3
Causality and the Environmental Hypotheses of ADHD
What causes ADHD? Despite such book titles as Joel Nigg’s excellent What Causes ADHD? [184], there is no definitive answer.
The etiology of ADHD is a psychiatric holy grail. Owing to the problematic nature of ascribing a cause to ADHD, a number of theories have emerged. Such theories have ranged from birth complications to too much television, then to the ever-popular poor diet and often back to the bad parent. Some of these theories are amazingly resistant to change, despite scientific objection. Such resistance is possibly due to their simplistic explanations, thus allowing them to gain momentum in the general media and the general population. Changes in brain function in ADHD are less sensational and more complicated than the “I blame the parents/teachers/television” views.
In my opinion the most persuasive evidence for a cause of ADHD comes from biomedical studies. In particular the areas of genetics and neuroscience have made outstanding contributions to our understanding of the disorder. However, such studies are not definitive and they fall short of an answer; the question of etiology still remains.
In order to find the most compelling case for a cause of ADHD, we have to evaluate the evidence. In criminal law, without direct evidence from one conclusive source (e.g. CCTV footage of the crime which clearly identifies the accused), the prosecution has to gather evidence from wherever possible – such as expert witnesses or forensics. On the other hand the defense has to disprove the case or at least place reasonable doubt on the prosecution’s account. The case for a neurobiological cause of ADHD has now gained momentum. No one single branch of science alone can conclusively identify the root cause, but by bringing along expert witness from the fields of genetics, psychiatry, neuroscience, psychopharmacology, and psychology we can build up the most convincing picture of etiology in ADHD. However, the defense (the anti-psychiatry lobby) will try to reduce the impact of such arguments and invoke alternatives such as the playground-friendly bad-parent hypothesis.
Clearly from the way I write I am biased. I have put neurobiology into the virtuous position of the prosecution – the upholders of rights and honesty. Other explanations I have relegated to the dubious art of defense. However, it is essential that a dialogue be continually made between the two sides. Without the argument, one standpoint would gain overall power of explanation in which evidence and discussion would not be required (this could lead to a frightening Kafkaesque world). Whilst this may appear somewhat less important, it is essential to remind us that medicine, psychiatry, and genetics, in particular, have been guilty of abusing their position. One only has to read the accounts of what happened during World War II, with the Nazi use of medicine to justify their policies, to realize how science and medicine can be severely misused [185].
Causality
Finding causality in some sciences is an easy academic exercise. In the psychological sciences it is a great challenge. In fact the word “cause” is often avoided, with tentative words like “association” or “link” being used to avoid grandiose statements reflecting causality. Furthermore, the search for a single cause may be futile; there is every chance that ADHD is a disorder of multiple etiologies.
The diagnostic manuals are also careful to avoid discussing the cause of ADHD. Instead they provide a reliable description of symptoms without reference to any underlying mechanism, neurobiological or otherwise.
The accuracy of diagnosis is paramount in searching for etiology. If we have poor measures of diagnosis, then the scientist’s job becomes all the more difficult. How can you find the cause of something when you don’t even know what it is in the first place? Although this is a somewhat extreme position, we have to accept the limitations of past and present accounts because of the changing nature of the diagnosis of ADHD.
Causality is difficult to pin down; we will have to look at evidence that is not direct or experimental in the true scientific sense. In science, if we have a question, we generate an experiment to see if it is correct or incorrect. ADHD is a human condition, and as such we cannot inflict it upon someone for experimental purposes; we cannot use children in an experimental situation. We can only make inferences about etiology from a retrospective standpoint: that is, looking at connections between events in a person’s history and the onset of symptoms. There are very few prospective studies that address ADHD, and such studies are costly in money and time – a potential lifetime.
Given that we cannot experiment on individuals by attempting to inflict ADHD, we have to find alternatives; the questions are too important not to be answered. To get around this problem, scientists are able to use animals – especially, but not exclusively, the rat. Whether we like it or not, animals are used in experiments. The concept of vivisection is of course highly contentious.1 However, animals are used and the results obtained from animal studies need to be addressed. The data from such animal studies require close scrutiny, but the information obtained can be invaluable and should not be discounted if credible. Such experiments allow direct manipulation of the animal’s biology to determine the behavioral effects.
