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Background: Adolescence, when the most complex behaviors are refined to adult sophistication, represents a major window of opportunity and vulnerability for neuropsychological development. To support and protect this complex and active brain growth, different nutritional components considered essential need to be acquired from the diet. For instance, omega-3 fatty acids are mainly obtained from seafood, seeds, and walnuts. Known for their rich lipid profile, walnuts contain sizable amounts of an essential fatty acid, alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid that is the precursor of two longer-chain omega-3 polyunsaturated fatty acids (omega-3 PUFA): docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. While there is growing evidence of neuropsychological improvements in the young developing brain associated with omega-3 PUFA intake, few studies have examined whether consuming walnuts during adolescence entails similar beneficial effects. There is a need to further explore the ways in which walnuts influence youthful brain function, particularly for the long-term. Thus, we designed the WALNUTs study (WSS), a population-based randomized controlled trial conducted in adolescents in Barcelona, Spain. We hypothesize that walnut intake will increase omega-3 PUFA tissue availability (particularly ALA) to a level that enhances the neuropsychological development during adolescence. Methodology/Design: We conducted a 6-month population-based randomized controlled trial in teenagers ( n = 800) and we aimed to determine the effectiveness of the intervention (four walnuts per day, or 30 kernel g, ~1.5g of ALA) in enhancing brain neuropsychological and socio-emotional development compared to a control group with no walnut intervention. Before randomization, different neuropsychological tests were recorded for all participants, and blood samples (in a subsample of participants) were collected to measure omega-3 PUFA levels at baseline, and all again, after randomization and the intervention. The data is now collected and we will conduct linear regression models to assess the effect of the intervention. Discussion: The WALNUTs (WSS) study results will allow us to better understand the role of plant-based omega-3 PUFA intake from regular walnut consumption on neuropsychological development during adolescence. Results could be translated into nutritional public health recommendations targeting teenagers. Trial Registration: ClinicalTrials.gov , U.S. National Library of Medicine, National Institutes of Health # NCT02590848. Retrospectively registered 29/10/2015.
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METHODS
published: 08 June 2021
doi: 10.3389/fped.2021.593847
Frontiers in Pediatrics | www.frontiersin.org 1June 2021 | Volume 9 | Article 593847
Edited by:
Veit Roessner,
University Hospital Carl Gustav
Carus, Germany
Reviewed by:
Kiran Veer Sandhu,
University College Cork, Ireland
Inge Van Der Wurff,
Open University of the
Netherlands, Netherlands
*Correspondence:
Jordi Julvez
jordi.julvez@iispv.cat
Specialty section:
This article was submitted to
Child and Adolescent Psychiatry,
a section of the journal
Frontiers in Pediatrics
Received: 11 August 2020
Accepted: 16 April 2021
Published: 08 June 2021
Citation:
Julvez J, Gignac F,
Fernández-Barrés S, Romaguera D,
Sala-Vila A, Ranzani OT,
Persavento C, Delgado A, Carol A,
Torrent J, Gonzalez J, Roso E,
Barrera-Gómez J, López-Vicente M,
Garcia-Esteban R, Boucher O,
Forns J, Burgaleta M, Sebastián N,
Canals J, Arija V, Basagaña X, Ros E,
Vendrell J, Salas-Salvadó J and
Sunyer J (2021) Walnuts, Long-Chain
Polyunsaturated Fatty Acids, and
Adolescent Brain Development:
Protocol for the Walnuts Smart Snack
Dietary Intervention Trial.
Front. Pediatr. 9:593847.
doi: 10.3389/fped.2021.593847
Walnuts, Long-Chain
Polyunsaturated Fatty Acids, and
Adolescent Brain Development:
Protocol for the Walnuts Smart
Snack Dietary Intervention Trial
Jordi Julvez 1,2,3
*, Florence Gignac 2,4 , Silvia Fernández-Barrés 2,3,4 , Dora Romaguera 2,5, 6,
Aleix Sala-Vila 7,8 , Otavio T. Ranzani 2, Cecilia Persavento 2, Anna Delgado 2, Albert Carol 2,
Jaume Torrent 2, Judith Gonzalez 2, Eduard Roso 2, Jose Barrera-Gómez 2,
Mónica López-Vicente 2, Raquel Garcia-Esteban 2,4 , Olivier Boucher 9, Joan Forns 2,
Miguel Burgaleta 4, Nuria Sebastián 4, Josefina Canals 10, Victoria Arija 10 ,
Xavier Basagaña 2,4 , Emilio Ros 6,11 , Joan Vendrell 1,12, Jordi Salas-Salvadó 1, 6,13 and
Jordi Sunyer 2,3,4
1Institut d’Investigació Sanitària Pere Virgili, Hospital Universitari Sant Joan de Reus, Reus, Spain, 2ISGlobal- Instituto de
Salud Global de Barcelona-Campus MAR, Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain, 3CIBER
Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain, 4Universitat Pompeu Fabra, Barcelona, Spain,
5Instituto de Investigación Sanitaria Illes Balears, Hospital Universitari Son Espases, Palma, Spain, 6CIBER Fisiopatología de
la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 7Barcelonaßeta Brain Research Center, Pasqual
Maragall Foundation, Barcelona, Spain, 8IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain, 9Centre de
Recherche du Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada, 10 Nutrition and Public Health Unit,
Research Group on Nutrition and Mental Health, (NUTRISAM), Faculty of Medicine and Health Science, Universitat Rovira i
Virgili, Reus, Spain, 11 Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clínic, Biomedical Research Institute August
Pi i Sunyer (IDIBAPS), Barcelona, Spain, 12 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades
Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain, 13 Human Nutrition Unit, Universitat Rovira i Virgili,
Department of Biochemistry and Biotechnology, Reus, Spain
Background: Adolescence, when the most complex behaviors are refined to
adult sophistication, represents a major window of opportunity and vulnerability for
neuropsychological development. To support and protect this complex and active brain
growth, different nutritional components considered essential need to be acquired from
the diet. For instance, omega-3 fatty acids are mainly obtained from seafood, seeds,
and walnuts. Known for their rich lipid profile, walnuts contain sizable amounts of an
essential fatty acid, alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid that is
the precursor of two longer-chain omega-3 polyunsaturated fatty acids (omega-3 PUFA):
docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. While there is growing
evidence of neuropsychological improvements in the young developing brain associated
with omega-3 PUFA intake, few studies have examined whether consuming walnuts
during adolescence entails similar beneficial effects. There is a need to further explore
the ways in which walnuts influence youthful brain function, particularly for the long-term.
