Attention-Deficit Hyperactivity Disorder

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Chapter 47 Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) has been described as the most common neurobehavioral disorder in childhood [Cantwell, 1996]. Prevailing opinion characterizes ADHD as a disorder of executive function attributable to abnormal dopamine transmission in the frontal lobes and frontostriatal circuitry. In large part, this concept is based on the clinical efficacy of medications affecting catecholamine transmission in these regions.

The first reference to behavior now associated with ADHD was by George Still in 1902, who referred to a deficit of “moral control.” Within the context of this broad concept, he made the following observation: “A notable feature in many of these cases of moral deficit without general impairment of intellect is a quite abnormal incapacity for sustained attention” [Still, 1902]. Strauss and Lehtinen [1947] used the term “minimal brain damage syndrome” to describe children with cognitive and behavioral deficits. In 1962, Clements and Peters coined the term “minimal brain dysfunction” to describe functional abnormalities in children in whom brain damage could not be demonstrated. Although widely accepted, this concept came under immediate challenge, as it included too heterogeneous a group of children [MacKeith, 1963]. The subsequent emphasis on attention and its neurologic substrate, the frontal lobe and frontostriatal circuitry, represents a refinement of the definition of the condition.

Diagnosis of Attention-Deficit Hyperactivity Disorder

ADHD is a clinical diagnosis based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (Box 47-1). Criteria are divided into two lists of symptoms, one for inattention and another for hyperactive-impulsive behavior. Based on the number of items identified, there are three classifications: ADHD/I (primarily inattentive type), ADHD/HI (primarily hyperactive-impulsive type), and ADHD/C (combined type). The revised diagnostic criteria of DSM-IV, with the inclusion of the three subtypes, increased the number of females, preschoolers, and adults with ADHD [Lahey et al., 1994]. Increased numbers in these groups resulted in an increase in the prevalence of ADHD from 3–5 percent with the DSM-III-R to about 12 percent; ADHD/I alone has been estimated to have a prevalence between 5.4 and 9 percent [Baumgaertel et al., 1995; Wolraich et al., 1996].

Box 47-1 Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder

A. Either (1) or (2):

(1) Six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

Inattention

often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities

often has difficulty sustaining attention in tasks or play activities

often does not seem to listen when spoken to directly

often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)

often has difficulty organizing tasks and activities

often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework)

often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools)

is often easily distracted by extraneous stimuli

is often forgetful in daily activities

(2) Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

Hyperactivity

often fidgets with hands or feet or squirms in seat

often leaves seat in classroom or in other situations in which remaining seated is expected

often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness)

often has difficulty playing or engaging in leisure activities quietly

is often “on the go” or often acts as if “driven by a motor”

often talks excessively

Impulsivity

often blurts out answers before questions have been completed

often has difficulty awaiting turn

often interrupts or intrudes on others (e.g., butts into conversations or games)

B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years

C. Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home)

D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning

E. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder and are not better accounted for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, or a personality disorder)

Code based on type:

314.01 Attention-Deficit/Hyperactivity Disorder, Combined Type: If both Criteria A1 and A2 are met for the past 6 months

314.00 Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months

314.01 Attention-Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months

Coding note: For individuals (especially adolescents and adults) who currently have symptoms that no longer meet full criteria, “In Partial Remission” should be specified.

It has been proposed that the core deficit in ADHD is impairment of behavioral inhibition, which leads to the other symptoms of ADHD. This model of impaired behavioral inhibition is limited to ADHD/HI and ADHD/C (i.e., those with hyperactive or impulsive symptoms) and excludes children with ADHD/I (i.e., those with inattention only) [Barkley, 1997]. The observation that overflow movements were the most discriminating finding between hyperactive boys (without learning disabilities) and normal control subjects seems to support the concept of impaired behavioral inhibition [Denckla and Rudel, 1978]. If this formulation is widely accepted, future classifications may call for separate diagnostic entities, such as attention-deficit disorder and behavioral-inhibition disorder. Some investigators have proposed that all three ADHD subtypes can be explained as disorders of attention or executive function (other than response inhibition), with symptoms of hyperactivity and impulsivity resulting from these impairments [Brown, 2000; Chhabildas et al., 2001; Weiss and Weiss, 2002]. Others also distinguish ADHD/HI and ADHD/C from ADHD/I, but they posit that the symptoms of hyperactivity and impulsivity can result from poor inhibitory control or differences in motivational style characterized by delay aversion [Sonuga-Barke, 2002].