Animal Models of ADHD
Despite the title of Kathy Hoopman’s All Dogs Have ADHD [186], clearly ADHD is not a problem seen naturally in animals – in fact some of the symptoms may have distinct evolutionary advantages to the animal [187]. Scientists, however, are able to manipulate a normal animal in order to mimic some of the symptoms of ADHD.
Animal models have several distinct advantages over using humans. The researcher can use experimental methodology and can control, for example, the genetic heritage, history, environment, and diet of the animal. In contrast, humans come with excess historical baggage that is difficult, if not impossible, to control for in experimental situations. Despite the advantage of animal models (namely the full control of the experiments), the modeling of neuropsychiatric disorders is in itself a science that requires close scrutiny and analysis [188–189]. The use of animals in psychiatric studies is an area that perhaps most people have some difficulty in comprehending, not the least because of the ethical dilemma, but also because it is not immediately apparent that we can extrapolate from the animal to the human. After all, what does a rat’s behavior tell us about the complexities of human behavior? To use animal models of behavior, we have to be aware of their limitations and do the utmost to ensure that the behaviors seen in the animals are centrally important to ADHD. How we achieve this has been debated, but guidelines provided by Professor Paul Willner have helped to establish the level of confidence one can have in using an animal model for ADHD [190–191]. According to Willner,
Models are tools. As such, they have no intrinsic value; the value of a tool derives entirely from the work one can do with it. … An assessment of the validity of a simulation [model] gives no more than an indication of the degree of confidence that we can place in the hypothesis arising from its use. [188] (p. 7)
The central components of assuring confidence in the animal model are predictive validity, face validity, and construct validity [189]. These are areas associated with the evaluation of psychometric tests, such as the rating scales, that have now been applied to animal studies.
Predictive validity allows questions about ADHD that cannot otherwise be addressed in the clinical setting, such as genetic manipulation, lesions of the brain, etc. Predictive validity comprises three subcomponents:
1 The animal model should be exacerbated by conditions that make the symptoms worse, e.g. certain environments or conditions, stress or drugs exacerbate ADHD symptoms.
2 The animal model should respond to all classes of clinically effective drugs, e.g. in the case of ADHD the animal model should be normalized by methylphenidate (Ritalin, Equasym, Concerta), atomoxetine (Strattera), or amphetamine.
3 There should be a correlation of potencies of these drugs to exert an effect in the animal model and the clinical setting, i.e. the doses used should translate from the clinic to the animal model and not be widely different.
Face validity refers to similarities seen between the symptoms of ADHD and the animal model’s behavioral repertoire. However, the description and categorization of ADHD symptoms are not fixed (note the changes in DSM criteria for ADHD). As the scientific knowledge of ADHD increases, the animal model should be able to assimilate this new information; if not, the animal model will need to be reappraised in the light of the new information and modified accordingly. Another feature of face validity is that the symptoms should be from a coherent cluster relevant to ADHD and not from a diverse set of behaviors; the central aspects of impulsivity; attention, and hyperactivity would be the best symptoms modeled [48]. ADHD is highly comorbid with other disorders; thus we need to make sure that we are describing ADHD in the animal model and not ADHD plus another disorder.
Despite its nature, there are difficulties associated with face validity. In particular we do not have a definitive view of ADHD, despite diagnostic criteria. If the central symptoms are not clearly identified and unique to ADHD, we cannot be entirely confident in the animal model. This criticism is not unique to ADHD and is common to many psychiatric problems. We should note this as a shortcoming and move on – diagnosis is not fixed and nor is our knowledge; we will need to account for new data within the animal model and hopefully this will get us closer to the truth of the neurobiological bases of ADHD.
Rats (and other animals) are not like humans in many ways. Different species will not always appear to have identical behaviors (i.e. have clear face validity), but some behaviors which are different across species have a similar theoretical and physiological basis. Thus construct validity bridges the gap between the disorder and the behavior seen in animals. Construct validity is the hardest of the three criteria to achieve. Construct validity is the theoretical rationale that is used to account for the symptoms comprising the disorder (e.g. many consider impulsivity as the central construct of ADHD).
To illustrate construct validity, Willner uses maternal behavior as an example. The human mother cares for her child, as does the rat mother her offspring – that is the maternal concept. However, the rat mother does not change her baby’s nappy, nor does she take it to baby groups. The rat’s maternal instinct is demonstrated by retrieving her offspring when it has been removed from the nest. She does this by picking it up in her mouth by the scruff of its neck and returning it back to the nest. Clearly we do not pick our children up by the scruff of their neck with our teeth, but the underlying principle of caring for one’s offspring is the same.
