasticity is sharply defined as a box, with a clear beginning and end, and no gradient over time. In a sensitive period, the degree of plasticity is relatively higher, but plasticity never ends. As a result, the end states from a critical period are irreversible or irretrievable, while in a sensitive period some degree of future enhancement or future recovery from harm is possible.

Scott et al. [46] have offered one characterization of these phenomena in development, noting that critical/sensitive periods merely represent periods of rapid development within systems, such that enhancement or deprivation during these periods of emergent and rapid maturation can respectively bring either substantial benefit or wreak substantial havoc on the systems involved. As has been summarized previously [11], if there are qualitatively distinct stages of malleability in development, then one must define them in terms of the specific system involved, as well as by the onset and terminus of the period and the specific inputs that are presumed to enhance or disrupt normal development.

At this point, we turn to discuss programming, a phenomenon similar to the critical/sensitive period as referenced in the nutrition literature.

Early Programming and Critical Periods

The notion of nutritional programming [47] is a popular one among the nutrition science community; a search on the phrase in Google ScholarTM in late 2019 generated over 190,000 entries. This notion emerged from a comprehensive epidemiological study of the Dutch hunger winter [48] in which food shortages precipitated by weather, bad crops, war, and a Nazi embargo of food transport to parts of the Netherlands limited pregnant women’s nutritional intake to only 400–800 calories per day. This restricted intake resulted in a remarkable increase in the incidence of coronary heart disease in the offspring whose mothers’ were exposed to restricted food intake early in gestation, markers of reduced renal function among those exposed in mid-gestation, and lifetime growth restriction among those exposed late in gestation [48]. The Barker hypothesiswas derived from observations in the UK that disproportionate fetal growth in middle to late gestation programmed later coronary heart disease in the offspring. The hypothesis regarding the fetal origins of adult disease expanded to the Developmental Origins hypothesis [49-52], the notion that, by influencing epigenetic processes, metabolic set points, or early inflammatory status, prenatal nutrition in some way “programs” the fetus or maladaptively prepares the fetus for an environment that will induce adiposity/obesity [53, 54] or other metabolic-based diseases [55]. It is a clear implication of the Barker/Developmental Origins hypothesis that the early part of life is in some way special in its malleability or capacity for enacting long-term changes in the organism. Such studies would presume to reveal a critical-period phenomenon in that it is the early stages of the organism’s development that serves as a causal vehicle for the efficacy of the exposure. Furthermore, the notion that the organism is “programmed” comes from the fact that the outcomes associated with fetal conditions reach far into the future and represent health and neurodevelopmental status in adulthood.

A key point about the original Barker study was that, for an observational study, it controlled fairly well for the timing of the deprivation. For example, subsequent secondary analyses noted that the effects varied as a function of the gestational state of the fetus [56]; malnutrition in early pregnancy was associated with a higher risk of coronary heart disease and accelerated cognitive aging [57], mid-gestation exposure had an increased prevalence of bronchial disease, and late/mid-gestation exposure was related to poorer glucose metabolism. It is not a far reach to extrapolate this to the idea that early nutrition extending into the postnatal period may also bring about programming effects; indeed, this case has been made for a number of different functions [58-60], and this argument takes on immediate weight given what is known about the postnatal development of the central nervous system and the potential effects of certain nutrients on brain and behavioral function [61-63].

Age and Timing in Nutritional Studies

Like much of the critical/sensitive-period research, studies lending support to early nutritional programming have largely been conducted with animal models [64]. While it has been argued that the animal data coupled with human clinical trials showing the effects of early nutritional manipulations are compelling [65], in the absence of systematic experimental data in which the age of exposure is manipulated, claims about early nutritional programming remain largely speculative.

In order to definitively establish a true critical/sensitive period or programming effects, one must manipulate the timing of the early intervention [11]. That is, it must be shown that vulnerability to risk or ability to benefit from enhanced conditions at a particular time during development is either absolutely or relatively higher at one time during development over others. Of course, human studies to experimentally vary the timing of adverse interventions to demonstrate the critical/sensitive period-programming effects are unethical, but it is possible and ethical to focus on timing in clinical trials that purport to provide interventions that benefit to their participants; indeed, from an economic point of view, one could argue that such a focus is necessary. Furthermore, going back to the original point in the critical period phenomenon about the dose of exposure interacting with timing [11], one might further argue that designs featuring dose × timing interactions would be ideal.