A review of the literature regarding the hypothesis that ADHD represents a primary deficit in executive control defined executive function as comprising “at least four factors: (1) response inhibition and execution, (2) working memory and updating, (3) set-shifting and task-switching and (4) interference control” [Willcutt et al., 2005]. There were significant differences between children with and without ADHD on tasks assessing executive function. Six of eight studies assessing working memory found impaired working memory in children with ADHD. The most consistent effects were observed in measures of response inhibition, vigilance, and planning; children with combined and inattentive types of ADHD differed from controls and did not differ from each other, whereas children with hyperactive-impulsive ADHD had minimal executive function impairment, suggesting that executive function weaknesses are primarily associated with inattention, rather than hyperactivity-impulsivity symptoms. The observation that fewer than half of the children with ADHD had significant impairment of any specific task of executive function, and that the correlation, while significant, tended to be small in magnitude, led the authors to conclude that their findings “do not support the hypothesis that executive functions deficits are the single necessary and sufficient cause of ADHD in all individuals with the disorder. Instead executive function difficulties appear to be one of several important weaknesses that comprise the overall neuropsychological etiology of ADHD” [Willcutt et al., 2005].

Inhibitory deficits and delay aversion in ADHD can be dissociated by specific types of tasks; either deficit alone is only moderately associated with ADHD, whereas these two deficits combined correctly classify nearly 90 percent of children with ADHD. Thus a formulation was proposed in which executive functions (EF) are divided into cognitive aspects, associated with dorsolateral prefrontal cortex (“cool” EF), in contrast to the affective aspects, associated with orbital and medial prefrontal cortex (“hot” EF). Inattention symptoms were attributed to deficits in “cool” EF, whereas hyperactivity-impulsivity symptoms reflected “hot” EF deficits. The authors noted that “the neuroanatomical substrates of cortical-striato-thalamo-cortical circuitry are now revealed to include spirals of one directional information from ‘hot’ ventral-medial/orbital/ventral striatal regions to dorsolateral/superior medial/anterior striatal ‘cool’ regions to even ‘cooler’ premotor and motor circuits” [Castellanos et al., 2006].

The use of the word “often” in the list of symptoms, coupled with qualification “to a degree that is maladaptive and inconsistent with developmental level,” lends an element of subjectivity to this diagnostic schema. Symptom rating scales for parents and teachers have been developed to assist in the ascertainment of diagnostic criteria [Conners, 1997]. The use of broader rating scales, such as the Child Behavior Checklist, provides information regarding the presence of other disorders, such as conduct disorder, oppositional defiant disorder (ODD), and anxiety disorder [Achenbach, 1991; Vaughn et al., 2000], which may warrant diagnoses other than ADHD [Jensen et al., 1997]. The Yale Children’s Inventory was developed to ascertain the presence of attentional deficits and learning disabilities [Shaywitz et al., 1986]. A comprehensive review of evaluation issues in ADHD concluded that no single test can be used to make the diagnosis and that it is up to the clinician “to choose a battery of measures that satisfies what is, to some degree, an individually determined level of diagnostic certainty” [Nass, 2005]. The American Academy of Pediatrics has endorsed the Vanderbilt ADHD rating scales for parents and teachers [Wolraich et al., 2003a, b] and has provided a complete “tool kit,” including a cover letter to teachers and scoring information, on the internet (http://www.nichq.org/about/index.html).

Developmental variability in the presentation of ADHD, and the inconsistency of behavior of children with ADHD in different settings and at different times in the same setting, add to the diagnostic confusion. In preschool children, in particular, the prevalence of ADHD-type symptoms [Blackman, 1999; Palfrey et al., 1985] and the transient nature of such symptoms in many cases [Barkley, 1998] make this a difficult diagnosis. Efforts have been made to provide a more objective basis for the diagnosis of ADHD, such as computerized continuous performance tests [Conners, 1985] or tests of variables of attention [Greenberg, 1993]. However, the correlation of these measures of attention with the behavioral disorder is not sufficient for their use as replacements for the behavioral criteria of DSM-IV [Barkley, 1991].

