Etiological Factors in ADHD

1. Etiological Factors in ADHD Article: Maternal Lifestyle Factors in Pregnancy Risk of ADHD James H. Johnson, Ph.D. University of Florida

2. Etiological Factors • In recent years increased information has accumulated regarding the etiological factors in ADHD. • Unfortunately, findings are often inconsistent and not all of the findings fit neatly together. • And, many of the studies are correlational in nature thus making it difficult to infer causality. • Nevertheless, research has has provided some basis for drawing inferences regarding the causal factors in ADHD. • Taken together these findings strongly suggest the role of biological factors as primary contributors.

3. Pregnancy and Birth Factors • In reviewing factors that my contribute to the development of ADHD, it seems appropriate to start by again noting that ADHD has been found to be related to a variety of pregnancy and birth complications. • Examples include various types of complications that could result in oxygen deprivation. • Cord wrapped around neck • Meconium Aspiration • Forceps Delivery • ADHD has also been linked to certain physical health problems in the mother. Examples include • Toxemia • Eclampsia

4. Low Birth Weight • Low birth weight is another factor that has been linked with elevated rates of ADHD. • Here research has suggested that rates of ADHD in low birth weight children are significantly higher than in children of normal birth weight • For example, in one study of extremely low birth weight (<901 grams) infants , Stjernquist and Svenningsen (1995) reported 25% of the premature sample to have ADHD at age 4, while none in the normative sample met the criteria for this disorder . • Similar findings have been obtained with children displaying birth weights of <1,500 grams.

5. Low Birth Weight • Of note is another study by Astbury et al. (1987) who examined low birth weight children focusing on differences between those who did and did not develop ADHD. • They found that children who later developed ADHD were ones who showed more extensive signs of hypoxia and ischemia. • In reviewing this literature, Lou (1996) hypothesizes that ADHD arises from these early hypoxic and ischemic episodes due to the high susceptibility of the neurons of the striatum to hypoxic injury. • He theorizes that this damage to the striatum leads to a disruption in the self regulation of behavior.

6. Prenatal Smoking • Maternal smoking during pregnancy has been hypothesized as an environmental factor that leads to the development of both behavioral and cognitive impairments. • This is believed to be due to the fact that nicotine causes fetal brain damage secondary to prolonged hypoxia as well as through nicotine's hypothesized role in modulating the dopanergic activity of the brain .

7. Prenatal Smoking • Over the past several years a number of studies have confirmed the association between maternal smoking and ADHD. • As an example, in one such study, Milberger et al. (1996) found that 22% of ADHD children (vs. 8% of normal children) had mother's who reported smoking a pack of cigarettes per day for at least 3 months during pregnancy. • This study was limited in generalizability, however, as all children in the ADHD group were boys. • In subsequent studies with both males and females these investigators found maternal smoking to be significantly higher in ADHD children of both sexes than in normals.

8. Maternal Alcohol Use • Findings related to ADHD and maternal alcohol are mixed. • Studies clearly indicate that alcohol use during pregnancy can contribute to physical and mental impairments in heavy drinkers, as in FAS, as well as less severe impairments. • Multiple studies have also suggested a link between prenatal alcohol use and the development of ADHD - although this relationship has not been found in all studies.

9. Maternal Alcohol Use • For Example, a recent study of prenatal exposure to alcoholby Mick et al (2002) , which also studied smoking, foundthat twice as many children with ADHD had mothers who eitherdrank alcohol daily or binged heavily during pregnancythan children without ADHD. • However, negative results were found by Hill et al (2002), who used dichotomizedexposure data collected retrospectively. • In this study,the univariate association between alcohol exposureand ADHD disappeared after adjusting for familialrisk of alcoholism, intrauterine exposure to smoking, and information regarding alcohol and parentalpsychopathology.

10. Maternal Alcohol Use • Conclusion: While there are a number of studies that do suggest a link between prenatal alcohol exposure and ADHD, there are also contradictory findings. • In some studies no relationship is found after controlling for other relevant variables. • More good research is needed ! • Question: Does the apparent link between alcohol exposure and ADHD result from some factor (or factors) that contributes, both to maternal drinking and to childhood ADHD?

