Omega 3/6 fatty acids; Learning; ADHD; Children; Attention; Behaviour

ADHD: Attention Deficit Hyperactivity Disorder; ALA: Alpha-linolenic Acid; ARA: Arachidonic Acid; ASD: Autistic Spectrum Disorder; DHA- Docosahexaenoic Acid; EPA: Eicosapentaenoic Acid; GLA: Gamma Linoleic Acid; MPH: Methylphenidate; PS: Phosphatidylserine; PUFA: Polyunsaturated Fatty Acids; RCTs: Randomised Controlled Trials; TS: Tourette Syndrome.

There is increasing evidence that nutritional insufficiencies, including that of omega-3 fatty acids can have adverse effects on brain development and neurodevelopment [1], thereby impacting on the ability to learn to and function sociably. It is well documented that humans once evolved on a diet providing a balanced 1:1 ratio of omega-6 to omega-3 fatty acids which is important for normal development throughout the life span [2]. Yet Western diets now have a ratio of omega-6 to omega-3 of 10:1 up to 20-25:1 – a profile distinctly different to that on which humans evolved and their genetic patterns were established [2].

Typically, the human brain is around 60 per cent fat [3] with the omega-3 fatty acid docosahexaenoic acid (DHA) being abundant in the brain and its neuronal membranes where it supports normal neurological function [4]. Equally, scientific literature implies that the evolution of the higher order of brain function in humans was once attributed to our omega-3 and DHA intakes, with DHA found to be densely accumulated in areas of the brain associated with learning and memory [5]. Concerns have been raised that modern diets lacking in omega-3 fatty acids may have adverse effects on a child’s learning, reading, and attention [6]. These links are not surprising given that brain cell membranes are rich in phospholipids composed of these fatty acids, with evidence that these facilitate transport across the membranes and modulate neurotransmitter systems [4,7,8].

Current evidence suggests that omega-3 status, especially DHA, may enhance cognitive performance including aspects of learning, memory and speed of performing cognitive tasks and children whose diets are low in these may benefit the most [9]. For example, Italian research has shown that children’s blood omega-3 levels tend to be highest in neonates (new-borns) and lowest in children, especially that of DHA indicating a decline from birth and that dietary intakes are generally inadequate [10]. An Oxfordshire cross-sectional evaluation of schoolchildren aged 7 to 9 years (n=493) showed that low DHA blood concentrations were associated with reduced reading ability, working memory and higher levels of parent-related oppositional behaviour and emotional liability [11]. Similarly, a UK study of 13 to 16-yearold teenagers (n=196) found omega-3 status to be low at baseline [12]. Other work comprised of boys aged 6 to 12 years observed that there were a greater number of behavioural problems including temper tantrums and sleeping problems amongst those with lower omega-3 fatty acids levels [13].

Amongst children with a history of school failure the prevalence of learning difficulties and developmental disorders, including dyslexia and dyscalculia has been reported to be 32 per cent (6.4 per cent in the general population) [14]. Dyslexia is the most common learning disability and is known to have multifactorial causes with defects in highly unsaturated fatty acid metabolism thought to be one possible underpinning factor [15]. In children with Attention Deficit Hyperactivity Disorder (ADHD), omega-3 levels have been shown to be lower compared with controls [16,17]. For example, one assessment using blood samples from 565 children aged 3 to 17 years found that children with Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Disorder (ASD) had low levels of EPA, DHA and arachidonic acid (ARA) and higher ratio of n-6/n-3 which corresponded with their symptoms [18]. A meta-analysis (based on 10 studies) concluded that omega-3 levels may contribute to reducing emotional lability and oppositional behaviour in subgroups of children with ADHD [17].

Unfortunately, children who move around the system may have a poor omega-3 status such as those in care (Looked After Children). They also have far higher rates of learning difficulties. The two factors may be linked. Greater knowledge and attention to their nutritional status could help to place them on a more positive path earlier on in life [19]. This may be particularly important if we consider the impact of early childhood adversity as childhood omega-3 status also tracks back to the periconceptual period with low DHA and ALA intakes in pregnancy and lactation correlating with infant and childhood fatty acid status [20,21].