Thus, we designed the WALNUTs study (WSS), a population-based randomized
controlled trial conducted in adolescents in Barcelona, Spain. We hypothesize that
walnut intake will increase omega-3 PUFA tissue availability (particularly ALA) to
a level that enhances the neuropsychological development during adolescence.
Julvez et al. Walnuts and Brain Development
Methodology/Design: We conducted a 6-month population-based randomized
controlled trial in teenagers (n=800) and we aimed to determine the effectiveness of
the intervention (four walnuts per day, or 30 kernel g, 1.5g of ALA) in enhancing brain
neuropsychological and socio-emotional development compared to a control group with
no walnut intervention. Before randomization, different neuropsychological tests were
recorded for all participants, and blood samples (in a subsample of participants) were
collected to measure omega-3 PUFA levels at baseline, and all again, after randomization
and the intervention. The data is now collected and we will conduct linear regression
models to assess the effect of the intervention.
Discussion: The WALNUTs (WSS) study results will allow us to better understand
the role of plant-based omega-3 PUFA intake from regular walnut consumption on
neuropsychological development during adolescence. Results could be translated into
nutritional public health recommendations targeting teenagers.
Trial Registration: ClinicalTrials.gov, U.S. National Library of Medicine, National
Institutes of Health # NCT02590848. Retrospectively registered 29/10/2015.
Keywords: neuropsychological development, dietary intervention, walnuts, omega-3 PUFA, ALA, randomized
controlled trial, adolescence
BACKGROUND
Adolescence is a critical period for brain development, mainly
because the prefrontal cortex, which is responsible for important
functions such as logical thinking, working memory, and
organizing skills, is the last region of the brain to mature around
the early twenties (1). Adolescence is also a time of refinement of
brain connectivity and complex behaviors. Indeed, it is a critical
period for the development of psychological and psychiatric
pathologies, such as substance abuse, schizophrenia, and mood
and anxiety disorders (13).
The brain is a highly active organ and its development and
metabolism require a large amount of energy and nutrients
(4,5). In this context, lack of essential nutrients may interfere
with brain development in youth. Therefore, enhancing these
complex processes, such as by adopting a healthy and balanced
diet providing essential nutrients, may have long-term functional
consequences (6).
Making up 15 to 30% of the brain’s dry weight (7),
PUFAs are an example of essential and semi-essential nutritional
components that are mostly obtained through the diet (mainly
from seafood, seeds, and walnuts) (8). Three of these PUFAs
play an essential role in brain development: long-chain omega-
3 acids—docosahexaenoic acid (DHA) and eicosapentaenoic
acid (EPA)—and the omega-6 acid arachidonic acid (AA).
Experimental and clinical studies have demonstrated the
importance of PUFAs in the function and architecture of
the central nervous system throughout various stages of life,
Abbreviations: AA, arachidonic acid; ADHD, attention deficit hyperactivity
disorder; ANT, attention network test; PUFAs, long chain polyunsaturated
fatty acids; ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA,
docosahexaenoic acid; SDQ, strengths and difficulties questionnaire; WSS, walnuts
smart snack study.
from neural development to neurodegeneration (4,7). In the
adolescent population, several large randomized controlled trials
of supplementation with DHA and EPA have reported a favorable
effect on neuropsychological and behavioral outcomes (9,10).
Thus, a large randomized controlled trial conducted in healthy
young adults using computerized cognitive tests found that
reaction time latencies and working memory were improved after
6 months of DHA supplementation (11).
Of all edible plants, walnuts are among the richest in the
vegetable omega-3 fatty acid and alpha-linolenic acid (ALA),
the precursor for DHA and EPA (12,13). However, ALA is
poorly transformed to EPA, while ALA itself has shown positive
effects on brain function (14). Walnuts are also rich in fiber,
vitamins, minerals, and other bioactive compounds capable of
improving brain health (12). Short-term walnut consumption
has been able to increase peripheral levels of EPA in humans
(15), and different experimental studies have pointed to potential
benefits in terms of cognition. Studies of walnut-fed rats fed
showed improvements in working memory (12), and in humans,
a parallel-group randomized controlled trial carried out among
447 older adults (mean age, 66.9 years) from Spain, found that
a Mediterranean diet supplemented with 30g/day mixed nuts
(including 15 g of raw, unprocessed walnuts) improved memory
and delayed age-related cognitive decline (16).
Nut studies examining cognitive outcomes in young people
are scarce. An observational cohort study assessed the association
of various foods on the cognitive function of children and
adolescents and reported a beneficial effect of nut consumption
on visual attention and processing (17). One small double-blind,
randomized, placebo-controlled crossover (8-week intervention
and 6-week washout) trial with walnuts carried out with young
college students aged 18 to 25 years showed improvements
in inferential verbal reasoning (18). However, no experimental
Frontiers in Pediatrics | www.frontiersin.org 2June 2021 | Volume 9 | Article 593847
Julvez et al. Walnuts and Brain Development
study focused on the effects of walnut consumption on
adolescents’ cognitive functions. Furthermore, a recent large
observational study with NHANES data of 26,656 adult
participants also found a protective association of walnut intake
against depressive symptom scores (19).
In view of these preliminary findings, there is a need to
further explore the potential brain development benefits of
walnut consumption during adolescence, a period when the
most complex behaviors are develop into adult sophistication.