11. Minor Physical Anomalies • As has been noted earlier, there seems to be evidence that ADHD may be associated with early defects in embryological development. • These early problems in embryological development are often reflected in minor physical anomalies displayed by children. • They are reflected in morphological features such as unusually small or large head circumference, slightly misshapen ears, high palate, as well as other features.

12. Minor Physical Anomalies • Waldrop and her associates have suggested that the presence of multiple minor physical anomalies is associated with ADHD in boys. • Here the number of anomalies has been found to be associated with early age of onset and severity of symptoms. • These associations suggest that problems with early embryological development may be related to both minor physical anomalies and the development of ADHD, at least in males.

13. Other Pregnancy and Birth Factors • Month of birth has also been suggested to be related to ADHD. • Births in September are overrepresented among children with ADHD. • Of what relevance is month of birth – The best answer is we don’t really know. • It has been suggested that season of birth may serve to influence the timing of seasonally mediated viral infections to which mothers and fetuses may have been exposed. • It has been suggested that this may account for nno more than 10% of ADHD cases.

14. The Role of Specific Toxins • Another environmental factor found in some studies to be related to ADHD is exposure to lead. • While the relationship is not strong, elevated lead burden bears a statistically significant relationship to symptoms of ADHD. • Although, only about 30+% of children with high lead burdens are judged to be hyperactive . . . • And, although most children with excessive lead burdens do not develop ADHD . . . • Evidence does suggest that lead can be a contributor to ADHD. • It does not,however, seem to be a major contributor in most children . [Note Oliver David’s Research]

15. Role of Neurological Insult • Multiple factors that can result in brain damage are associated with ADHD. • For example, as we have seen, anoxia is associated with increased frequencies of hyperactivity and attention problems. • ADHD occurs more often in children with seizure disorders, who are presumed to have neurological involvement • As noted earlier, diseases such as encephalitis can result in symptoms of ADHD as can various types of infections. • We also know that frontal lobe injury can cause symptoms of ADHD. • There is also some suggestion that right parietal lobe lesions may contribute to ADHD.

16. Neurological Factors • These findings suggest that neurological insult can result in an increased probability of developing ADHD. • However, most children with ADHD do not have a significant history of brain injury. • Indeed, such injuries are unlikely to account for the development of ADHD in most children. • In fact probably 95% of hyperactive children show no evidence of documented neurological impairment. • This does not mean, however, that biological factors are not involved.

17. Relationship to Thyroid Disorder • Earlier we noted that physical conditions such as thyroid disorder can result in or mimic this disorder. • Some children have a genetically based hypersensitivity to thyroid hormones. • This is referred to as RTH for Resistance to Thyroid Hormone • One study has found that 70% of individuals with RTH met diagnostic criteria for ADHD. • Other research has suggested that 64% of patients with RTH display hyperactivity or learning disabilities.

18. Relationship to Thyroid Disorder • Despite these findings and others which have documented a link between RTH and at least mild to moderate symptoms of ADHD, only 1 in 2,500 children with ADHD show RTH. • This suggests that thyroid dysfunction is unlikely to be a major cause of ADHD. • RTH children with ADHD may show a more positive behavioral response to liothyronine, than do ADHD children who do not have RTH. • While not a major cause of ADHD, the effects of RTH is a good example of how biological factors, other than clear neurological impairment, can result in ADHD symptomatology.

19. Genetics: Family Aggregation Studies • Studies dating as far back as the 1970's indicated that children with hyperactivity tend to frequently have parents with ADHD and other psychiatric disorders. • Adoption studies also suggested that, for hyperactive children, there were higher rates of hyperactivity in biological than adoptive parents. • In the 1990's there were numerous other studies that provided more convincing information regarding the possible genetic contribution to ADHD.

20. Genetics: Family Aggregation Studies • For example, Biederman et al found between 10 and 35% of the immediate family members of children with ADHD to display this disorder. • Risk for siblings of children with ADHD was approximately 32%. • Other studies by Biederman have suggested that, if a parent has ADHD, the risk to the offspring is 57%. • Thus, family aggregation studies find that ADHD clusters among biological relatives of children or adults with this disorder. • This strongly implies a hereditary bases for this condition.