Unlike most other developmental disorders ADHD is treated with medication along with psychological interventions. ADHD is a complex condition where performance on cognitive tasks is reduced compared with neurotypical individuals [22]. Presently, in the USA alone the economic burden of ADHD due to medication costs is estimated to be 77 billion dollars [23]. Typically, methylphenidate (MPH) is the firstline pharmacological treatment for ADHD. However, side effects such as sleep disturbances, growth and appetite reduction are reported for some children [24]. Whilst traditional stimulant medications have a role to play in ADHD management there have been concerns about their long-term use amongst children with ADHD [24-26].

Taken together, the present paper sets out to evaluate the role of omega-3/6 fatty acids in relation to aspects of learning in children and young people, particularly in the context of ADHD management.

The National Centre for Biotechnology Information (NCBI) search engine (PubMed) and Rayyan software used to create systematic reviews [27] were used to extract relevant publications. For inclusion, studies were undertaken during the last 5 years (January 2012 to September 2017). All publications were English-language human randomised controlled trials conducted on children or young people aged 3 to 18 years. Recent evidence has shown that the identity of omega-3 can successfully be blinded to participants [28]. Articles were excluded if they were published before 2012 or a pilot study.

Key search terms included omega-3 and omega-6 fatty acids combined with ‘attention deficit hyperactivity disorder’, ‘autism spectrum disorder’, ‘developmental coordination disorder’ (including brain dysfunction), ‘cognition’, ‘attention’ (including concentration and disruptive behaviour), ‘learning’, ‘literacy’, ‘reading’, ‘spelling’ word blindness, dyslexia and dyspraxia) and ‘behaviour’. The search focused on ‘children’ and ‘young people’ which included those who were looked after or institutionalised.

Data files extracted from the NCBI collection depository and Rayyan software were evaluated with the following being collated: 1) Author and country of research, 2) Subjects (number of participants, gender, baseline health and conditions), 3) Mean age, 4) Study design and methods, 5) Type and dose of supplements and 6) Main findings (Table 1).

Table 1: Omega 3/6 fatty acids and aspects of learning.

The NCBI and Rayyan Systematic Reviews software search identified 31 papers meeting the outlined criteria. A total of 1192 publications using the specified search terms were identified [27]. Once the RCT criteria was applied a further 1111 studies were excluded. A further 48 studies were removed as the abstract was not written in English language. This left 33 studies meeting the systematic review criteria. Further evaluation of abstracts identified one pilot trial and one methodological review. Subsequently, a further 2 publications were excluded leaving 31 RCTs in the final analysis. Two of these papers were replicas but have been included as different aspects of the papers related to different two outcomes screened – ADHD and educative outcomes [29,30]. Subsequently, the sample size projections were equated from 29 studies.

The algorithm of the qualifying publications is shown in Figure 1. Of these, six studies were conducted in the UK, four in Europe, six in the USA, three in Australasia, three in Mexico, two in Asia, two in Israel, two in Iran and one in India. Twenty-two studies (n=3,336) showed overall benefits, ranging from improvements in blood fatty acid levels to improved sleep (Table 1) [6,12,25,29-48].

Figure 1: Algorithm for identifying trials.

ADHD

Amongst those with ADHD learning difficulties and disabilities are typically present whilst hyperactivity may or may not occur [49]. Fourteen RCTs recruited children or young people with ADHD at baseline. The age range of children and young people included extended was from 4-18 years (Table 1). One trial focused on the safety of phosphatidylserine (PS) enriched with 300 mg omega-3 fatty acids (namely EPA) finding that this was safe and well tolerated when taken by children with ADHD for up to 30 weeks [35].

Over half of the trials (8 studies) focusing on ADHD reported general benefits in symptoms [25,29-32,40-42]. Three studies provided a 9:3:1 ratio of fatty acids (558 mg EPA, 174 mg DHA and 60 mg GLA; Equazen) with two showing notable improvements in ADHD scores [25] and blood fatty acid composition which correlated with improved ADHD symptoms (defined as responders) [40]. In terms of broader aspects of learning improved attention, spelling and reduced oppositional behaviour were evident amongst 53 Australian children (n=53) taking EPA, DHA and LA supplements over 4-months [29].

Similarly, another 4-month trial found that omega-3 supplementation (particularly DHA) improved ADHD symptoms along with word reading, spelling, the ability to divide attention, reduced parent-rated oppositional behaviour, hyperactivity and restlessness in children with ADHD and comorbid learning difficulties [30]. Other studies showed that PS-omega-3 when taken over 30 weeks reduced children’s ADHD symptoms with effects being more prominent amongst those with hyperactivity-impulsivity, emotionally and behaviourally-dysregulated ADHD [41].