Moreover, adolescents represent a population that tends to
be less targeted by health studies investigating the effects
of environmental exposure on brain development (6). By
conducting a population-based randomized controlled
trial, the WALNUTs (WSS) study aims to assess whether
walnut consumption has potential beneficial effects on
teenage brain function using different neuropsychological
and behavioral assessments.
We hypothesized that walnut supplementation for 6 months
would enhance neuropsychological and behavioral (socio-
emotional) development among healthy teenagers. We further
hypothesized that a walnut intervention for 6 months would
increase omega-3 PUFA tissue availability.
METHODS AND MATERIALS
Trial Design
WALNUTs (WSS) is a multi-school, parallel (two-group),
controlled, 6-month superiority randomized clinical trial in a
large population-based sample aiming to include 800 healthy
teenagers in Barcelona, Spain. After data collection, 771
participants were equally randomized in two groups (386/385),
but because of some exclusions post-randomization, 748 were
finally included. Study subjects were randomly assigned to two
intervention groups just after baseline assessments: the walnut
group (n=370, consuming walnuts daily and advised to follow
general healthful eating recommendations, such as eating a
piece of fresh fruit every day) or control group (n=378,
not consuming walnuts and advised also to follow the same
general healthful eating recommendations). They were assessed
at baseline and after the intervention by several internationally
validated neuropsychological tests and behavioral rating scales.
Due to the project’s budget limitations, a random subsample of
200 adolescents per group of intervention (n=400) were targeted
to measure changes in omega-3 PUFA biomarkers. We finally
got 270 participants, 139 in the walnut group and 131 in the
control group. All participants randomized to the walnut group
received 30g/day of kernel walnuts to be incorporated into their
diet for free. The type of walnuts selected, Californian walnuts, is
estimated to contain about 9 g of ALA per 100 g (20,21). There is
evidence that young Spanish subjects between 10–13 and 14–17
years of age consume on average 5.7 g (SD 24.5 g) and 6.1 g (SD,
20.8 g) of nuts daily (22), which supports the feasibility of our trial
design. Figure 1 shows the project’s design and structure.
Eligibility Criteria
The participants eligible were adolescents aged between 11 and
16 years attending regular schools in Barcelona. Originally, the
study protocol was designed to recruit adolescents aged 12–15
years; however, the schools facilitated participant recruitment
through the classes, and there were children a bit younger and
older that we did not want to exclude if they were willing
to participate in the study. Exclusion criteria include those
consuming supplements of omega-3 PUFAs regularly, eating
walnuts on a daily basis, and/or having an allergy to walnuts
and/or gluten. Subjects were excluded also if they reported
lactose intolerance or an allergy to cereals, dried fruits, peanuts,
soy, sesame, or sulfites, since the walnut industry manipulates
these products and there could be traces of them in the walnut
packages. Eligible candidates who were siblings of family units
were randomized and allocated to the same group and analyzed
as clusters.
Sample Size
Prior to data collection, the statistical power of the study for
neuropsychological outcomes was based on 400 participants per
group. Six primary outcomes were considered: the N-back task,
the Attention Network Test (ANT), the Tests of Primary Mental
Abilities (PMA-R, the Spanish adaptation), the Roulettes Task
(adapted from the Cups Task), the Strengths and Difficulties
Questionnaire (SDQ), and the Attention Deficit Hyperactivity
Disorder (ADHD) DSM-IV form list. The cognitive outcomes
with mean values of 100 (SD 15) units corresponding to the
standard values of neuropsychological scores in the general
population (23) were considered, with a correlation between
them of 0.25. The targeted intervention effect was a change of
3 units, based on previous studies in adult samples (16,18). We
considered a type I error of 0.05 and corrected calculations for
multiplicity using the Benjamini-Hochberg method. A 10% loss
of follow-up was assumed. Additionally, we assumed that the
final models had an R2of 20%. With all these considerations, the
study would have 95% power to detect the effect with at least one
outcome, 90% to detect the effect with at least two, 80% to detect
the effect with at least 3, 70% to detect the effect with at least 4,
55% to detect the effect with at least 5, and 31% to detect the effect
with all six outcomes. Similar power calculations can be made
from the final participation sample of 748 participants.
Procedures
Recruitment and Randomization
An experienced fieldwork technician with the help of two more
experts recruited participants in collaboration with the Barcelona
school system. We first obtained permission from the boards
of several schools in Barcelona to inform them about the
trial. Then, we provided the schools with a recruitment fllier
to assess willingness to collaborate and grant us permission
to contact interested families by telephone. Families interested
in participating contacted us through the school and filled
out a form with their telephone number. Trained personnel
contacted the parents and explained the study in detail.
Fieldworkers verified the eligibility criteria of each candidate.
We performed age-, gender-, and maternal education-stratified
random computerized sampling within each school to assign
adolescents to one of the two groups. In order to avoid
Frontiers in Pediatrics | www.frontiersin.org 3June 2021 | Volume 9 | Article 593847
Julvez et al. Walnuts and Brain Development
FIGURE 1 | Project design and structure.
contamination, we gave the walnuts for free to the corresponding
group and asked participants to consume them at home.
Implementation and Adherence
All families received a basic guide to the seasonal fruits needed
to follow healthful diet recommendations (eating a piece of
fresh fruit every day) in order to ensure implementation and
adherence. The control group received the same instructions,
including the general recommendation to eat a piece of fresh
fruit every day, as well as feedback to encourage them to
remain in the study. Families in the walnut intervention
group received additional instructions on how to encourage
participants to eat their daily allotment of walnuts, which
we supplied for free in sachets of 30 grams; no other
recommendations were given. We asked parents to supervise
the intervention by checking the subject’s adherence to the
walnut consumption. To evaluate adherence to the intervention,
the Survey Monkey web-based platform was used weekly.
Participants in the walnut group were contacted in the middle
of the study, and recipes for dishes containing walnuts were
provided; they were also asked to report their daily walnut
consumption weekly, using the Survey Monkey platform and
to cross off the days they had or hadn’t eaten the allocated
amounts of walnuts on a calendar, in order to evaluate
adherence to the intervention. Moreover, the participants
were eligible for a periodic raffle for completing the Survey
Monkey reports weekly. The prize was entrance tickets to a
science museum.