The motor examination may help distinguish between children with a learning disorder and those with ADHD; it is best to evaluate a child between the age of 5 years and the onset of puberty, a period of rapid change in motor development, when quantitative examination of the motor system, such as the Physical and Neurological Examination for Soft Signs (PANESS) [Denckla, 1985], may demonstrate evidence of motor disinhibition [Denckla, 2003].

Controversies in the Diagnosis of Attention-Deficit–Hyperactivity Disorder

The DSM-IV clinical criteria for diagnosing ADHD (see Box 47-1) indicate a number of qualifications that are too often ignored, resulting in an incorrect diagnosis [American Psychiatric Association, 1994]. The text explicitly states that the findings need to be present “to a degree that is maladaptive and inconsistent with developmental level.” Behavior that may not be typical but is not maladaptive does not warrant a diagnosis of ADHD. Similarly, unreasonable expectations of a child at a young age may result in a false diagnosis. The diagnostic criteria are followed by a number of statements regarding the context of the symptoms. Item C states, “Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home).” This provision allows for the possibility that a child in an inadequate school environment, perhaps with excessive class size, hostile peers, or inexperienced teachers, may present with findings that are unique to that setting rather than represent a disorder of attention. Similarly, a chaotic home environment may explain the child’s presentation. The importance of verifying the presence of symptoms in two or more settings is underscored by a study that found an increase in the incidence of ADHD diagnoses in: states with school accountability laws; students with older or nonwhite teachers; children from a single-parent family, from the lowest income quintile, with a US-born father, or born to a young (<18 years) or older (>38 years) mother [Schneider and Eisenberg, 2006]. Item D reiterates that “there must be clear evidence of clinically significant impairment in social, academic, or occupational function.”

Perhaps most important is item E, which states, “The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder and are not better accounted for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, or a personality disorder).” If a child has symptoms that meet the diagnostic criteria for ADHD in the context of these other disorders, treatment should be directed at these other conditions before concluding that the child has a disorder of attention. Not addressed in item E of the DSM-IV criteria are studies that have demonstrated that children with specific neurologic disorders can present with symptoms that meet criteria for ADHD but are attributable to the neurologic disorder rather than a primary disorder of attention. A study by Walters et al. [2000] demonstrated symptoms of impaired attention and hyperactivity in children diagnosed with restless leg syndrome; treatment of the sleep disturbance resolved the so-called ADHD symptoms. Disordered breathing during sleep has also been found to manifest with symptoms consistent with ADHD [Gottlieb et al., 2003]. There are reports of children with focal epileptic discharges having symptoms suggestive of ADHD that resolved when the spike activity was suppressed with antiepileptic drugs [Holtmann et al., 2003; Laporte et al., 2002]. Many symptoms of ADHD are prevalent in individuals with neurogenetic syndromes as part of the behavioral phenotype [Pelc and Dan, 2008]. Future versions of the DSM should add neurological disorders (e.g., sleep disorders, epilepsy, neurogenetic syndromes) to the list of conditions in item E that must be excluded before ADHD is diagnosed. Refining the diagnosis of ADHD will facilitate ascertainment of the physiological and genetic underpinnings of ADHD and its treatment.

The question of conditions coexisting with ADHD is quite complex. Should a diagnosis of ADHD be reserved for individuals with an isolated disorder of attention, hyperactivity, or impulsivity, with an alternative classification used to describe children who meet DSM-IV criteria for ADHD in the context of other neurodevelopmental problems? Denckla [2003] used the term pseudo-ADHD to describe children with comorbidities or confounding factors. In a paper describing a father and son both with orbitofrontal epilepsy and associated attention difficulties and hyperactivity, the term attention-deficit hyperactivity syndrome was used to make a distinction from the specific disorder of ADHD [Powell et al., 1997], analogous to the distinction between Parkinson disease and parkinsonism. It has been proposed that ADHD be divided into subgroups based on the patterns of comorbidity [Biederman et al., 1991].