With regard to adjunctive roles, in one 12-month randomised study of 90 children taking either omega-3/6 fatty acids (the ratio was 9:3:1 EPA; DHA: GLA; Equazen), MPH or a combination found that ADHD symptoms reduced significantly amongst those taking omega-3/6 and MPH whilst Clinical Global Impressions–Severity (CGI-S) scale scores (a measure of symptom severity) decreased slowly and consistently amongst the omega-3/6 group [25]. In another study where ADHD children were being treated with MPH, they were allocated to take a capsule containing omega 3 and 6 fatty acids over 6 months. Statistically significant improvements were noted at 6-months in attention, cooperation with teachers and parents and impulsivity with reporting’s of academic performance, completion of work, restlessness and aggressiveness was also found to improve [42]. A smaller 4-week RCT comprised of 50 Indian children with ADHD noticed that those taking Atomoxetine along with 180 mg EPA and 120 mg DHA had reduced ADHD scores (along with inattention and hyperactivity) particularly in the combined type of ADHD [31].

Two studies looked at foods as a vehicle for omega-3/6 delivery. Amongst 174 Chinese children with ADHD (and lower IQs) eggs enriched with EPA and DHA over three months improved erythrocyte fatty acid profile and visual acuity [33]. A 16-week study recruiting just boys found that daily margarine consumption providing 650 mg EPA/DHA reduced ADHD symptoms and parent-rated attention in children with ADHD and typically developing children alike [32].

Other studies report more generic benefits. For example, an Iranian double-blind trial consisting of 103 children found that 635 mg EPA and 195 mg DHA reduced markers of oxidative stress and inflammation when taken over 8 weeks [36]. Other German research comprised of 95 six to 12-year olds showed that an omega-3 fatty acid mix taken daily over 16-weeks improved EPA and DHA erythrocyte levels and children’s working memory [34].

Some studies reported limited effects. A 12-week trial consisting of 76 male adolescents with ADHD allocated to omega-3/6 fatty acids or a placebo did not observe any significant effects in the Conner’s Teacher Rating Scale, aggression, impulsivity, depression, or anxiety [50]. A small Iranian trial (n=40) did not support the efficacy of PUFA in ADHD although reductions in Parent ADHD Rating Scale Scores (for impulsivity) were significantly higher in the PUFA group after adjustment for the effect of age, sex, and dose of methylphenidate [51].

ASD and other conditions

Autism Spectrum Disorders (ASD) impact considerably on learning and communication that can affect around 1% of children (USA data) [52]. To date three studies have investigated the effects of omega-3/6 fatty acids in relation to ASD or other learning conditions.

In an internet-based RCT five to eight-year olds (n=57) with autism taking 1.3 g of omega-3 fatty acids daily over 6 weeks had reduced hyperactivity compared with the placebo group, although this was not statistically significant [37]. A similar sized trial tested the effects of DHA supplementation (200 mg/d over 6 months) on the main symptoms of ASD amongst three to 10 years olds (n=48). Whilst those receiving the supplementation experienced a 431% median increase in plasma DHA levels no statistically significant effects on the main symptoms of ASD were observed [53].

Tourette syndrome (TS) is another common neuropsychiatric disorder in children where motor and vocal tics are presented which can vary in severity [54]. A recent double-blind RCT allocating 33 children with TS to either omega-3 fatty acids or an olive oil placebo over 20 weeks observed some benefits in relation to reduced tic-related impairment [38]. Unfortunately, the small sample size and olive oil placebo may have confounded the strength of these results.

Cognition

Amongst healthy school-aged children there is growing evidence that omega-3 fatty acids including DHA can have favourable roles on aspects of cognition or behaviour [55]. Five studies focused on omega-3/6 fatty acids and aspects of cognition, with varying effects. Amongst older malnourished Mexican children (8 to 12 years) 3-month omega-3 supplementation improved 11 out of the 18 neuropsychological variables studied in more than 50 per cent of children [39]. Alongside this processing speed, visual-motor coordination, attention and executive function improved in more than 70 per cent of the omega-3 supplemented children [39].

