DHA and Cognitive Development: An Update on the Science

Research continues to investigate the potential benefit of DHA fortification for cognitive function.
DHA and Cognitive Development




Joyce C. McCann, PhD, Associate Staff Scientist | 
Bruce N. Ames, PhD, Senior Scientist | Nutrition & Metabolism Center | Children's Hospital Oakland Research Institute | Oakland, CA

Long chain polyunsaturated fatty acids (LCPUFAs) are present in all cell membranes in the body. However, one omega-3 LCPUFA —docosahexaenoic acid (DHA)—is unusually highly concentrated in neuronal membranes in the brain (as well as in retinal cell membranes). DHA is not widely distributed in the diet, but is present in some foods like fatty fish. The human body, including some cells in the brain, has some capacity to synthesize DHA from its essential omega-3 fatty acid precursor, a-linolenic acid (ALA). However, most DHA supplied to the developing brain comes from the mother, either through the placenta during pregnancy, or in breast milk after birth. 

The brain develops very rapidly during the last trimester of fetal life and the first two years of childhood (termed the "brain growth spurt"). During this time two critical events occur: the formation of some 100 trillion synaptic connections (termed "synaptogenesis"), and the development of the myelin sheath. In addition, LCPUFAs, particularly DHA and the omega-6 LCPUFA arachidonic acid (AA), accumulate rapidly. 

For some twenty years there has been a great deal of scientific interest in determining whether cognition or behavior is influenced by how much DHA is available during the brain growth spurt, and in understanding the biological roles of DHA in the brain. In this article, we provide a brief overview of the current status of the scientific evidence. 

Is DHA Required for Normal Cognitive or Behavioral Function?
In order to ask this question, experiments must be designed that vary the supply of DHA to the brain. If DHA were considered to be an essential fatty acid, this type of experiment would not be ethically permitted in humans. However, as it happens, different infant feeding practices have provided three experimental paradigms that result, as is now known from autopsy studies, in different concentrations of DHA in the brain. These include infants that are breastfed, infants consuming formula without DHA, and infants consuming DHA-fortified formula.

Autopsy studies indicate that feeding infants breast milk (as compared to non-DHA-fortified formula) results in 11-40% higher concentrations of DHA in the brain. 1-5 (For review, see Cunnane et al. and Lauritzen et al.) 6-7 The third practice—feeding infants formula supplemented with LCPUFAs—is likely to result in brain concentrations of DHA intermediate between those in brains of infants fed breast milk and those fed unsupplemented formula.* 

In rodents, where more severe dietary restriction protocols can be applied, the availability of ALA, the essential fatty acid precursor of DHA, can be limited. This fourth experimental design results in dramatically lower brain concentrations of DHA, as much as 85% lower (see Greiner et al. for an example).11

Assessing cognitive or related mental functions is a difficult task. Many different kinds of performance tests are used. Tests in human studies include standardized global tests that screen broadly for cognitive-related functions (such as the Bayley Scales of Infant Development),12 and tests that target more specific functions, such as the development of language and communication skills (e.g., the MacArthur Communicative Development Inventory). 13 Commonly used in rodent studies are tests that measure aspects of spatial learning, such as the radial maze; anxiety, such as the elevated plus maze; or stimulus-response learning, such as brightness discrimination tests. 14

Evaluation of results in any performance test must consider potential confounders. For example, many tests rely on vision or motor activity, and thus possible effects of DHA on visual or motor development could theoretically influence the outcome. In fact, there are a number of studies that suggest the importance of a plentiful supply of DHA for normal visual development, particularly for premature infants. A recent review discusses additional complexities in interpreting results of behavioral tests. 15


Human Studies Inconclusive 
A large number of studies that compared performance of children who were breastfed or formula-fed have been conducted over more than a 20-year period. The great majority of these studies found that children who were breastfed scored higher on a variety of performance tests. Furthermore, the longer children were breastfed, the better their scores were. The interpretation of this conclusion is complicated, however, because the decision to breastfeed is associated with a number of potentially confounding factors—such as socioeconomic status, home environment, maternal IQ, the fact that breastfeeding itself has a nurturing quality that could affect later test performance, and the number of potentially active ingredients that are present in breast milk (other than DHA) that could be responsible for enhancement effects. 

Randomized controlled trials (RCTs) that compare the performance of children fed differently supplemented formulas are the gold standard study design because many variables can be controlled for, including the quantity and composition of LCPUFA formula supplements. RCTs, however, are also subject to confounding that can complicate the comparison of results in different trials, such as the use of different formulas or oils or other sources of variability in DHA status of infant groups. 