There are three steps to achieving construct validity: (1) identification of the variable – the behaviors to be modeled, e.g. inattention, impulsivity, and hyperactivity; (2) the degree of homology between the two behaviors, e.g. whether the hyperactivity seen in the classroom is similar to the increased rearing on the hind limbs of a rat in a cage; and (3) the significance of the variables in the clinical picture, e.g. whether they are trivial behaviors in the great scheme of ADHD symptoms or are at the heart of the disorder (i.e. impulsivity).
An animal model of ADHD can be achieved by manipulating the animal. It could be via surgery, pharmacology, or breeding/genetics. There have been a number of animal models of ADHD, e.g. hyperactive rats selected from other less active rats [192], rats that are reared away from other rats in social isolation [193], rats exposed to toxins [194], rats with anoxia [195], rats with brain lesions [196–200], genetic breeding manipulations [201], and recently the identification of ADHD in dogs [202]. There is even the possibility that ADHD symptoms can be modeled in robots [203]. Quite why anyone would want a robot with ADHD is beyond my imagination, but such studies are of academic interest! Of all the animal models of ADHD, the most used is the spontaneous hypertensive rat (SHR) [204]. That is hypertensive not hyperactive. The SHR is a genetic model of ADHD and these are hyperactive during 3–4 weeks of age. They have also been shown to have behaviors such as impulsivity and a lack of sustained attention (see [205] for review). The SHR has good face validity and predictive validity [191]. However, when it comes to construct validity, we cannot be as confident. In the chapters that follow we will see that our theoretical understanding of the processes that have gone wrong in ADHD are hotly contested. Without a unified consensus on what the construct is in the human, the attempt to gain this in the rat and for it to be valid is somewhat distant. Another limitation of this model of ADHD is the short window of opportunity that is available when using the SHR. After 4 weeks of age the rat is hypertensive, which is therefore different from ADHD (see [205]). It would be of considerable benefit if we could chart the developmental trajectory of ADHD in the rat and not at this very specific time in development.
Despite the above limitations, the SHR is an important tool in studying the processes in ADHD – it just happens to be an imperfect tool.
The Environment
In the context of this chapter the environment is everything that impinges upon the organism. Changes in the environment as a causal factor have not been restricted to just ADHD. One review noted that there was an increase in a number of childhood problems such as diabetes, asthma, hay fever, autism, cancer, and obesity [206].
The environment in utero: pregnancy, birth complications, and teratology
The brain is a delicate precision instrument that can be affected during development at numerous stages, from conception through to death. Owing to its delicacy, it has to be protected, and in utero the protection for the environment is via the mother’s body. It is of great interest to science to determine if irregular pregnancies or birth traumas are a cause of ADHD; the evidence points to a number of factors that should be considered in studies of the disorder [207]. Clearly damage to the brain in utero can have devastating consequences, as evident in, for example, Fetal Alcohol Syndrome (FAS) [208].
The literature on birth complications as a causal factor of ADHD is inconclusive. Some have found an effect of prenatal complications such as eclampsia or those needing assisted delivery [209–210], whereas others have not found such a link [211–212]. One has to exercise a degree of caution when assessing the impact of birth interventions such as forceps delivery or Ventouse, which have been associated with developmental delays [213]. The mere fact that assistance is required indicates that there are already problems with the delivery. These problems necessitating assistance may by themselves be a risk factor. Other features of pregnancy, such as nausea, especially towards the end of pregnancy, have been associated with a rise in behavioral problems [214], but again the reason for the nausea needs elucidation. In a study of twins, which assesses the genetic component of ADHD, Sharp et al. [215] found that the affected twin was more likely to have experienced a difficult birth and be of a lower birth weight. Given the large genetic component associated with ADHD, it might be considered somewhat surprising that an interaction between pregnancy/birth complications and genetic factors did not emerge [216]. This latter study placed the focus on birth complications, especially hypoxia [reduced oxygen to the brain], which may lead to neural damage (see [217]), and has since been supported by a Canadian study [218]. That is not to say that genetics are not implicated, but the mechanisms of interaction are far from understood.