Amongst a UK sample of healthy mainstream children taking DHA/EPA over 16-weeks few cognitive effects were observed and one was in favour of the placebo group [43]. An Australian trial found DHA to be less effective than EPA (EPA appeared to help their brains work ‘less hard’) at improving neurocognition in young people after 30-days of supplementation [56]. One UK trial which recruited young adult females found that DHA supplementation (400 mg/day over 50- days) had no effects on cognitive enhancement [57]. Similarly, a Swiss trial involving anaemic children found that DHA/EPA did not help to improve cognition, working memory or memory retrieval [58].

Educative outcomes and behaviour

Six studies evaluated omega-3/6 fatty acids in relation to educative outcomes or aspects of behaviour. Amongst main school children a double-blind trial found that omega-3/6 supplementation improved 9-10 year olds reading ability – particularly clinically relevant ‘phonologic decoding time’ and ‘visual analysis’ time [6]. These findings were even more pertinent amongst children with attention problems who showed significant treatment benefits [6]. Another 12-week trial carried out on typically developing East End London teenagers aged 13 to 16 years found that disruptive behaviour improved in the active supplement (EPA and micronutrients) but declined in the placebo group [12]. One trial recruiting children from the community found that drinking a fruit beverage containing 1 g/day of omega-3 over 12 months led to significant post-treatment reductions in antisocial and aggressive behaviour [44].

In the UK DHA Oxford Learning and Behaviour (DOLAB) study an algal-derived DHA supplement taken over 16-weeks was found to improve reading in those who were initially underperforming (baseline reading performance ≤ 20th centile) and reduce parent-rated behaviour problems [45]. Two other trials recruited children with ADHD at baseline. For example, a randomized crossover trial observed that EPA, DHA and LA supplementation over 4-months significantly improved children’s attention, spelling and oppositional behaviour whilst reducing hyperactivity [29]. Equally, earlier work by the same team of scientists found that omega-3 PUFA improved literacy and behaviour in 7-12 years old with ADHD [30].

Other

Three studies have looked at other effects of omega-3/6 fatty acids which could indirectly affect omega fatty acids status and ability to learn. For example, a recent 12-week RCT providing 7 to 14-year olds with omega-3/6 fatty acids showed that children with a higher body weight had lower levels of EPA and DHA accumulation indicating that dosing may need to be based on weight [48]. Similarly, another recent trial observed that supplementation with 2 g/day of omega-3 fatty acids substantially increased blood levels, more so in smaller children, implying a possible U-shaped curve in relation to bodyweight and omega response [46]. Increased EPA also correlated positively with children’s clinical mood response [46].

A third trial focusing on sleeping patterns in healthy children aged 7 to 9 years discovered that providing algal DHA daily over 16 weeks was associated with on average of 7 fewer waking episodes and 58 minutes sleep more per night compared to the control [47].

Discussion

Latest evidence indicates that children of today have altered omega-3/6 fatty acids profiles with a tendency towards inadequate omega-3 status [10-13,59]. There are many underpinning reasons behind this. Low intake of oily fish is one with latest evidence showing that children aged 4 to 10 years eat just 2 g of oily fish daily (less than one-fifth of a portion per week) [60]. Equally, evidence from meta-analysis publications implies that fatty acids profiles are altered amongst children with ADHD and ASD with a tendency towards lower EPA, DHA and ARA levels and a higher ratio of omega-6 to 3 fatty acids, with a possible genetic aetiology underpinning this [16,17,42].

From the RCTs evaluated 8 trials found that omega-3/6 fatty acids may help to reduce ADHD symptoms in school-aged children and young people [25,29-32,40-42] which has the potential to assist them in the context of classroom learning. A growing body of evidence also suggests that omega-3/6 fatty acids have an adjunctive role to play, helping to lower the dose and compliance with ADHD medications such as MPH, particularly when taken in a 9:3:1 ratio of EPA to DHA and GLA [25,61]. For example, a combination of omega-3/6 with MPH has been found to permit lower doses of MPH (monotherapy, 1.0 mg/kg/day; combination, 0.8 mg/kg/day) [25]. A recent critical review paper concluded that two patient groups could benefit from omega-3 fatty acids: 1) Those with mild ADHD where these could replace stimulant treatments and 2) Those with severe ADHD or side effects from stimulant treatments where omega-3 fatty acids could reduce the amount of stimulant medication needed and resultant side-effects experienced [61]. Meta-analytical work has also demonstrated that omega-3 supplementation monotherapy can improve clinical symptoms and cognitive performance in children and teenagers with ADHD indicating that this may be a suitable treatment option [62]. Where studies yield inconsistent findings the dose and ratio of fatty acids should be considered alongside methodological rigour.