RESULTS
Dietary Assessment
A food frequency questionnaire (FFQ), validated for the Spanish
population (24) and adapted to the adolescent range, was
administered to all adolescent participants at baseline and at the
end of the intervention (after 6 months). Additionally, a short
FFQ was completed every 3 months. We added the measurement
of dietary patterns to our study in order to control for these
factors in secondary analyses, since diet can be changed after a
nutritional intervention.
Frontiers in Pediatrics | www.frontiersin.org 4June 2021 | Volume 9 | Article 593847
Julvez et al. Walnuts and Brain Development
Neuropsychological and Behavioral Testing
Multiple primary endpoints concerning the neuropsychological
and behavioral development of adolescents was assessed before
randomization, at baseline (pre-intervention) and after 6 months
(post-intervention). A total of six tests (six primary outcomes)
developed for assessing children and adolescents were used to
measure changes from baseline in the main score for each of
the tests for neuropsychological (working memory, attention,
fluid intelligence and executive function) and behavioral (socio-
emotional and ADHD symptoms) outcomes (25). The first
primary outcome measurement was the N-back task, which is
a computer-based test assessing working memory using series
of numbers. The stimulus appears in the laptop screen one by
one. Children were invited to press a button in the keyboard
when the stimulus is the same as the previous one in the 1-back
level. In 2-back, they were required to press the button when the
stimulus in the screen is the same as the one presented two trials
back. In 3-back, they had to press when the stimulus was the
same as the one presented three trials back. The outcome is d:d
prime (d’)=z(hit rate) - z(false alarm rate) (26). The second
measurement was the Attention Network Test (ANT), also
known as the flanker test, which is also a computerized test aimed
at examining sustained attention based on reaction times to target
stimuli. The test provides several attention functions (orienting,
alerting, and conflicting); however, hit reaction time standard
error is the “gold standard” to measure sustained attention,
since it is the reaction time variability during the attention task
(27,28). The third measurement was the inductive reasoning
subtest (fluid intelligence) of the Tests of Primary Mental
Abilities (PMA-R, the Spanish adaptation) (29). The fourth
measurement, the Roulettes Task (adapted from the Cups Task),
was a gambling task aiming to assess risky decision making, i.e.,
whether the participants adjust their risky behavior according
to the probabilities and importance of the outcome (cognition
influenced by emotion) (30). The fifth measurement was the self-
reported version of the Strengths and Difficulties Questionnaire
(SDQ). It consists of 25 questions, organized in a general score of
problem behavior and five subscales aimed to assess emotional
symptoms, conduct problems, hyperactivity/inattention, peer
relationship problems and pro-social behavior (31). The
sixth measurement was the Attention Deficit Hyperactivity
Disorder (ADHD) DSM-IV form list. We asked the teacher
of the adolescent to answer 18 multiple-choice questions in
order to rate his/her ADHD performance. The scores were
transformed into a number of symptoms and diagnostic criteria
for ADHD and inattentive and hyperactive subtypes. The
administration of these neuropsychological tests was carried out
by a trained psychologist and fieldwork technicians, and the
tests were hold at the schools after securing comfortable and
quiet quarters.
Laboratory Determinations
The venipuncture blood collection was done by a nurse at the
schools after securing appropriate conditions at baseline and
after 6 months of intervention. The red blood cell proportions
of omega-3 fatty acids (DHA, EPA and ALA) and omega-6 fatty
acids (AA), among other fatty acids, were determined by gas
chromatography at baseline and after 6 months of intervention.
Details on quality control for this method are described elsewhere
(32). The results were expressed in relative amounts (percent of
total fatty acids).
Clinical Evaluation and Other Secondary
Measurements
In addition to the neuropsychological and behavioral endpoints,
secondary intermediate outcomes of interest were measured
at baseline and after 6 months of intervention. We aim
to explore whether there are changes in height (in cm),
weight (in kg), waist circumference (in cm), and blood
pressure. These other health outcomes can be affected by
changes in the diet: particularly walnut intake can improve
cardiometabolic indicators (33). Height was measured using the
stadiometer model SECA 214, weight by the weighing scales
SECA 770 model, and waist circumference with the SECA
201 tape model. Blood pressure (systolic and diastolic) were
measured (in triplicate) after 5 min of rest with an OMROM
705-CPII device in the dominant arm. All measurements
were done by a trained nurse at the schools and followed
standard procedures.
Additionally, at baseline, two questionnaires of
sociodemographic and clinical characteristics and lifestyle
factors were obtained to collect covariables such as parental
education and socio-economic level, parental mental health
status, sociodemographic characteristics, adolescent health
history, and lifestyle habits such as physical activity, sleep
duration, and daily screen time exposure. Further estimations of
environment and ambient pollution based on home and school
geo-localizations were recorded.
Finally, in the same subsample of 270 participants, we
collected extra samples of blood and urine before and after the
nutritional intervention to assess potential secondary effects of
the intervention and also to investigate the biological effects
of other important risk factors collected in this study, such as
lifestyle factors, environmental exposure, nutritional status, and
the mental health status of the participants.
DATA ANALYSIS
Descriptive statistics (frequencies, means, standard deviations
for normally distributed data; medians and interquartile ranges
for nonparametric data) will be used to describe the baseline
characteristics of the walnut and control groups. To assess
the effect of the intervention on brain development, we use
multivariable linear regression models. Similar regression models
will be used to assess the effect of the intervention on red blood
cell PUFA proportions, particularly ALA, as outcome variables.
To assess the proportion of the effect of the intervention on
brain development that is mediated by red blood cell PUFA
changes, results will be compared in models with and without
the mediator. All analyses will be based on the intention to
treat in order to estimate the effectiveness of a public health
recommendation (i.e., to encourage eating 30 g of walnuts per
day). We also plan to conduct a per-protocol analysis with
Frontiers in Pediatrics | www.frontiersin.org 5June 2021 | Volume 9 | Article 593847
Julvez et al. Walnuts and Brain Development
those who comply with the intervention, i.e., single days of
reporting eating walnuts (100 days during 6 months) (34).