The studies looking at birth trauma and interventions do not account for a single cause of ADHD; not everyone who has ADHD has had complications in utero or at birth, and conversely not everyone with birth complications has ADHD. Indeed birth complications are associated with numerous outcomes, not just ADHD [213]. A Polish study looked at birth complications and breast feeding in a group of children who were classified (but not diagnosed) by rating scales as having ADHD by the ICD-10 criteria. Unlike earlier studies, they did not find an effect of birth complications, but they did find a reduced duration of breast feeding with ADHD [219]. Given that ADHD infants are more likely to bite, this is not surprising, and we cannot conclude from this study that breast is best and its absence a causal factor in the disorder.
A number of factors complicate the appealing judgment that events during pregnancy and birth are linked to ADHD. Factors such as the sex of the child (males are more vulnerable), parental education, socio- economic status, and age of mother are all mixed in with the pregnancy factors [220–221]. Premature births have been associated with ADHD [222–223], and low birth weight remains a frequent factor in those with ADHD [224–226], although, in general, low birth weight was associated with attentional problems rather than hyperactivity [227–228]. Of course, there are many reasons for a low birth weight, such as smoking and alcohol use, both of which are implicated in ADHD. A study by Mick et al. [229] controlled for such variables and found low birth weight may explain 13 percent of ADHD cases.
Finally, mothers’ obesity and overweight were associated with ADHD symptoms in their offspring [230], so there is yet another benefit from a healthy diet prior and during pregnancy. Quite how this can be incorporated into a comprehensive theory of ADHD is unclear, but the evidence is beginning to emerge that obesity and ADHD may share some common mechanisms, in terms of both genetics and neuropharmacology [231–237].
Smoking during pregnancy is a risk factor for many adverse outcomes [238]. Not surprisingly, maternal smoking has been associated with a greater risk of ADHD symptoms [239–244]. A recent study by Thapar et al. [245] has studied smoking in mothers who have had assisted conceptions. They looked at mothers who were and were not genetically related to the offspring. Such a design should be able to differentiate smoking from genetic influences. They found that smoking did have an effect on weight, but not on ADHD symptoms; symptoms of ADHD were higher in the related mother and not the unrelated mothers, thus genes may play a role in ADHD.
Whilst there are other variables that may be linked to maternal smoking during pregnancy, e.g. mother’s age and educational level, the question remains: Is it smoking, or is it the nicotine that is the main culprit? When smoking a cigarette, one is inhaling some 4,000 chemicals, one of which is nicotine – the one that is addictive. Smoking has many effects on the unborn child, such as hypoxia [246]. Hypoxia has been suggested as a possible factor in causing ADHD [247] and has been linked with the regions of the brain that are thought to be dysfunctional in the disorder [248]. There are few studies that have looked at hypoxia in humans; those that have have not found conclusive evidence [249]. However, that is not to say that there is no effect; it may just be too subtle to detect and be part of other complications. To understand these differences, further experimental studies in animals have been undertaken which have found some degrees of support for hypoxia in the manifestation of symptoms associated with ADHD and the neurochemistry and neuroanatomy of the disorder [250–253].
That leaves us with nicotine. In human studies it is impossible to disentangle smoking and nicotine. However, animal studies are able to address this question experimentally. Prenatal exposure to nicotine has been demonstrated to increase hyperactivity in rat offspring [254–258] and cause cognitive deficits [259–260] and impulsivity [261]. How this exposure achieves such changes is still subject to scrutiny, but it does alter nicotine receptors in the brain, which is dependent upon the stage of development [262]. Furthermore, prenatal exposure to nicotine has effects on developing dopaminergic neurons, which one might expect if ADHD was all down to the brain chemical dopamine (see chapter 7), but the effect of nicotine is far greater on noradrenergic systems (those using noradrenaline or norepinephrine, to use its name in the USA) and this has been argued to possibly contribute to some of the ADHD symptoms [263]. Many authors suggest that there is an interaction between genes and nicotine exposure [217, 264], with some suggesting a relationship between dopamine genes and nicotine exposure in utero [265].