Even a quick perusal of the literature, however, shows that the extant nutrition clinical trials almost entirely exclude the timing or age at which manipulations are implemented. For the most part, nutritional interventions are implemented as early as possible in infancy, and if they show efficacy that persists, as has been established in some cases [66], it is tempting to propose that an early programming effect has taken hold. However, in the absence of exposure to a nutrient for an equivalent duration at a later age, it is by no means clear that this programming effect is endemic to early prenatal or postnatal life. Those who design such trials likely understand the potential importance of timing well, but the conduct of such trials obviously requires tremendous resources to simply establish efficacy; establishing that a nutrient’s efficacy is greater at one age than at another may seem like a luxury. However, until there is evidence that benefit varies with the age at which a nutrient is provided, one cannot have evidence for a critical/sensitive period or for an age-specific programming effect.

In the absence of clinical trials that comprehensively address the issue of age and timing in their designs, one way to examine the relative efficacy across ages is to compare completed trials that have varied the age of their interventions, but where outcome measures were more or less harmonized. This has been done to some degree for the examination of differences in outcome as a function of dose [67], although dose still remains an understudied factor in much of the literature on early nutrition. One potential example approximating this approach is represented by 2 trials conducted in our laboratory over the last 2 decades. The DIAMOND trial [66, 68] involved postnatal supplementation with 4 doses of docosahexaenoic acid (DHA) but with a constant level of arachidonic acid (ARA) compared to a placebo. The KUDOS trial [69-71] involved prenatal supplementation with 1 dose of DHA, again compared to a placebo. While the trials are too different in their manipulation and in their fundamental sample demographics to compare directly here, they do share a fair number of harmonized outcome variables in the domain of postnatal cognitive development to invite a putative inference that postnatal supplementation might produce more pervasive long-term positive effects on infant child neurocognition [72] than prenatal supplementation. On the other hand, the prenatal supplementation produced clear metabolic effects [73] that were not evident from the postnatal trial. While these outcomes and comparisons cannot be considered definitive, they do invite a vision of what might be possible with broadly harmonized outcomes for clinical trials in the future in the field of nutrition.

Summary and Conclusions

Critical and sensitive developmental periods have been key concepts in developmental science for over a century; they have a long history for biobehavioral development and have particularly special importance with respect to the plasticity of the brain. In such developmental periods, certain experiences, exposures, or conditions are thought to exert disproportionate influence over the long-term development of the organism due to the fact that the organism is in a particularly malleable state. Examples of putative critical/sensitive periods in biobehavioral development include the establishment of social and food preferences (imprinting), shaping the structure and function of sensory systems, and possibly the area of language and language acquisition. There is still considerable debate over the nature of critical/sensitive periods, but one hypothesis is that such phases are simply the epiphenomenon of systems that are undergoing rapid maturation or change.

While critical- and sensitive-period concepts have often been used with respect to studies of early nutrition, they also underlie the concept of nutritional programming, as the implication of programming (particularly within the context of the Fetal/Developmental Origins hypothesis) is that the prenatal period is presumably a time when various metabolic systems are malleable and can be influenced by conditions of maternal physiology and environmental exposures, including nutrient intake.

Critical to the establishment of any critical/sensitive period (and by extension, to any claim for prenatal programming) is the demonstration that an intervention shows improved efficacy when implemented at one age relative to other ages. For example, in order to establish the existence of a critical period for omega-3 effects on neurodevelopment, one would have to show that supplementation at, say, birth to 6 months of age, would have far more influence on outcome measures than supplementation from 6 to 12 months; obviously, from a design standpoint, this would necessitate feeding 2 age groups for an equivalent duration. While parametric manipulation of the age of nutritional interventions is relatively commonplace in animal models, the results of preclinical studies do not necessarily translate to human trials [74], and so, any conclusion about the critical/sensitive periods in nutrition or nutrition programming must be viewed as speculative. It may be that if enough trials have harmonized outcomes, meta-analyses that include age of feeding, duration of feeding, and dose would advance the field as close as possible to answering this question.

Disclosure Statement

This work was supported by NIH grants U54 HD090216, R01 HD086001, R01HD083292, and R01 HD083292. The writing of this article was supported by Nestlé Nutrition Institute. The authors declare no other conflicts of interest.