21. Genetics: Twin Studies • Large scale twin studies in the 90's have been quite consistent in finding high heritability for ADHD. • For example, Gilger et al (1992) found that, if one twin was diagnosed with ADHD, the concordance for the disorder was 81% in monozygotic twins and 29% in dizygotic twins. • In summarizing results of ADHD twin studies, Stevenson (1994) concluded that the average heritability is .80 for symptoms of this disorder. • Other studies are consistent in suggesting that 70 -90% of the trait of hypearactivity-impulsivity is due to genetic factors (averaging around 80%).

22. ADHD: Molecular Genetics • Molecular genetics has begun to identify specific genes related to ADHD. • A “dopamine type 2 gene” has been found to be related to ADHD as well as Tourette’s and alcoholism. • More recently a "dopamine transporter gene" and a “dopamine repeater gene”have been identified. • This latter gene, found to be related to ADHD in multiple studies, seems to be related to post-synaptic sensitivity in the frontal and prefrontal cortical regions, and to be associated with executive functions.

23. ADHD: Molecular Genetics • With developments in molecular genetics occurring at an increasingly rapid rate (due to the Human Genome Project), in the near future, we may have genetic tests that can provide early screening for ADHD and possibly associated comorbidities. • Would these be useful? Why/Why Not? • Genetic factors are clearly strongly implicated in the development of this disorder. • Indeed, hereditary is probably the most well supported etiological factors in the development of ADHD

24. Psychophysiological Studies • Studies using psychophysiological measures of nervous system electrical activity, measured in different ways (EEG, GSR), have been somewhat inconsistent in findings group differences between ADHD and normal control children. • However, when differences from normals are found, they are consistently in the direction of diminished arousal or arousability in children with ADHD.

25. Psychophysiological Responsivity • In addition to regular EEG and GSR studies, there are also a number of Evoked Potentials studies where EP's have been obtained while children with ADHD are performing vigilance tasks. • While results vary, the most consistent pattern has been lower amplitude responses in certain portions of their ERP's which are thought to be related to functioning of the prefrontal regions of the brain. • These types of responses suggest an under responsiveness of ADHD children to stimulation. • It is interesting to note that this under responsiveness is corrected with stimulant medication

26. Neuropsychological Findings • Results from research involving neuropsychological testing has often suggested that children with ADHD have problems; • in inhibiting behavioral responses, • with working memory, • with planning and organization, • with verbal fluency, • with perserveration, • In motor sequencing, • with other “frontal lobe” functions.

27. Neuropsychological Findings • Research suggests that, not only do children with ADHD show these types of executive functioning deficits, but siblings of children with ADHD, who do not have ADHD themselves, have milder but significant impairments in these same executive functions. • These findings suggest possible genetic risk for executive function deficits in families that have ADHD children , even if symptoms of ADHD are not fully manifest in family members. • Taken together, findings in this area provide support for the view that dysfunction of the prefrontal lobes likely play a significant role in the development of ADHD.

28. Studies of Cerebral Blood Flow • Studies of cerebral blood flow in ADHD and normal children have consistently shown decreased blood flow to the prefrontal regions and pathways connecting these regions to the limbic system via the striatum and specifically its anterior region (the Caudate Nucleus) • Studies using PET scans to assess cerebral glucose metabolism in the frontal regions have found diminished metabolism in, adults and adolescent with ADHD.

29. Studies of Cerebral Blood Flow • Significant correlation's between diminished metabolic activity in the left anterior frontal region and severity of symptoms in adolescents with ADHD have also been demonstrated • This demonstration of a relationship between decreased metabolic activity in specific brain regions and severity of ADHD symptoms is crucial to documenting the importance of the link between brain activation and ADHD related behaviors • Other studies have also suggested decreased blood flow to the striatum, which is increased with stimulant drugs.