Maternal alcohol consumption and fetal exposure has been associated with a number of adverse outcomes in offspring, including ADHD. When studies of alcohol have been done, however, there have been contradictory findings [266]. Unlike nicotine, alcohol is a complex molecule that interacts with many neurochemical systems and brings about behavioral [267] and structural changes to the brain [268]. The studies that have looked at alcohol have often studied large amounts of alcohol consumption. Such studies have been confounded by concomitant nicotine intake. If we look at alcoholic mothers, we are looking at something more than alcohol itself. We are looking at genetics, social environments, and much more besides. However, studies have found links between parental alcoholism and ADHD (e.g. [269]), whereas a recent study looking at low doses of alcohol did not find an effect on ADHD-like symptoms once smoking was taken out of the equation [270]. Furthermore, there was no difference between siblings who had been differentially exposed to alcohol in utero [271]. When it comes to high levels of alcohol exposure, a link to ADHD emerges [272]. Thus there may be a pseudo-dose response relationship between maternal alcohol intake and ADHD [273]. In a review of the literature surrounding Fetal Alcohol Syndrome, it was noted that these children also demonstrated higher levels of the ADHD-I subtype [274]. Such studies are not able to address causality, but do convey a risk factor. Experimental animal studies are supportive of a role of alcohol in ADHD symptoms [275–276] in which prenatal exposure reduces dopamine activity in adulthood [277]. However, the complex neuropharmacological mechanisms of alcohol need to be partitioned and explained in greater detail with regard to ADHD.
When looking at environmental influences or teratogens as potential risk factors in ADHD, the obvious candidates of trauma, smoking, and drinking have been met with varying degrees of support. However, two other variables are frequently associated with ADHD: low birth weight and sex.
Low birth weight is implicated either directly or indirectly as a consequence of smoking, for example. Low birth weight has been associated with the symptoms and prevalence of ADHD [228, 237, 278]. Removing the confounding variable of premature birth revealed little effect on higher cognitive or executive functioning [279], with only a small number of children being diagnosed with ADHD [280]; Mick et al. [229], moreover, state that it is a minor factor in ADHD. If low birth weight is a factor in ADHD, then it becomes necessary to understand the causes of low birth weight distinct from premature birth. It will no doubt be these causes that are important, and not low birth weight. Low birth weight is therefore just a correlation and evidence of another problem.
It is not surprising that being male is a risk factor; after all, the epidemiological data state that. However, in the context of risk factors, males may be more vulnerable to all the above-mentioned variables.
In an article titled “The Fragile Male,” Kraemer reviews the literature that points to males’ greater vulnerability from conception onwards [281]. The male embryo is more vulnerable to insult and trauma, with more resultant deaths [282]. At birth the female child is 4–6 weeks more physiologically advanced than her male counterpart [283] (cited by Kraemer [281]). However, a direct link between the intrauterine environment and ADHD has not been supported [284].
There are many other conditions that may affect the fetus so as to increase the likelihood of ADHD. Those who wish to read more about these other lesser factors should go to Millichap [285].
Not only are there risk factors in utero, but in the immediate months following birth, those with ADHD were observed to have had more neonatal problems involving surgery, anesthesia, and oxygen [218].
The environment: families and society
One cannot deny that there is an association between a dysfunctional family environment and ADHD [286–287], but is it the cause? Parents can be and are responsible for shaping and reinforcing good behavior; the same applies for bad behavior. However, the symptoms of ADHD go beyond such simplistic explanations. The focus on bad behavior, owing to its salient nature and obvious impact, can be misleading and serve only to divert the focus away from the neurocognitive impairments in the ADHD child that are thought to underlie the symptoms. One could argue that the very nature of ADHD and the solutions available make the parent an educated and highly efficient agent of behavior modification; that interventions can fail is less to do with parents and more to do with the disorder and its severity. Finding the cause of ADHD and attributing blame are different processes. Blaming the parents is not helpful; it may just alienate a group of people who are instrumental in changing behavior.
Most children are identified as having ADHD when they go to school. Changes to a more formal and performance-measured education system have been argued to be an exacerbating factor in ADHD. Has the increase in administrative workloads of teachers contributed to a lack of time and tolerance to deal with effective classroom management? Certainly the changes in education have an effect, but the system does work for the majority. We should not blame teachers in the same way we should not blame parents – although the evidence suggests that those working in the education system see the parent as the main culprit [3].
Society in general has also been identified as a causal factor in the increase of ADHD, and it is indeed appealing to attribute responsibility to modern society, with all the fast-paced changes it has undergone in recent centuries, for the appearance of the disorder. Cross-cultural studies investigating ADHD are illuminating here.