References

1. Jang H, Serra C. Nutrition, epigenetics, and diseases. Clin Nutr Res. 2014 Jan;3(1):1–8.
2. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr. 1994 May;59(5):955–9.
3. Power C, Parsons T. Nutritional and other influences in childhood as predictors of adult obesity. Proc Nutr Soc. 2000 May;59(2):267–72.
4. Giles LC, Whitrow MJ, Rumbold AR, Davies CE, de Stavola B, Pitcher JB, et al. Growth in early life and the development of obesity by age 9 years: are there critical periods and a role for an early life stressor? Int J Obes. 2013 Apr;37(4):513–9.
5. Cioffi LA. General theory of critical periods and development of obesity. Bibl Nutr Dieta. 1978;(26):17–28.
6. Cusick SE, Georgieff MK. The role of nutrition in brain development: the golden opportunity of the “first 1000 days”. J Pediatr. 2016 Aug;175:16–21.
7. McCance RA. Critical periods of growth. Proc Nutr Soc. 1976 Dec;35(3):309–13.
8. Georgieff MK, Brunette KE, Tran PV. Early life nutrition and neural plasticity. Dev Psychopathol. 2015 May;27(2):411–23.
9. Ilich JZ, Brownbill RA. Nutrition through the life span: needs and health concerns in critical periods. In: Miller TW, editor. Handbook of stressful transitions across the lifespan. Springer; 2010. pp. 625–41.
10. Herman DR, Taylor Baer M, Adams E, Cunningham-Sabo L, Duran N, Johnson DB, et al. Life Course Perspective: evidence for the role of nutrition. Matern Child Health J. 2014 Feb;18(2):450–61.
11. Colombo J. The critical period concept: research, methodology, and theoretical issues. Psychol Bull. 1982 Mar;91(2):260–75.
12. Bornstein MH. Sensitive periods in development: structural characteristics and causal interpretations. Psychol Bull. 1989 Mar;105(2):179–97.
13. Bailey DB Jr, Bruer JT, Symons FJ, Lichtman JW. Critical thinking about critical periods. Paul H Brookes Publishing; 2001.
14. Stockard CR. Developmental rate and structural expression: an experimental study of twins, ‘double monsters’ and single deformities, and the interaction among embryonic organs during their origin and development. Am J Anat. 1921;28(2):115–277.
15. Lorenz K. Imprinting. Auk. 1937;54(3):245–73.
16. Bowlby J. The nature of the child’s tie to his mother. Int J Psychoanal. 1958 Sep-Oct;39(5):350–73.
17. Lorenz KZ. The companion in the bird’s world. Auk. 1937;54(3):245–73.
18. Hess EH. Imprinting in birds. Science. 1964 Nov;146(3648):1128–39.
19. Klopfer PH. Stimulus preferences and imprinting. Science. 1967 Jun;156(3780):1394–6.
20. Haywood HC, Zimmerman DW. Effects of early environmental complexity on the following response in chicks. Percept Mot Skills. 1964 Apr;18(2):653–8.
21. Salzen EA, Meyer CC. Imprinting: reversal of a preference established during the critical period. Nature. 1967 Aug;215(5102):785–6.
22. Burghardt GM, Hess EH. Food imprinting in the snapping turtle, Chelydra serpentina. Science. 1966 Jan;151(3706):108–9.
23. Darmaillacq AS, Chichery R, Dickel L. Food imprinting, new evidence from the cuttlefish Sepia officinalis. Biol Lett. 2006 Sep;2(3):345–7.
24. Frank LH, Meyer ME. Food imprinting in domestic chicks as a function of social contact and number of companions. Psychon Sci. 1970;19(5):293–5.
25. Bernays E, Weiss M. Induced food preferences in caterpillars: the need to identify mechanisms. Entomol Exp Appl. 1996;78(1):1–8.
26. Hubel DH, Wiesel TN. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J Physiol. 1970 Feb;206(2):419–36.
27. Wiesel TN. Postnatal development of the visual cortex and the influence of environment. Nature. 1982 Oct;299(5884):583–91.
28. Barlow HB. Visual experience and cortical development. Nature. 1975 Nov;258(5532):199–204.
29. Wiesel TN, Hubel DH. Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J Neurophysiol. 1965 Nov;28(6):1029–40.