The presumption that a response to psychostimulant medication indicates that the underlying problem is ADHD can lead to an erroneous diagnosis. Psychostimulant medications can ameliorate depression [Janowsky, 2003], chronic fatigue syndrome [Turkington et al., 2004], and daytime somnolence caused by sleep disorders [Happe, 2003; Ivanenko et al., 2003], and enhance normal individuals’ cognitive functioning and behavior [Rapoport et al., 1978]. A positive response to psychostimulants has no diagnostic significance.

Neurobiology of Attention-Deficit Hyperactivity Disorder

Advances in structural and functional imaging, clinical neurophysiologic techniques, and molecular genetics have been applied to the evaluation of children with ADHD and have provided important insights into this condition. However, inconsistency in the inclusion and exclusion criteria among studies, particularly related to comorbidity, limits comparisons between studies and their conclusions.

Structural Imaging

Cortical Structures

Reports of reductions in volume of prefrontal regions, more so in the right than left hemisphere, have been described in children with ADHD [Castellanos et al., 1996; Filipek et al., 1997]. A later study further localized involvement to prefrontal and premotor areas [Mostofsky et al., 2002]. In this study of 12 males with ADHD, children with conduct, mood, and anxiety disorders were excluded, but 3 children with coexistent ODD were included. A study involving other brain regions reported reductions in total cerebral volume with a negative correlation between gray-matter volumes and symptom severity [Castellanos et al., 2002]. However, the impact of coexisting conditions on anatomic findings was not considered or described (i.e., it was unclear if there was an association between severity of symptoms and coexisting conditions). Serial examinations found that most volume differences between ADHD and control subjects remained stable; however, the size of the caudate nucleus, which initially was smaller in the ADHD group, became comparable with that in the control group during adolescence. This finding reflected a greater rate of reduction in caudate size in the normal than in the ADHD group. Normalization of the caudate nucleus in adolescents with ADHD may relate to the observation that ratings for hyperactivity and impulsivity are decreased in that age group compared with those in younger children [Hart et al., 1995]. A study using serial magnetic resonance imaging (MRI) scans to measure cortical thickness over time found that typically developing children without ADHD reached peak cortical thickness in the frontal cortex between the ages of 7 and 8 years. In contrast, children with ADHD reached this developmental milestone between the ages of 10 and 11 years. Both groups of children underwent cortical thinning from this peak point of thickness throughout adolescence [Shaw et al., 2007]. A subsequent study compared repeated neuroimaging studies of children with ADHD not taking psychostimulants to an age-matched group of children with ADHD who were taking psychostimulant medication during the inter-scan interval. Comparison was also made to a group of children without ADHD. The decision whether or not to treat with psychostimulants was left up to the treating physician and the family, thus was not randomly assigned. A comparison of the groups taking stimulants and not taking stimulants showed no significant differences in gender, IQ, or clinical characteristics. The neuroanatomic analysis revealed that there was more rapid cortical thinning in the group not taking psychostimulants (0.15 mm/yr) compared to the group taking psychostimulants (0.03 mm/yr). Thus, whereas at baseline there were no significant group differences in cortical thickness, at the end of the study the non-treatment group had a significantly thinner cortex than the treatment group. The authors hypothesize that the “psychostimulant induced increases in age appropriate levels of cognition and action, and perhaps underlying localized fronto-parietal neural activity, might foster cortical development within the normal range” [Shaw et al., 2009].