Benefits of omega-3/6 fatty are apparent in healthy mainstream children indicating an extended role for omega 3/6 supplementation, particularly in relation to improving aspects of literacy such as reading ability, phonological decoding time and visual analysis [6], behaviour [12] and antisocial tendencies [44]. In terms of underpinning mechanisms research using sustained attention tasks shows that omega-3/6 supplementation can increase in brain activation in the prefrontal areas and improve task performance in both typically developing children and those with ADHD [56,63]. So, it seems that the effects of omega-3/6 fatty acids may involve attention networks rather than being mediated by dopaminergic cognitive control networks [32]. This may be one reason why there were some inconsistencies in findings amongst studies focusing on cognitive performance.

It is also evident that the role of omega-3/6 fatty acids appears to impact on other aspects of children and young people’s health, such as their sleep [47] and mood [46]. A recent cross-sectional study has also shown that an elevated omega-6 to 3 ratio was associated with an increased risk of mood disorders in young people with an ultra-high risk (UHR) phenotype [64]. These areas, in particular, also warrant further observation and study. Body weight is another interesting area, with recent suggestions that tailored omega doses may be needed according to children’s and young people’s body weight [46,48].

Clearly, in order for the effects of omega-3/6 fatty acids to have clinically significant effects these need to be taken in a suitable ratio, dose and for a sufficient duration, ratio and in an adequate dose [31]. In several studies a 9:3:1 ratio of EPA to DHA and GLA has been used with clinical efficacy – improving fatty acid blood composition [40], ADHD scores [25] and reading ability in mainstream children [6]. As erythrocytes typically only survive in the body for around 120 days supplementation trials shorter than this may not be long enough to detect changes in fatty acids concentrations and compositions [9,50]. Furthermore, the turnover of fatty acids in the brain is thought to be rather low in 6 to 12 years old, indicating that longer periods of supplementation and/or higher doses may be needed to modify the fatty acid content of their central nervous system [65]. Future studies should also account for possible interaction effects of age, apoliprotein E genotype, gender and include brain imaging techniques to further study underpinning mechanisms [9]. In some studies, the absence of a measure of baseline fatty acid status, such as percentage of DHA in erythrocytes or monitoring of subsequent changes is another design weakness that can make the generality of some findings uncertain [57]. It is also possible that certain outcome measures such as the Connors Teaching Rating Scale are not sensitive enough to detect small improvements in behaviour [66]. Teacher rating scales have been regarded as being problematic and multiple questions have been raised regarding their reliability [66].

With regard to general limitations more RCTs are needed for other learning-related conditions and problems such as ASD, dyslexia and Developmental Co-ordination Disorder (also known as Dyspraxia) alongside continued research into the significance of maternal omega-3/6 fatty acid consumption. Whilst some studies indicate general dietary inadequacies [67] and selective eating habits [68] amongst such groups, detailed trials are needed. There is also some evidence that brain inflammation may be involved in the pathogenesis of neuropsychiatric diseases such as autism [52] which could impact on omega-3 requirements. The effects of nutrient combinations (zinc, magnesium, iron) alongside omega fatty acids also warrants further study as this may provide greater benefits than isolated nutrients [69]. More focused research is also needed on under-represented groups such as looked after children who are more likely to be omega deplete.

In conclusion, a growing body of evidence indicates that supplementing the diet with omega-3/6 fatty acids may help to reduce ADHD symptoms in children and young people and could assist mainstream school populations. Latest clinical evidence points towards improvements in reading, spelling, attention and behaviour, in particular. Strongest evidence exists for those with: 1) ADHD or comorbid conditions. 2) Suboptimal omega-3 status or 3) Academic underperformers. It is now important to communicate such findings to early year’s providers, parents, carers, schools and those who are in contact with children and young people that could benefit from omega 3/6 fatty acids during their years of learning.

This review was supported by Equazen. The views expressed are those of the authors alone and Equazen had no role in writing the review.

Many thanks to Dr J Delange for helping to identify key scientific papers for this review.