30. PET SCAN • This is a P.E.T. scan (positron emission tomography) of the human brain. • The brain on the left is the brain of person without ADD and the brain on the right is that of a person with ADD. • This study was conducted to determine brain activity by measuring glucose metabolism. • This was the first study to show differences in brain activity between ADD and non-ADD brains.

31. PET SCAN • The red areas within (not surrounding) the brain represent metabolic activity. • The non-ADD brain has more metabolic or electrical activity (red) than the ADD brain. • This metabolic activity is partly responsible for an individuals' ability to focus and concentrate and is the result of the neurotransmitters or brain chemicals (i.e. dopamine, serotonin, etc.). • Higher levels (or a greater uptake or utilization) of neurotransmitters increase the metabolic activity.

32. PET SCAN • The ADD brain is generally metabolically less active (or understimulated), than the non-ADD brain. • It relies on external factors in order to become stimulated enough to focus and concentrate. • Therefore, the verbal and/or physical impulsivity or activity that is part of the ADD individual is necessary to stimulate the brain. • Medication increases the metabolic activity of the brain and reduces the need for external stimulation.

33. MRI Studies • Early MRI studies found differences in the area of the Corpus Callosum, with this structure being smaller in children with ADHD. – Not always replicated. • Other MRI studies have found children with ADHD to have a smaller left caudate nucleus than did normal children. • These findings are interesting in light of the results of earlier blood flow studies suggesting lower levels of activation in this specific area in children with ADHD.

34. MRI Studies • Several more recent MRI studies, with larger samples, have replicated these early results by finding that ADHD children had significantly smaller anterior right frontal regions, a smaller caudate nucleus, and smaller golbus pallidus regions that normals. • Research has also found decreased cerebellar volume in children with ADHD. • Work in this area suggests that abnormalities in the development of the frontal-striatal regions, and other brain structures, may underlie the development of ADHD.

35. Neurotransmitter Deficiencies • The possibility of a neurotransmitter dysfunction in children with ADHD has been suggested for many years. • This notion seemed to result from observations of the response of children with ADHD to stimulant drugs. • The fact that stimulant drugs have an impact on ADHD and that they increase dopamine has contributed to the neurotransmitter dysfunction hypothesis.

36. Neurotransmitter Deficiencies • There is more direct evidence of neurotransmitter deficiencies from studies of cerebral spinal fluid in ADHD and normal children which suggests decreased dopamine levels in ADHD children • There is also some evidence of a deficiency in the availability of norepinephrine in children with ADHD. • This is of interest given that a very new non-stimulant ADHD medication, Straterra, is thought to act on norepinephrine levels.

37. PSYCHOSOCIAL FACTORS IN ADHD • There is little evidence for the role of psychosocial factors in the development of ADHD, although factors such as parent-child conflict may exacerbate problems in a child with ADHD. • Psychosocial factors may also contribute to the development of certain comorbid disorders that may complicate the clinical picture.

38. Etiology: Overview • In reviewing the literature on the etiology of ADHD, Barkley suggests … • “It should be evident from the research…that neurological and genetic factors make a substantial contribution to symptoms of ADHD and the occurrence of this disorder. • A variety of genetic and neurological etiologies (e.g., pregnancy and birth complications, acquired brain damage, toxins, infections, and genetic effects) can give rise to the disorder through some disturbance in a finalcommon pathway in the nervous system

39. Etiology: Overview • That final common pathway appears to be the integrity of the prefrontal cortical-striatal network • It now appears that hereditary factors play the largest role in the occurrence of ADHD symptoms in children. • It may be that what is transmitted genetically is a tendency toward a smaller and less active prefrontal-striatal network.

40. Etiology: Overview • The condition can also be caused or exacerbated by pregnancy complications, exposure to toxins, or neurological disease • Social factors alone cannot be supported as causal in this disorder, but such factors may exacerbate the condition, contribute to its persistence, and more likely, contribute to the forms of comorbid disorders associated with ADHD.

41. Etiology: Overview • Cases of ADHD can arise without genetic predisposition if the child is exposed to a significant disruption or neurological injury to this final common neurological pathway, but this would seem to account for only a small minority of ADHD children.