The nominal statistical significance will be set at the P<
0.05 level (two-sided) for the primary outcomes. Statistical
analyses are performed with STATA. A detailed statistical
analysis plan will be established before database lock and
any analyses.
Using multiple primary endpoints, the study will be
considered successful if the results of either one of the primary
endpoints is statistically significant in favor of the experimental
treatment and/or treatment adherence. In this case, we will
report for each primary endpoint a nominally significant level
and the corrected p-value determined by the method for
multiplicity adjustment.
DISCUSSION
To the best of our knowledge, this is the first medium-term
randomized intervention trial aiming to assess the effect of
walnut consumption on adolescent brain development. The
selected battery of neuropsychological and behavioral tests
will provide the opportunity to enrich the interpretation
of the findings. However, the design of this study is not
exempt from potential limitations. First, the study selected
walnuts for their richness in essential fatty acids, particularly
ALA, with the hypothesis that they have an effect on the
young developing brain. However, using walnuts will make
the true PUFA content of the diet less consistent than if
administered via a daily pill supplement. While the PUFA
concentrations of California walnuts are fairly stable, we
will minimize this potential bias by standardizing walnut
dosage and type for the duration of the intervention. In
any case, we measured the ALA biomarker in blood before
and after the intervention as objective proof of adherence to
the intervention. Second, performing a double-blind dietary
trial, the gold standard of clinical trials, is problematic and
known to be an important limitation in feeding studies
of whole foods (35,36). However, investigators performing
biochemical determinations and statistical analyses are blinded
to the intervention. Third, ensuring compliance of adolescents
with daily walnut consumption for a period of 6 months is
difficult and may result in lack of adherence and losses to
follow-up. To offset this limitation, we planned to contact
participants in the middle of the study, distribute recipes for
dishes containing walnuts, ship walnuts to subjects’ homes or
schools for free, and ask the parent/tutor to supervise the
intervention. In summary, this randomized feeding trial intends
to focus on nutritional and neuropsychological sciences in the
adolescents, a population group infrequently evaluated in clinical
and public health research (https://www.nature.com/collections/
vbmfnrsssw).
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding authors.
ETHICS STATEMENT
The studies involving human participants were reviewed
and approved by CEIC Parc Salut Mar (approval number:
2015/6026/I). Written informed consent to participate in this
study was provided by the participants’ legal guardian/next of kin.
AUTHOR CONTRIBUTIONS
JJ, SF-B, and DR developed the study protocol and/or sections of
the study protocol. JJ, SF-B, and DR revised the study protocol
and/or sections of the study protocol. JJ, FG, SF-B, DR, and
OR drafted the manuscript. CP, AD, AC, JT, JG, and ER were
involved in the fieldwork of the study. All authors revised the
manuscript for important intellectual content, approved the
version to be published, and agreed to be accountable for all
aspects of the work.
FUNDING
The study for the outlined protocol was supported by Instituto de
Salud Carlos III through the projects CP14/00108 & PI16/00261
(co-funded by European Regional Development Fund A way
to make Europe). JJ and AS-V hold Miguel Servet-II contracts
(grants CPII19/00015 and CPII17/00029, respectively) awarded
by the Instituto de Salud Carlos III (Co-funded by the European
Social Fund Investing in your future). OR holds a Sara Borrell
contract (CD19/00110) from the Instituto de Salud Carlos III. J
Salas-Salvadó and gratefully acknowledges the financial support
by ICREA under the ICREA Academia program. The California
Walnut Commission (CWC) has given support by supplying the
walnuts for free. The funders have no role in the study design,
collection, management, analysis, or interpretation of data or the
writing of the report or decision to submit it for publication.
ACKNOWLEDGMENTS
We thank the study participants, families, and the schools (Escola
Padre Damián; Escola Proa; Escola Sant Miquel; Escola Solc; IES
Ernest Lluch; IES Front Marítim; IES Galileo Galilei; IES Joan
Boscà; IES La Sedeta; IES Montserrat; IES Príncep de Viana; IES
Verdaguer) that accepted to participate and give support to the
development of this study. We also thank Silvia Fochs and Nuria
Pey for giving extra support during the fieldwork. CIBERESP and
CIBEROBN are initiatives of ISCIII, Spain.
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Conflict of Interest: JJ, AS-V, and EmR have received grants for research through
their institutions from the California Walnut Commission (CWC), Folsom,
California. ER has also received honoraria for consulting and presentations from
the CWC and is a nonpaid member of its Scientific Advisory Council, besides
having received honoraria for presentations from Danone JS-S reports serving on
the board of the International Nut and Dried Fruit Council (nonpaid member of
the scientific committee) and receiving grant support from this entity through his
institution. He also reports serving on the Executive Committee of the Instituto
Danone Spain. He has also received research funding (walnuts, olive oil, hazelnuts,
and almonds for the PREDIMED study) from the CWC; Patrimonio Comunal
Olivarero, Spain; La Morella Nuts, Spain; and Borges S.A., Spain, respectively. He
reports receiving consulting fees or travel expenses from Nuts for Life and the
Australian Nut Industry Council.
All remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflic of interest.
Copyright © 2021 Julvez, Gignac, Fernández-Barrés, Romaguera, Sala-Vila,
Ranzani, Persavento, Delgado, Carol, Torrent, Gonzalez, Roso, Barrera-Gómez,
López-Vicente, Garcia-Esteban, Boucher, Forns, Burgaleta, Sebastián, Canals, Arija,
Basagaña, Ros, Vendrell, Salas-Salvadó and Sunyer. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Pediatrics | www.frontiersin.org 7June 2021 | Volume 9 | Article 593847
... With the use of data from both in vitro and in vivo research, this revised review clarifies the therapeutic potential of walnuts in treating illnesses of the nervous system, including Parkinson's disease, Alzheimer's disease, depression, epilepsy, and pain. The walnut's abundance of bioactive compounds, such as gallic acid, protocatechuic acid, ferulic acid, sinapate, ellagic acid, phydroxybenzoic acid, p-coumaric acid, quercetin 3-galactoside, juglone, vanillic acid, myricetin, kaempferol, apigenin, luteolin, daidzein, and others, is responsible for these positive effects (Julvez et al., 2021). ...