The argument that society and the way we live give rise to the behavioral pattern in some individuals is cited as a strong case against the neurobiological argument. The case is compelling, and to some extent I agree with it, but my counter-argument is that those with ADHD differ in their ability to adapt to these societal changes. You can blame society, but the question still remains: Why is it that approximately 5 percent of the population have ADHD and the remaining 95 percent do not? (Of course they may have something else, but that is another story). Remember it is easier to change an individual than a society, and if we do change society, it may be unsuitable for a different 5 percent of the population.
Food additives, allergies, and responses
The notion that certain food additives, such as colorings and preservatives along with sugars, can give rise to ADHD appears to be misplaced [288]. Perhaps these chemicals can transiently alter some behaviors in children which are also symptoms in ADHD, but the evidence suggests that they are not responsible for causing the disorder [289–291]. The diagnostic criterion for ADHD in the DSM-IV requires the symptoms to be present for at least six months and across different situations. The fact that the child has sugar-loaded chocolate or sweets and goes hyperactive is not going to fulfill the criteria necessary for diagnosis – it just means that it is best they do not have too much chocolate.
Again the portrayal by the media of a malevolent food industry grips the parental conscience, and such attitudes, once formed, can be remarkably difficult to change. Reports that have indicated a link between additives and hyperactive behavior do not imply a causal relationship [292], although others have suggested causality [293]. Studies that have looked at a general population of children have demonstrated increases in ADHD-like behaviors with additives [296] and these may be a risk factor in ADHD [294]. A recent report has indicated that artificial colors and/or a sodium benzoate preservative in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population [295]. The main offenders used in this study were:
- E110 – sunset yellow.
- E122 – carmoisine.
- E102 – tartrazine.
- E124 – ponceau 4r.
- E211 – sodium benzoate.
- E129 – allura red AC.
These were placed in a mixture, and therefore hyperactivity cannot be attributed to individual additives. Furthermore, the older children responded to two different mixes whereas the younger group responded to only one mix. And how they affect other component of ADHD remains to be determined.
Such studies suggest that food additives such as colorings and preservatives are not causal factors in ADHD, but they may exacerbate pre-existing conditions. Furthermore, it may be the case that the inclusion of food additives in the diet is a factor that pushes sub-clinical cases into diagnosed ADHD. This possibility is just conjecture and requires systematic investigation. In the meantime, additives are probably best avoided where possible.
Clearly it is advisable to look at diet. This should be from a general nutritional point of view rather than as a causal agent of ADHD, however. Where diet may be useful is as a part of a treatment plan within the context of the disorder [296].
Fatty acids in ADHD
The use of fish oils has gained considerable support. Their deficiency has been linked with several disorders [297] and has been argued to be linked to comorbidity [298]. Increasingly, research points to the role of fatty acids that can be derived from fish oils (e.g. omega 3) in learning and attention [299]. Research has led to an increase in the marketing and availability of products that aim to redress a potential shortfall of fatty acids in our diets. Studies indicate that increasing the levels of dietary requirements with supplements is beneficial [300–301], although earlier reports were not so positive [302–303]. The doubt that these early studies may cast on the role of fatty acids should not be taken too strongly, however; back in those days the quality of the supplements used was different to those in today’s research. Other studies that show negative effects of supplementation have methodological problems that reduce their utility, e.g. the use of a short time interval between commencement of treatment and testing (4 months) [304] and the concealment of the supplement in food, thus rendering the exact dose taken unknowable [305]. The studies that show a positive effect also need to be closely scrutinized; some have been funded by the companies that make the supplements, and thus a financial role in the results needs to be evaluated.
The exact mechanism by which fatty acids help is incompletely understood, but they appear to be crucial in the developing brain and involve dopamine (DA) and noradrenaline (NA), the two main neurochemicals implicated in ADHD [306]. In patients diagnosed with ADHD, the level of fatty acids was seen to be lower than in control groups [307–314], leading some to conclude that fatty acids might be linked to some of the behaviors seen in the disorder [315]. Furthermore a fatty acid deficiency syndrome (FADS) characterized by dry hair and skin, frequent thirst and urination [316] was also evident in ADHD, although Sinn has argued that FADS is not a good predictor of a positive response to fatty acid supplementation [317]. Supplementation with fatty acids in ADHD could be of some benefit in managing the symptoms, although the effects also tend to be evident is control groups [317–321] or in subgroups that had ADHD-I or comorbidities, e.g. learning difficulty and reading–writing disorder [322]. Furthermore, the picture of effectiveness is clouded in one study where parental ratings showed a statistically significant improvement but teachers’ ratings did not [318].