Subcortical Structures

Findings in the basal ganglia have been inconsistent, with reports of volume reductions in the right caudate nucleus and globus pallidus [Castellanos et al., 1996] or in the left caudate [Filipek et al., 1997]. The study by Castellanos et al. [1996] included children with “mild–moderate” conduct disorder (CD), ODD, anxiety disorder, and reading disorders. However, re-analysis of the data by excluding the children who had CD or ODD found a more robust correlation between volume reductions in the right prefrontal, caudate, and globus pallidus and ADHD. In the study by Filipek et al. [1997], children with coexistent conditions were excluded. In addition to the anatomic differences between children with ADHD and control subjects, this study revealed differences in structural abnormalities between children with ADHD who were considered responders to psychostimulants and those who were not. A study of monozygotic twins discordant for ADHD [Castellanos et al., 2003] revealed reduced caudate volume in the affected twin. In another report on twins discordant for ADHD [Sharp et al., 2003], fathers of twins discordant for ADHD had lower ADHD scores than fathers of ADHD singletons. The rate of breech presentation was greater in affected twins than affected singletons. The data suggested that the discordant twins represented nongenetic instances of ADHD, possibly caused by injury in utero, and that the caudate abnormalities in these individuals might not be pertinent to ADHD that is genetic in nature. No abnormalities have been reported in the putamen, and there have been few studies of the globus pallidus in children with ADHD [Durston et al., 2003]. A study utilizing large deformation diffeomorphic mapping (LDDMM) found that boys with ADHD had significant shape differences and decreases in overall volume of the basal ganglia compared to controls, whereas girls with ADHD did not have volume or shape differences. Children with comorbidities, including other neuropsychiatric disorders, conduct disorders, mood disorder, generalized anxiety disorder, obsessive-compulsive disorder, learning disabilities, or speech and language disorders, were excluded from this analysis [Qiu et al., 2009].

Cerebellum

Reductions in total cerebellar volume [Castellanos et al., 1996, 2002] and in the volume of the cerebellar vermis alone in ADHD compared with control subjects have been described [Castellanos et al., 2001; Mostofsky et al., 1998]. These differences could have been caused by different methods for serially measuring volume, making comparisons between studies difficult. These studies included children who had a high percentage of coexistent conditions, such as ODD, CD, and learning, mood, and anxiety disorders, but the decreased volume of the cerebellar vermis in the ADHD group remained when children with disruptive behavioral disorders were removed from the analysis. However, the subgroup with ADHD and coexisting mood or anxiety disorders had the smallest vermian volumes.

Functional Imaging

The clinical benefit from medications affecting catecholamine levels has led to a focus on frontostriatal circuitry and dopamine pathways in ADHD. Functional magnetic resonance imaging (fMRI) studies have demonstrated abnormal activation of frontostriatal regions in children with ADHD. In normal children, maturation is associated with increased activation of the ventral frontostriatal regions and improved inhibitory control [Durston et al., 2002]. A comparison of ADHD with normal control subjects demonstrated greater frontal activation and lower striatal activation during response inhibition in 10 children with ADHD (8 ADHD/C, 2 ADHD/I; children with high comorbidity scores were excluded). Administration of methylphenidate also resulted in improved performance in a test of response inhibition, associated with increased frontal activation in ADHD children and control subjects, and increased striatal activation in the children with ADHD [Vaidya et al., 1998].

Single-photon emission computed tomography (SPECT) has been used to investigate children with ADHD. One study compared 8 adolescents with “pure” ADHD against 11 with ADHD and coexistent conditions during a test of variables of attention (TOVA) [Lorberboym et al., 2004]. Children with coexistent conditions (e.g., ODD, CD, mood disorders, learning disorder alone or in combination) had decreased temporal lobe perfusion in response to the TOVA compared with the pure ADHD children, who had some but not statistically significant decreases in frontal lobe perfusion. Regional differences in perfusion between the two groups may explain the better rate of response to stimulants in the pure ADHD group and suggests that different treatments for the two groups may be warranted.

Untreated adults with ADHD (with no psychiatric comorbidity) have increased striatal dopamine transporter (DAT) levels compared with normal control subjects (as measured by binding to technetium-99m TRODAT-1, the first ^99mTc-labeled ligand identified by SPECT that specifically binds DAT), which decreased after 4 weeks of methylphenidate treatment [Krause et al., 2000]. This finding, along with increased striatal activity on positron emission tomographic (PET) scanning in adolescents with ADHD compared with normal control subjects [Ernst et al., 1999], suggests a role for excess dopaminergic activity in the striatum or nucleus accumbens in persons with ADHD [Solanto, 2002].