30. Freeman RD, Bonds AB. Cortical plasticity in monocularly deprived immobilized kittens depends on eye movement. Science. 1979 Nov;206(4422):1093–5.
31. Wiesel TN, Hubel DH. Extent of recovery from the effects of visual deprivation in kittens. J Neurophysiol. 1965 Nov;28(6):1060–72.
32. Harwerth RS, Smith EL 3rd, Crawford ML, von Noorden GK. Behavioral studies of the sensitive periods of development of visual functions in monkeys. Behav Brain Res. 1990 Dec;41(3):179–98.
33. Kiorpes L. Visual development in primates: neural mechanisms and critical periods. Dev Neurobiol. 2015 Oct;75(10):1080–90.
34. Lewis TL, Maurer D. Effects of early pattern deprivation on visual development. Optom Vis Sci. 2009 Jun;86(6):640–6.
35. Hickey TL. Postnatal development of the human lateral geniculate nucleus: relationship to a critical period for the visual system. Science. 1977 Nov;198(4319):836–8.
36. Lewis TL, Maurer D. Multiple sensitive periods in human visual development: evidence from visually deprived children. Dev Psychobiol. 2005 Apr;46(3):163–83.
37. Hensch TK. Critical period mechanisms in developing visual cortex. Curr Top Dev Biol. 2005;69:215–37.
38. Mitchell DE, Cynader M, Movshon JA. Recovery from the effects of monocular deprivation in kittens. J Comp Neurol. 1977 Nov;176(1):53–63.
39. Movshon JA. Reversal of the behavioural effects of monocular deprivation in the kitten. J Physiol. 1976 Sep;261(1):175–87.
40. Cynader M, Berman N, Hein A. Recovery of function in cat visual cortex following prolonged deprivation. Exp Brain Res. 1976 May;25(2):139–56.
41. Lickliter R. Prenatal visual experience alters postnatal sensory dominance hierarchy in bobwhite quail chicks. Infant Behav Dev. 1994;17(2):185–93.
42. Lickliter R. Prenatal Sensory Ecology and Experience: Implications for Perceptual and Behavioral Development in Precocial Birds. In: Slater PJB, Snowdon CT, Roper TJ, Brockmann HJ, Naguib M, editors. Advances in the Study of Behavior. Vol. 35. Academic Press; 2005. pp. 235–274.
43. Werker JF, Hensch TK. Critical periods in speech perception: new directions. Annu Rev Psychol. 2015 Jan;66(1):173–96.
44. Kral A, Dorman MF, Wilson BS. Neuronal Development of Hearing and Language: Cochlear Implants and Critical Periods. Annu Rev Neurosci. 2019 Jul;42(1):47–65.
45. Johnson JS, Newport EL. Critical period effects in second language learning: the influence of maturational state on the acquisition of English as a second language. Cognit Psychol. 1989 Jan;21(1):60–99.
46. Scott JP, Stewart JM, De Ghett VJ. Critical periods in the organization of systems. Dev Psychobiol. 1974 Nov;7(6):489–513.
47. Langley-Evans SC. Nutrition in early life and the programming of adult disease: a review. J Hum Nutr Diet. 2015 Jan;28 Suppl 1:1–14.
48. Schulz LC. The Dutch Hunger Winter and the developmental origins of health and disease. Proc Natl Acad Sci USA. 2010 Sep;107(39):16757–8.
49. Gillman MW. Developmental origins of health and disease. N Engl J Med. 2005 Oct;353(17):1848–50.
50. Gluckman PD, Hanson MA. The Developmental Origins of Health and Disease. In: Wintour EM, Owens JA, editors. Early Life Origins of Health and Disease. Boston (MA): Springer US; 2006. pp. 1–7.
51. Hanson M, Gluckman P. Developmental origins of noncommunicable disease: population and public health implications. Am J Clin Nutr. 2011 Dec;94(6 Suppl):1754S–1758S.
52. Barker DJ. The developmental origins of adult disease. J Am Coll Nutr. 2004 Dec;23(6 Suppl):588S–595S.
53. Symonds ME, Mendez MA, Meltzer HM, Koletzko B, Godfrey K, Forsyth S, et al. Early life nutritional programming of obesity: mother-child cohort studies. Ann Nutr Metab. 2013;62(2):137–45.
54. Budge H, Gnanalingham MG, Gardner DS, Mostyn A, Stephenson T, Symonds ME. Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity. Birth Defects Res C Embryo Today. 2005 Sep;75(3):193–9.