Maternal levels of fatty acids have been linked to brain development where reduced levels are associated with impairment both psychologically and physiologically in the rat [323–324] and human [325]. The effects of fatty acid deprivation in the rat are possibly reversible, depending on the time of the intervention with a supplement [326].
In a recent summary of the role of maternal fatty acids, Sheila Innis at the University of British Columbia points out that western diets are low in omega 3 and high in omega 6 (this is undesirable [327]), which could have a negative influence on brain development [29]. It is tempting to conclude that this is behind the increase in ADHD in western societies, but more needs to be done before we can say that with any degree of confidence.
Genetic studies have not found a conclusive link between fatty acid genes and ADHD, except where alcohol has been consumed during pregnancy [328], but obviously the presence of alcohol itself is a confounding variable. Others have suggested that the deficiency in fatty acids is a result of a faulty metabolism [329].
One also has to remember that during childhood and adolescence the brain is still developing (see [330]), even up to the age of 25 years; thus the brain is vulnerable to toxicological challenges (e.g. additives) and deprivation of essential nutrients (e.g. omega 3) at several different critical stages in its development throughout gestation and for a considerable amount of time after birth.
The data are limited on the effects of fatty acids on the developing human brain. A recent study has shown that the blood levels of fatty acids are reduced in adolescents with ADHD despite a similar intake with non-ADHD groups, thus supporting metabolic changes in adolescent ADHD [331]. Such studies are cross-sectional in design and take individuals at one point in their life and compare them against another group; clearly it would take a lot of time and money to follow a cohort of participants from birth to adulthood. Perhaps animal studies will help illuminate the role of fatty acids in development as rats reach maturity earlier. To date, research indicates that the effects of supplementation are dependent upon developmental periods [326].
Finally, supplementation with fatty acids appears to be of either no effect or of a positive effect. There are no reports to my knowledge that supplementation with fatty acids is harmful, and therefore its continuation may be warranted and not just for ADHD, although a good diet should avoid this necessity [332–333]. An interesting question that needs an answer is: If you are on the threshold of a diagnosis, does supplementation keep you sub-clinical?
Trace elements in ADHD
Trace elements such as iron and zinc have also been associated with ADHD. Iron supplements have been suggested as beneficial [334–336], on the basis that iron is essential in neural development and dopaminergic neurotransmission [335, 337–339], behavior and cognitive functioning [336, 340–342].
Studies have found a greater iron deficiency when ADHD is comorbid [343], and iron deficiency has been highlighted as a possible alternative to ADHD or at least should be eliminated during diagnosis (see chapter 2). The role of iron needs to be investigated further with regard to ADHD, as one recent study was not able to detect a relationship [307], and the possible use of iron supplements should be treated with caution, as there is a narrow spectrum of effect where toxicity becomes a problem if the dose is exceeded.
Another element that has been linked with ADHD is zinc (see [344–345]). Zinc is essential for the metabolism of carbohydrates, proteins, nucleic acids, and the fatty acids (see [346]). Studies have linked zinc deficiencies with ADHD [313, 345, 347–348], leading to suggestions that supplementation may be beneficial [314, 346].
The possibility of a zinc deficiency as the cause of ADHD needs further research. Interestingly, studies using zinc supplements have found it enhanced or predicted the response to ADHD medications [346, 349–350]. Perhaps the interaction would allow for either an improved therapeutic response or reduced dose of medication. Again this is conjecture and needs experimental validation.
Earlier, it was noted that lead poisoning should be ruled out as an alternative diagnosis to ADHD (see Table 2.1). Lead has been argued to produce ADHD-like symptoms in the monkey [351]. Early studies in children did not support the role of lead in ADHD [352]; however, in a more recent study children with ADHD were more likely to have been pre-exposed early in development to high levels of lead [353]. Early lead exposure has been associated with ADHD in other populations [354–355]. Such has been the concern that there has been a call for controls to be put in place concerning toxins [356] and for immigrants to the US to be screened for lead poisoning when suspecting ADHD because other countries use lead-based products more than the USA [357]. Furthermore, when we consider iron deficiency in ADHD, Konofal and Kortese have argued that iron is a protective agent against lead toxicity [358], with recent evidence seen in rats [359].
Television and computer games
Television viewing and the use of other electronic media, e.g. Internet and videogames, coincides with the perceived increase in the incidence of ADHD. The simple argument is too much television viewing or videogame playing is a risk factor contributing to the disorder.