A number of these RCTs have been conducted, and while a few reports suggest positive effects of supplementation, other studies do not. The Cochrane group, a well respected organization that conducts expert reviews, concluded in 2004, that available evidence did not support suggestions that LCPUFA-supplementation benefited neural development.16-17 Since our 2005 review,18 we are aware of two new RCTs. 19-20 One of these was a study in preterm infants which observed significantly better performance on the Bayley Scales at 118 weeks of age for infant groups fed LCPUFA-supplemented formula compared to controls fed unsupplemented formula.21 This study was funded by a major infant formula company, which recently announced they will add LCPUFAs to all of their infant formulas (a decision based evidently on the strength of their study). The other study,2 a follow-up at 4 years of age of a group of term infants who had been fed supplemented or unsupplemented formula, found no significant differences between these groups in performance on the Wechsler Preschool and Primary Scale of Intelligence.† Thus, despite a great deal of effort, the results of RCTs are not consistent, and overall do not provide a compelling result, either for or against an effect of LCPUFA supplementation. 

Various explanations have been offered for why the majority of RCTs have yielded mixed results (see our review for citations).23 These include possible differences in the sensitivity of global tests such as the Bayley Scales, and tests targeted at more specific neural domains, such as look-duration or problem-solving tests (for recent discussion, see Cheatham et al.),24 inadequate supplementation levels of DHA in formulas, poor study quality, ability of term infants fed unsupplemented formulas to synthesize their own DHA, absence of cognitive deficits when differences in brain concentrations of DHA are small due to brain plasticity (i.e., ability of the brain to adapt), or inability of performance tests to detect subtle differences in performance resulting from relatively small differences in brain concentrations of DHA. In addition, the RCTs themselves—because of uncertain group sizes required to detect significant effects on behavior and inevitable uncontrolled variability in outpatient studies—are inherently limited in their ability to discern subtle differences. Most of the above explanations focus on the possibility that negative results in RCTs may be false negatives; a balanced discussion should obviously also consider the possibility that positive results are false positives. 25 A recent review discusses methodological improvements that may help to fine tune future RCTs.26

Rodent Studies Suggest Need for DHA 
The great strength of animal studies is that they afford the opportunity for more flexibility in design and greater ability to control experimental variables than can be achieved in human studies. The most commonly used experimental design in animals involves limiting the dietary supply of ALA, the precursor of DHA, which is not feasible in human studies since ALA is an essential fatty acid (EFA). Almost all of over 30 rodent studies conducted over more than a 15-year period reported deficits in performance on a variety of different cognitive or behavioral tests for ALA-restricted offspring. Furthermore, importantly, when DHA alone was added back to ALA restricted animals, performance improved dramatically, providing important evidence, at least on its face, that DHA is needed for normal brain function. 

However, evaluating the significance of these studies is complicated by the severity and non-specificity of the experimental design. For example, to deplete brain DHA typically requires a generation or more of dietary restriction, and restricting ALA is likely to have multiple effects. Also, the studies are limited by potential confounders including effects on vision or motor function, and by the uncertain relevance to humans of results in rodents. For additional recent review, see Fedorova et al.27

DHA Function in the Brain 
Though precise molecular mechanisms are not well defined, DHA appears to have a variety of important functions in the brain. It is highly concentrated in the phospholipids of synaptic membranes, and appears to be important for membrane flexibility, which improves the efficiency of protein-protein signaling essential for signal transduction.28 Membrane flexibility also appears to be neuroprotective (see Hashimoto et al. for an example).29

An additional neuroprotective mechanism may involve DHA-derived lipid messengers (termed docosanoids) that inhibit apoptosis (cell death) brought on by oxidative stress in the brain.30 DHA is also known to modify the expression of a number of genes in the brain by binding to specific transcription factors.31-32 The products of these genes are known to be involved in critical brain functions including signal transduction and synaptic plasticity. 

It is also well established that DHA increases neurite outgrowth in cell culture systems. A recent study observed decreased neurogenesis in fetal brains of rat dams restricted for ALA, the essential fatty acid precursor of DHA.33 Several reviews and examples of other recent work in this very active area of research are recommended for further reading.34-40


Summary and Conclusions
Though there is still a great deal of work to be done to elucidate molecular mechanisms, it is now clear that DHA is involved in several critical brain functions. However, despite a significant body of work, there is still not definitive evidence in human RCTs that clearly and reproducibly demonstrates that the absence of supplemental DHA in infant formula during the first two years of life results in deficits in cognitive or behavioral performance. In contrast, studies in rodents suggest that severe depletion of brain DHA does result in performance deficits in offspring. 

The relative merits of hypotheses suggesting that negative RCT results could reflect brain plasticity or difficult-to- detect weak effects due to small decreases in brain DHA are important to follow up. The former hypothesis suggests there may not be adverse consequences of relatively small reductions in brain DHA, whereas the latter suggests that relatively small reductions could result in subtle performance deficits difficult to detect. Others have discussed needed developments in the design and interpretation of cognitive and behavioral tests that should enhance their ability to detect weak effects.41 Also, if experts can agree on reliable biochemical or molecular markers, constructing a dose-response curve in rodents relating the degree of reduction in brain DHA to effects on neural function would be of great value.