55. Tarrade A, Panchenko P, Junien C, Gabory A. Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism. J Exp Biol. 2015 Jan;218(Pt 1):50–8.
56. Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Twin Res. 2001 Oct;4(5):293–8.
57. de Rooij SR, Wouters H, Yonker JE, Painter RC, Roseboom TJ. Prenatal undernutrition and cognitive function in late adulthood. Proc Natl Acad Sci USA. 2010 Sep;107(39):16881–6.
58. Patel MS, Srinivasan M. Metabolic programming in the immediate postnatal life. Ann Nutr Metab. 2011;58 Suppl 2:18–28.
59. Wiedmeier JE, Joss-Moore LA, Lane RH, Neu J. Early postnatal nutrition and programming of the preterm neonate. Nutr Rev. 2011 Feb;69(2):76–82.
60. Neu J, Hauser N, Douglas-Escobar M. Postnatal nutrition and adult health programming. Semin Fetal Neonatal Med. 2007 Feb;12(1):78–86.
61. Colombo J. Recent advances in infant cognition: implications for long-chain polyunsaturated fatty acid supplementation studies. Lipids. 2001 Sep;36(9):919–26.
62. Wainwright PE, Colombo J. Nutrition and the development of cognitive functions: interpretation of behavioral studies in animals and human infants. Am J Clin Nutr. 2006 Nov;84(5):961–70.
63. Carlson SE, Colombo J. Docosahexaenoic Acid and Arachidonic Acid Nutrition in Early Development. Adv Pediatr. 2016 Aug;63(1):453–71.
64. Symonds ME, Gardner DS. Experimental evidence for early nutritional programming of later health in animals. Curr Opin Clin Nutr Metab Care. 2006 May;9(3):278–83.
65. Lucas A. Role of nutritional programming in determining adult morbidity. Arch Dis Child. 1994 Oct;71(4):288–90.
66. Colombo J, Carlson SE, Cheatham CL, Shaddy DJ, Kerling EH, Thodosoff JM, et al. Long-term effects of LCPUFA supplementation on childhood cognitive outcomes. Am J Clin Nutr. 2013 Aug;98(2):403–12.
67. Yelland LN, Gajewski BJ, Colombo J, Gibson RA, Makrides M, Carlson SE. Predicting the effect of maternal docosahexaenoic acid (DHA) supplementation to reduce early preterm birth in Australia and the United States using results of within country randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2016 Sep;112:44–9.
68. Colombo J, Carlson SE, Cheatham CL, Fitzgerald-Gustafson KM, Kepler A, Doty T. Long-chain polyunsaturated fatty acid supplementation in infancy reduces heart rate and positively affects distribution of attention. Pediatr Res. 2011 Oct;70(4):406–10.
69. Carlson SE, Colombo J, Gajewski BJ, Gustafson KM, Mundy D, Yeast J, et al. DHA supplementation and pregnancy outcomes. Am J Clin Nutr. 2013 Apr;97(4):808–15.
70. Colombo J, Gustafson KM, Gajewski BJ, Shaddy DJ, Kerling EH, Thodosoff JM, et al. Prenatal DHA supplementation and infant attention. Pediatr Res. 2016 Nov;80(5):656–62.
71. Colombo J, Shaddy DJ, Gustafson K, Gajewski BJ, Thodosoff JM, Kerling E, et al. The Kansas University DHA Outcomes Study (KUDOS) clinical trial: long-term behavioral follow-up of the effects of prenatal DHA supplementation. Am J Clin Nutr. 2019 May;109(5):1380–92.
72. Lepping RJ, Honea RA, Martin LE, Liao K, Choi IY, Lee P, et al. Long-chain polyunsaturated fatty acid supplementation in the first year of life affects brain function, structure, and metabolism at age nine years. Dev Psychobiol. 2019 Jan;61(1):5–16.
73. Kerling EH, Hilton JM, Thodosoff JM, Wick J, Colombo J, Carlson SE. Effect of Prenatal Docosahexaenoic Acid Supplementation on Blood Pressure in Children with Overweight Condition or Obesity: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2019 Feb;2(2):e190088.
74. Symonds ME, Budge H, Stephenson T. Limitations of models used to examine the influence of nutrition during pregnancy and adult disease. Arch Dis Child. 2000 Sep;83(3):215–9.

John Colombo

Department of Psychology and Schiefelbusch Institute for Life Span Studies

University of Kansas, 1000 Sunnyside Avenue

Lawrence, KS 66045 (USA)

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