... In the human liver, ALA from walnuts is subsequently transformed into vital PUFAs like EPA (20:5n-3) and DHA (22:6n-3) via a sequence of successive desaturation and elongation processes. In addition to lowering oxidative stress and modifying immunological function, EPA and DHA are crucial for brain health because they preserve synaptic plasticity, neuronal membrane integrity, gene expression, and neurogenesis (Julvez et al., 2021). ...
... The therapeutic claims made by many researchers in their publications are supported by a wealth of expertise and clinical findings. In scientific studies, the usage of these tree nuts as useful nutrients for the prevention or perhaps treatment of AD may be given greater weight than the molecular actions ascribed to the phytochemicals (Julvez et al., 2021). ...
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The books cover a wide variety of nutrients and exercise effect on brain function. The chapters included in this book include,1.Exploration of Medicinal Crop Sesbania Grandiflora for Brain Health2. The Neurobiological Effects of Chocolate Consumption: A Scientific Review. Green Leafy Vegetables and cognition 4. Shankhpushpi and Brahmi, 5.Ginkgo Biloba effect on brain, 6.Effect of Saffron, 7. Blueberry, 8. walnut, and 9. turmeric has been evaluated extensively.
... The current study is based on a cross-sectional design using baseline information from the Walnuts Smart Snack (WSS) trial [24]. The purpose of this intervention was to determine if dietary supplementation with 30 g of raw walnut kernels per day for six months resulted in beneficial improvements in cognitive and socioemotional development when compared to a control group of healthy adolescents [25]. ...
... Participants completed several neuropsychological tests and provided information on their lifestyle and dietary preferences prior to randomization. All information about the clinical trial procedure is described in the WSS protocol [24]. Participants who had complete baseline data on the food frequency questionnaire and the neuropsychological tests were eligible for the present study (n = 643). ...
... In this cross-sectional study conducted within the framework of the WSS Intervention Trial [24], we observed the association between PCA-derived dietary patterns and neuropsychological outcomes in the adolescent population. Six dietary patterns were identified that demonstrate specific characteristics: "low consumption of meat and fish", "fruits", "dairy products, soft drinks and juices", "nuts", "low consumption of calorie-dense foods" and "mixed diet". ...
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A balanced diet is relevant for neuropsychological functioning. We aimed to analyze the association between dietary patterns and neuropsychological outcomes in a sample of healthy adolescents of the Walnuts Smart Snack (WSS) cohort from Barcelona city. We performed principal components analysis (PCA) to determine dietary patterns in the adolescent sample using a food frequency questionnaire (60 items). Multiple linear regression models were performed to analyze the association between PCA dietary patterns with neuropsychological outcomes: Strengths and Difficulties (SDQ) externalizing and internalizing scores, Attention Network Test (ANT) Impulsivity Index and Emotional Recognition Task (ERT) scores. We additionally adjusted the models for child sex, age, body mass index (BMI), physical activity and maternal education. Six dietary patterns were identified in PCA analyses. "low consumption of calorie-dense foods" dietary pattern had a negative association (protective) with the both SDQ outcomes (p value < 0.001) and "Nuts" dietary pattern showed a negative (protec-tive) association with impulsivity index (1 = −24.60, 95% CI = −36.80, −12.41, p value < 0.001). Overall, our main results suggest that healthy dietary patterns, including higher intakes of "nuts" and a preference of "low consumption of calorie-dense foods" dietary patterns, could provide a beneficial association with neuropsychological functions during the adolescence period. The associations may include improvements of externalizing and internalizing problem symptoms, and impulsivity.
... This is a cross-sectional study using baseline data from an existing database provided by the WALNUTs project (5,6). The original aim of WALNUTs cohort was the assessment of a nutritional intervention based on daily walnut intake and its impact on cognitive function. ...
... The other confounding variables related with child and maternal characteristics and lifestyle factors were assessed by the administration of a child and parental self-reported general questionnaire during baseline assessments. Finally, a fieldwork nurse measured child anthropometrical characteristics following standardized proceedings (5,6). ...
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Objective: We examined the association between Mediterranean diet and psychosocial functioning among high school students from Barcelona, Spain. Methods: This is a sample of healthy teenagers (11 to 16 years old) recruited during 2016–2017 from 12 high schools in Barcelona. The 622 participants responded the Mediterranean Diet Quality Index for Children and Adolescents (KIDMED) and the Strengths and Difficulties Questionnaire (SDQ). Multivariable linear regression models were applied to assess the associations between KIDMED and SDQ scores and adjusting for potential confounders. Results: KIDMED score was negatively associated with SDQ total problem score (β = -0.20 (95% CI = -0.38; -0.02)) and conduct problem score (β = -0.08 (95% CI = -0.14; -0.03)). KIDMED score was positively associated with prosocial behavior subscale score (0.08 (0.03; 0.14)). Conclusion: Adherence to Mediterranean diet is beneficial for some domains of psychosocial functioning. Dietary patterns are important for mental health during the adolescence.
... The Strengths and Difficulties Questionnaire (SDQ) is a screening questionnaire for emotional and behavioral problems in children and young people that assesses the impact of difficulties on the child's life, including (1) emotional symptoms, (2) conduct problems, (3) hyperactivity/inattention, (4) peer relationship problems and (5) prosocial behavior [19][20][21] . Past validation studies have shown that the total SDQ score can be considered as a predictive factor for mental health disorders, as children with high SDQ scores have an increased probability for clinical disorders 22,23 . ...