Proton MR spectroscopy has also been used to study children with ADHD [Sparkes et al., 2004]. N-acetyl-aspartate (NAA), glutamate/glutamine/γ-aminobutyric acid (Glx), choline, and creatine (Cre) levels in the right prefrontal cortex and left striatum during a test of response inhibition were compared between ADHD children and a control group. A negative correlation between the NAA/Cre ratio and reaction time in the ADHD group was found, compared with a positive correlation in the control group. Children with ADHD with NAA/Cre levels more comparable with those in controls also had much longer reaction times. These findings were thought to reflect preferential use of the prefrontal cortex by children with ADHD during tasks of response inhibition. Of the 8 children with ADHD in this study, 5 had ODD, and 1 had a generalized anxiety disorder; the interpretation of these results, as they apply to ADHD compared with other disorders, is unclear.

Clinical Neurophysiology

Event-related potential (ERP) studies in ADHD children suggest a lack of frontal lobe inhibitory processes, particularly in pathways involving the anterior cingulate cortex. In one study using a Go/NoGo task designed to assess inhibition, no significant performance differences were found between children with ADHD and normal control subjects [Smith et al., 2003]. However, children with ADHD had larger ERPs than the control group to a warning stimulus that provided no information helpful for task performance, suggesting a lack of inhibition to an irrelevant stimulus in the ADHD group. A second study found shorter-latency and higher-amplitude ERPs that were thought to reflect an inhibitory process in the ADHD group [Falkenstein et al., 1999]. These findings suggested that children with ADHD need to trigger inhibition processes earlier and more strongly to achieve the same behavioral performance as control subjects. Individuals in this study likely did not represent a pure ADHD group because they had higher scores in oppositional, delinquent, and aggressive behaviors and social problems. A third study found that the children with ADHD and without coexisting conditions had significantly longer reaction times to target stimuli and made significantly more omission errors than the control group, but did not differ in the number of commission errors [Fallgatter et al., 2004]. The ERP data indicated diminished activation of the anterior cingulate cortex in the Go/NoGo trials in the ADHD group, suggesting deficits in prefrontal response control. This deficit in prefrontal response control was distinguished from deficits in response inhibition. Because the latter study excluded ADHD children with comorbidity, it more strongly suggests that abnormalities in activation of the anterior cingulate cortex may be specific to ADHD.

Genetic Studies

Concise reviews of advances in the genetics of ADHD, including findings that may account for the ADHD subtypes, comorbidities and responses to specific medications, are provided in a commentary and editorial in journal issues devoted to this topic. As summarized by DV Pauls: “there is overwhelming evidence that ADHD is inherited and that genetic factors play a significant role in its manifestation” [Pauls, 2005; Faraone, 2006]. Evidence of dopaminergic involvement has led to molecular genetic studies of dopamine transporter and receptor genes [Kent, 2004]. Pursuit of the DAT gene (SLC6A3, formerly designated DAT1) was in part caused by the fact that psychostimulant medications inhibit activity of DAT. An association between ADHD and the 480-base pair alleles at a variable number tandem repeat (VNTR) in SLC6A3 has been reported [Cook et al., 1995]. A subsequent study confirmed these findings and demonstrated a significant relation between SLC6A3 high-risk alleles and the number of hyperactive-impulsive symptoms, but not inattentive symptoms [Waldman et al., 1998]. The study involved 117 probands, all but one of whom met criteria for ADHD; the remaining child had ODD. Most children with ADHD frequently had symptoms of or were diagnosed with ODD, CD, and depression or dysthymia. Two subsequent studies, one with a similar rate of coexisting conditions [Palmer et al., 1999] and one with a much lower rate [Swanson et al., 2000], failed to replicate the association between SLC6A3 and ADHD.

The dopamine D4 receptor gene (DRD4) has also been associated with ADHD. A 48-base pair VNTR in the third exon of DRD4, also referred to as the DRD4 7-repeat allele, was suggested based on a review of previous studies [Faraone et al., 200l]. Children with ADHD who had the 7-repeat allele had a greater degree of impulsivity (i.e., faster and less accurate responses), were significantly more active (based on Actigraph measures), and had greater total ADHD symptoms scores than those without the allele. However, no differences were seen using measures of attention or response inhibition. The ADHD children with the 7-repeat allele also had higher rates of ODD and CD.