Studies have found that more than one hour a day gaming is linked with an increase in inattention and ADHD-like symptoms in non-diagnosed adolescents [360]. A recent study was unable to find a difference in the time spent playing videogames between ADHD children and control groups, but behavior during game playing was different: ADHD children were less likely to stop playing of their own volition, and were more likely to show sign of videogame addiction [361]. Add to this the report that Internet addiction is associated with the symptoms of ADHD [362] and especially impulsivity [363] and the picture fits with reward theories of addiction (see chapter 9).
Before we decide that all videogames are bad, we should consider the benefits of the gaming format in evaluation and training of those with ADHD. Many dull neuropsychological tests may benefit from a more captivating format. Children with ADHD can perform poorly on videogames compared to non-ADHD groups, but this is dependent on the nature of the game and the task requirements [364], which has been argued to be comparable to actual neuropsychological tests [365]. Children with ADHD have difficulties with games that involve memory [364] and demonstrate increased risk-taking behavior [366]. By making the games more interesting, one can keep the person motivated – neuropsychological tests rarely do that!
Contrary to popular belief, there may be a cognitive benefit, as seen in expert gamers across domains such as attention and executive function [367–372]. The question remains: Can games be used to improve cognitive skills in ADHD? The answer is a possible yes! Computer games have also been argued to be useful in the treatment of ADHD and other psychiatric disorders such as anxiety and autism [373]. The positive effects of videogame play, coupled together with biofeedback, have been developed as a spin-off from a NASA project. Pope and Bogart [374] and subsequently Pope and Palsson (cited in [373]) developed the Extended Attention Span Training (EAST) system. EAST is a modification of NASA technology used to increase the mental engagement of pilots, but does this in the form of a videogame that responds to brain electrical activity (brain waves). SMART (Self Mastery and Regulation Training) is a modification of the EAST 2003 BrainGames system which has an interactive training tool that is compatible with Sony PlayStation videogames. The SMART BrainGames system uses biofeedback to make a videogame respond to the activity of the player’s body and brain. As the player’s brain waves come closer to an optimal state of attention, the videogame’s controller becomes easier to control, or if a player becomes bored or distracted and the brain waves change, then the controlling of the game becomes more difficult. This encourages the player to continue producing optimal patterns or signals to succeed at the game with improvements in attention and hyperactivity (further information can be obtained from the NASA website).2 Clearly some interventions to help ADHD are “rocket science”!
What about television viewing? Early exposure to excessive television has been linked to attentional problems in children [375], but these authors (Christakis et al.) are cautious of extending findings to the causality of ADHD. Television viewing may influence cognitive abilities, but it is not a factor in ADHD [376]. In 2006 a paper came out with the title “There is No Meaningful Relationship between Television Exposure and Symptoms of Attention-Deficit/Hyperactivity Disorder,” which should put an end to the story … for now [377]. Whether television viewing is a cause or consequence of ADHD remains unknown [378]. Indeed parents often comment that their child is only focused and sitting still when watching television. Therefore such activities as TV viewing may be masking the symptoms of ADHD (albeit temporarily) and provide respite for the exasperated parent. It would be extremely interesting to see how parents and carers use such activities as an adjunct to other interventions. Access to these media is often used as a reward during behavioral management; thus if they were detrimental to the individual their use as a reinforcer would be dangerous.
Summary
Looking for a single causative agent in ADHD may be a pointless exercise. If we accept that the brain is somewhat different in ADHD, then this aberration can still arise form a plethora of sources, ranging from toxins to birth trauma to environments. However, it is still important to find out how environments and biology interact to bring about ADHD. The only way to do this is through good science. Of course, ethics and morals mean we cannot apply putative causative mechanisms to induce ADHD within people or inflict it on them to see if our hypotheses are correct. The only way to do this is via animal experiments, but these too come with their own problems and need to be evaluated carefully. We will see in the remaining chapters how science has focused on a genetic-neurobehavioral hypothesis, but still searches for details of the elusive cause!
Notes
1 It is beyond the scope of this book to be able to provide a full account of the moral, ethical, and scientific use of animals in experiments. I recommend any reader who is interested in the debate to look at the websites of the British Union for the Abolition of Vivisection (BUAV) (http://www.buav.org) and the Research Defence Society (RDS) (http://www.rds-online.org.uk).