... No additional consent was needed for this study, all of the participants were offered free tickets to the science museum of Barcelona. The specifics of the WALNUTs cohort formation were described in previous publications 21,65 . The current manuscript used a subset of 372 baseline blood samples before any dietary intervention originally described in a previous work 65 . ...
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... In FinnTwin12, this may be because we non-randomly included twins at elevated familial risk for alcoholism in the intensive sub-study 63 . In WALNUTs, we only included participants with available proteome assay 62 . ...
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The exposome, encompassing all external and internal environmental factors, provides a comprehensive understanding of the complex etiology of mental health. This study investigated the relationship between the external exposome during mid-adolescence and plasma proteomic biomarkers of mental health in 935 participants from the FinnTwin12 (Finland) and WALNUTs (Spain) cohorts. The mid-adolescent external exposome included 60 exposures. Biomarkers included 26 plasma proteins (mean age 22) for FinnTwin12 and 31 (mean age 13) for WALNUTs. The exposome-wide proteome-wide analysis revealed seven exposures (related to lifestyle, indoor environmental quality, natural environment, and family environment) linked to six proteins. Greenspace-related exposures were associated with proteins in both cohorts. However, these exposures showed no direct association with concurrent measures: the psychopathology factor or depressive symptoms. Twin analyses indicated genetic influences in some covariations between exposures and proteins. These findings provide evidence for mid-adolescents about the association between external environments and proteomic biomarkers of mental health.
... No additional consent was needed for this study, all the participants were offered free tickets to the science museum of Barcelona. The specifics of the Walnuts cohort formation were described in previous publications [29,30]. The current manuscript used a subset of 372 baseline blood samples before any dietary intervention originally described in a previous work [30]. ...
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Adolescence is a critical developmental period marked by significant physiological, psychological, and behavioural changes. Sex-specific biological factors can play a major role in their progression. Liquid chromatography – tandem mass spectrometry proteomic analysis was used to measure the plasma proteome abundances in 197 adolescents (11-16 years old) from the WALNUTs cohort. Orthogonal partial least squares discriminant analysis (OPLS-DA) revealed clear sex-based proteomic distinctions, with 76 proteins significantly differing between males and females after correcting for age and BMI. Gene Ontology enrichment analysis of these proteins highlighted pathways related to cell adhesion and extracellular matrix organization reflecting sex-specific developmental trajectories during puberty. Bioinformatic analysis revealed 37 proteins significantly associated with the total score of the Strengths and Difficulties Questionnaire (SDQ), with additional sex-specific associations emerging in subgroup analyses. Plasma protein abundancies in males exhibited stronger correlations with SDQ externalizing subscale scores, while in females the associations with the internalizing score were more prominent, consistent with known behavioural sex differences. Immune response and blood coagulation pathways were implicated in these associations, particularly in females, while no significant pathway enrichment was observed for males. These findings highlight both shared and sex-specific proteomic features associated with the SDQ scores in adolescents, emphasising the need to consider sex differences in proteomic studies. The results provide a critical step toward identifying biomarkers and pathways underlying sex-specific psychological and developmental processes in adolescence.
... Walnut consumption (1-2 oz daily) may enhance cognitive function and a long-term dietary supplementation of walnuts can (a) significantly enhance memory function, learning abilities, motor coordination, and anxiety-related behavior and (b) attenuate oxidative stress by improving the balance between free radicals and antioxidants and associated neuronal cell death. Studies point to the potential benefits of early and ongoing nutritional interventions using walnuts for preserving cognitive function and suggest the possibility of using walnuts as a treatment intervention for ASD [114]. ...
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Special diets or nutritional supplements are regularly given to treat children with autism spectrum disorder (ASD). The increased consumption of particular foods has been demonstrated in numerous trials to lessen autism-related symptoms and comorbidities. A case study on a boy with moderate autism who significantly improved after three years of following a healthy diet consisting of pumpkin and walnuts was examined in this review in connection to a few different neurophenotypes of ASD. We are able to suggest that a diet high in pumpkin and walnuts was useful in improving the clinical presentation of the ASD case evaluated by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological variables. Using illustrated figures, a full description of the ways by which a diet high in pumpkin and nuts could assist the included case is offered.
Chapter
Metabolic syndrome is a combination of interrelated metabolic risk factors, such as obesity, dyslipidemia, insulin resistance, increased oxidative stress, hypertension, and systemic inflammation, collectively impairing overall health. Addressing metabolic syndrome concerns through dietary improvements and strategically incorporating functional bioactive compounds is a recognized approach. Diets enriched in bioactive compounds such as polyunsaturated fatty acids, carotenoids, and polyphenols are important considerations to target metabolic syndrome. Omega (n)-3 polyunsaturated fatty acids (PUFA), particularly alpha-linolenic acid (ALA), the essential PUFA from vegetarian sources, and longer-chain PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from marine sources improve conditions associated with metabolic syndrome. Foods containing n-3 PUFA are also rich in antioxidants such as carotenoids and polyphenols that provide beneficial health effects to combat metabolic syndrome disorders. This book chapter compares and contrasts the effects of vegetarian and marine sources enriched in ALA, and EPA/DHA, on metabolic pathways to target metabolic syndrome. Furthermore, the effects of antioxidants from vegetarian and marine sources on the regulation of metabolic pathways are compared to provide beneficial health effects in metabolic syndrome. Integrating bioactive-rich marine and vegetarian foods is an excellent strategy for effectively managing the complications linked with metabolic syndrome.