Does the Evidence Support the Addition of LCPUFAs to the Infant Diet? 
Clearly, the issue is complicated, but such is the nature of science—results cannot usually be tied up neatly with a bow. On the positive side, in our opinion, there are five reasons that support adding LCPUFAs to the infant diet: (1) The Food and Drug Administration (FDA) has not questioned the manufacturers' determination that DHA and AA are Generally Recognized As Safe (GRAS) for use in infant formula,42 and a number of studies indicate that LCPUFA-supplemented infant formula containing both DHA and AA does not adversely affect growth;43-44 (2) DHA is normally present in breast milk; (3) the autopsy results discussed here strongly suggest that infants who consume unsupplemented formula will have less DHA in their brains than infants who consume supplemented formula or breast milk; (4) a large body of evidence, some of which is discussed here, indicates that DHA plays an important role in brain function; (5) although the several types of studies in both humans and animals discussed here do not prove causality, they do suggest that small differences in brain concentrations of DHA—such as most likely occur between infants fed supplemented or unsupplemented formulas—may result in subtle cognitive or behavioral effects that are currently difficult to detect in human RCTs, but nevertheless could be significant.45

On the cautionary side, several theoretical concerns about the safety of LCPUFA supplements were discussed by experts in a 2002 report on preterm infant formulas prepared for the Center for Applied Nutrition at the FDA.46 In 2004, an expert committee at the National Academy of Sciences delineated a broad array of tests necessary to fully assess the safety of adding new ingredients to infant formula.47 To our knowledge not all of these tests have been conducted for LCPUFAs. Based on our own work, we are acutely aware that LCPUFAs are among the most easily oxidizable of all the fatty acids. We found high levels of toxic hydroperoxides in lipid emulsions given intravenously to preterm infants, which were subsequently shown to increase markedly with light exposure.48 Infant formulas are packaged in opaque containers, and the antioxidant vitamins C and E are added to improve shelf life. Under the Infant Formula Act, manufacturers are required to monitor the stability of their formulas and to keep a file of complaint letters.49 The FDA web site (http://www.fda.gov) has extensive information on regulations on ingredients and formulas.

To date, the American Academy of Pediatrics (AAP) has not taken an official position on whether or not to recommend use of LCPUFA-supplemented formulas.50 However, they point out that several relatively large RCTs comparing LCPUFA-supplemented and unsupplemented formulas have shown no difference in the incidence of neonatal conditions thought to be related to oxidant damage. The AAP concludes that, despite limited data specifically addressing theoretical concerns, these RCT results suggest that the supplemented formulas used were safe. It is our hope, since almost all infant formulas now contain LCPUFAs, that the AAP will decide to more fully address this issue by developing a policy that recognizes the complexities and uncertainties, but that also provides some needed guidance for pediatricians.51

* Direct autopsy evidence is not available that compares brain DHA concentrations in human infants fed unsupplemented and LCPUFA-supplemented formulas. However, a recent autopsy study in non-human primates reported roughly a 30% lower concentration of DHA in the visual cortex of pre-term infants fed unsupplemented as compared to LCPUFA-supplemented formula.8 In humans, significant differences in plasma concentrations of DHA in unsupplemented and supplemented formula comparison groups are well documented (see Carlson et al. and Boehm et al. for examples).9-10

† Group sizes were very small in this study. The study also examined visual acuity, with mixed results. It is noted that a breastfed reference group was also included, and scores on the Wechsler verbal IQ test were significantly higher for children who had been breastfed than for both the unsupplemented formula group and for a group fed formula containing DHA but not AA. Scores for the breastfed group were not significantly different from the infant group fed formula supplemented with both DHA and AA, which could suggest some effect, though if there is an effect it appears to be very marginal. While investigators concluded "DHA and AA-supplementation of infant formula supports visual acuity and IQ maturation similar to that of breastfed infants," this conclusion is not, in our opinion, supported by the data. The key finding from this study relevant to whether supplementation of infant formula with DHA/AA results in improved cognition over unsupplemented formula is that the LCPUFA supplemented and unsupplemented groups did not differ statistically in performance on the cognitive tests.

Note: This article was adapted by the authors from their 2005 review published in the American Journal of Clinical Nutrition, with some additional references added.52 The review is part of a series on effects of micronutrient deficiencies on brain development and cognitive function (choline, iron, vitamin D).53-55



Joyce C. McCann, PhD, is an Associate Research Scientist at Children's Hospital Oakland Research Institute. Prior to coming to Children's Hospital, Dr. McCann was a Staff Scientist at Lawrence Berkeley Laboratory and a private consultant specializing in scientific evidence in environmental health policy.



Bruce N. Ames, PhD, is a Professor of the Graduate School in Biochemistry and Molecular Biology, University of California, Berkeley, and a Senior Scientist at Children's Hospital Oakland Research Institute. He is a member of the National Academy of Sciences and was a recipient of the U.S. National Medal of Science in 1998.



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