A third dopamine receptor gene, DRD5, has been linked to ADHD. One study that examined a number of candidate genes, including DRD3, DRD4, DRD5, and genes for four enzymes involved in dopamine metabolism, found no significant association between the children with ADHD and genetic polymorphisms [Payton et al., 2001]. However, the 138 ADHD children in this study frequently had coexisting conditions, including ODD (57.5 percent), CD (11.6 percent), and tic (12.3 percent), anxiety (2.7 percent), and depressive (1.4 percent) disorders. Another study also included children with coexistent conditions (Tourette’s syndrome or tics in 34 percent, CD or ODD in 25 percent, anxiety or depression in 8 percent), and linkage to DRD5 only reached significance when restricted to the children who had a response to methylphenidate [Tahir et al., 2000]. Information was not provided about whether the methylphenidate responders had fewer coexisting conditions. Linkage of the DRD4 gene to methylphenidate responders was also observed. However, this study found an inverse relationship between DRD4 and DSM scores and comorbidity ratings.

Studies of DNA from ADHD probands, parents, and healthy controls found a significant association of ADHD with two NET1 single-nucleotide polymorphisms and two DRD1 single-nucleotide polymorphisms. There was no association with polymorphisms in ten other genes previously reported as candidate genes. There were no significant differences in anatomic brain MRI measurements between the children with NET1 or DRD1 gene types; nor was there a relationship between the genetic findings and cognitive or behavioral measures. This study represented the first replication of a previously described association between ADHD and polymorphisms in NET1 and DRD1 genes [Bobb et al., 2005].

In a study of a group of children from families of European descent with an ADHD proband, the ADHD probands were assessed by a child psychiatrist; parental ADHD was assessed through the use of an ADHD self-report scale. The ADHD cohort consisted of 335 parent–child trios of European descent and a set of 2026 ethnically matched, disease-free children as a control group. There was no significant difference in copy number variants (CNV: deletions, duplications, or size) between the patient and control groups. A search for CNVs spanning more than ten consecutive single-nucleotide polymorphisms (SNPs) for deletions, or more than twenty SNPs for duplications present in at least one parent, along with one or more related probands, but not in the controls, yielded 158 deletions and 64 duplications from 154 probands. These CNVs encompassed or overlapped 229 distinct genes, with the largest family of genes affected being the olfactory receptor superfamily. Twenty-two of these genes had previously been implicated in various neurological and neuropsychiatric disorders, including Tourette’s syndrome (2 genes), autism (4 genes), and schizophrenia (15 genes). An additional 8 genes had been recently identified as having structural variants in autism and schizophrenia. Reviewing the gene set for genes associated with nervous system development, function, and behavior, the authors found genes associated with learning, cognition, and hindbrain development. Two genes, the PTPRD and GRM5 genes, were thought to be particularly interesting putative candidate genes for ADHD; one, involving the protein tyrosine phosphatase gene, was detected in four unrelated ADHD probands. Two of the four ADHD probands with the PTPRD deletion reported symptoms consistent with restless leg syndrome. All three children in a family found to have the GRM5 variant met the criteria for ADHD; the GRM5 gene, a glutamatergic receptor gene, has been postulated to play a role in ADHD. Thus the CNVs found in this ADHD were significantly enriched for genes reported as candidate genes in other neuropsychiatric disorders and in neurodevelopmental pathways [Elia et al., 2009].

Other Potential Causes of Attention-Deficit Hyperactivity Disorder

Data reported from the National Longitudinal Survey of Youth [NLSY, 1979] associated hours of television watched per day at ages 1 and 3 years with parental reports of attentional problems at age 7 [Christakis et al., 2004]. The children did not necessarily have clinically diagnosed ADHD; rather, they were scored as having attentional problems by the parents. Although the interaction between environmental influences and genetic endowment is well accepted, such preliminary data suggest the need for further investigation because of issues of cause and effect, limitations in adjusting for confounders, potential for biased reporting, and selective recall.