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Background: Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear. Methods: We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations. Findings: In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p
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Background Consumption of nuts improves cardio-metabolic risk factors in clinical trials and relates to lower risk of cardiovascular disease (CVD) in prospective observational studies. However, there has not been an adequately powered randomized controlled trial to test if nuts supplementation actually reduces incident CVD. In order to establish the feasibility of such a trial, the current study aimed to assess the acceptability and adherence to long-term nut supplementation amongst individuals at high CVD risk in China. Methods This protocol described a 6-month trial performed in Ningxia Province in China among participants with a history of CVD or older age (female ≥65 years, male ≥60 years) with multiple CVD risk factors. Participants were randomized to control (received non-edible gift), low dose walnut (30 g/d), or high dose walnut (60 g/d) groups in a 1:1:1 ratio. Walnuts were provided at no cost to participants and could be consumed according to personal preferences. Follow-up visits were scheduled at 2 weeks, 3 months and 6 months. The primary outcome was fasting plasma alpha linolenic acid (ALA) levels used as an indicator of walnut consumption. Secondary outcomes included self-reported walnut intake from the 24 h dietary recalls. The target sample size of 210 provided 90% statistical power with two-sided alpha of 0.05 to detect a mean difference of 0.12% (as percent of total fatty acid) in plasma ALA between randomized groups. Results Two hundred and ten participants were recruited and randomized during October 2019. Mean age of participants was 65 years (SD = 7.3), 47% were females, and 94% had a history of CVD at baseline. Across the three study groups, participants had similar baseline demographic and clinical characteristics. Discussion This trial will quantify acceptability and adherence to long-term walnut supplementation in a Chinese population at high risk of CVD. The findings will support the design of a future large trial to test the effect of walnut supplementation for CVD prevention. Trial registration NCT04037943 Protocol version: v3.0 August 14 2019
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Background: Multiple studies have shown a Mediterranean diet, characterized by their olive oil and nut consumption, to be correlated with lower depression risk. Objective: To examine whether part of this reduced risk in the United States is attributable to walnut consumption, we analyzed data on walnut consumption and depression scores from the National Health and Nutrition Examination Survey (NHANES). Methods: NHANES survey data for 2005 through 2014 was pooled for adults with 24 h recall dietary data. Depression scores were based on PHQ-9 self-report responses. A total of 26,656 participants were characterized as reporting the consumption of walnuts with high certainty, walnuts with other nuts, other nuts, or no nuts. Results: After an adjustment for covariates, walnut consumers showed lower depression scores compared to non-nut consumers. The least square mean for total depression score was 26% lower for walnut with high certainty consumers than for non-nut consumers (p < 0.0001), and the association was stronger among women (32%, p < 0.0001) than men (21%, p = 0.05). The significant contributors to this difference were due to walnut consumers reporting greater interest in doing things (p = 0.003), less hopelessness (p = 0.02), and feeling more energetic (p = 0.05) than non-nut consumers. Non-nut consumers were more likely to have trouble concentrating (p = 0.02), to feel they were moving or speaking abnormally (p = 0.03), and to have thought they were better off dead (p = 0.002). Conclusions: Depression scores were significantly lower among nut consumers and particularly walnut consumers as compared to non-nut consumers. After controlling for potential covariates, walnut users had scores significantly lower than other nut consumers. The difference was strongest among women, who are more likely than men to report higher depression scores.
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Impulse control, an emergent function modulated by the prefrontal cortex (PFC), helps to dampen risky behaviors during adolescence. Influences on PFC maturation during this period may contribute to variations in impulse control. Availability of omega-3 fatty acids, an essential dietary nutrient integral to neuronal structure and function, may be one such influence. This study examined whether intake of energy-adjusted long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] was related to variation in impulse control and PFC activity during performance of an inhibitory task in adolescents (n = 87; 51.7% female, mean age 13.3 ± 1.1 years) enrolled in a longitudinal neuroimaging study. Intake of DHA + EPA was assessed using a food frequency questionnaire and adjusted for total energy intake. Inhibitory control was assessed using caregiver rating scale (BRIEF Inhibit subscale) and task performance (false alarm rate) on a Go/No-Go task performed during functional MRI. Reported intake of long-chain omega-3 was positively associated with caregiver ratings of adolescent ability to control impulses (p = 0.017) and there was a trend for an association between intake and task-based impulse control (p = 0.072). Furthermore, a regression of BOLD response within PFC during successful impulse control (Correct No-Go versus Incorrect No-Go) with energy-adjusted DHA + EPA intake revealed that adolescents reporting lower intakes display greater activation in the dorsal anterior cingulate, potentially suggestive of a possible lag in cortical development. The present results suggest that dietary omega-3 fatty acids are related to development of both impulse control and function of the dorsal anterior cingulate gyrus in normative adolescent development. Insufficiency of dietary omega-3 fatty acids during this developmental period may be a factor which hinders development of behavioral control.
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Impulse control, an emergent function modulated by the prefrontal cortex (PFC), helps to dampen risky behaviors during adolescence. Influences on PFC maturation during this period may contribute to variations in impulse control. Availability of omega-3 fatty acids, an essential dietary nutrient integral to neuronal structure and function, may be one such influence. This study examined whether intake of energy-adjusted long-chain omega-3 fatty acids (eicosahexaenoic acid (EPA) + docosahexaenoic acid (DHA)) was related to variation in impulse control and PFC activity during performance of an inhibitory task in adolescents (n= 87; 51.7% female, mean age 13.3+1.1 years) enrolled in a longitudinal neuroimaging study. Intake of DHA+EPA was assessed using a food frequency questionnaire and adjusted for total energy intake. Inhibitory control was assessed using caregiver rating scale (BRIEF Inhibit subscale) and task performance (false alarm rate) on a Go/No-Go task performed during functional MRI. Reported intake of long-chain omega-3 was positively associated with caregiver ratings of adolescent ability to control impulses (p=0.017) and there was a trend for an association between intake and task-based impulse control (p=0.072). Furthermore, a regression of BOLD response within PFC during successful impulse control (Correct No-Go versus Incorrect NoGo) with energy-adjusted DHA+EPA intake revealed that adolescents reporting lower intakes display greater activation in the dorsal anterior cingulate, potentially suggestive of a possible lag in cortical development. The present results suggest that dietary omega-3 fatty acids are related to development of both impulse control and function of the dorsal anterior cingulate gyrus in normative adolescent development. Insufficiency of dietary omega-3 fatty acids during this developmental period may be a factor which hinders development of behavioral control.
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