Special Article

Attention-Deficit Hyperactivity Disorder (ADHD)

Kytja K. S. VoeUer, MD

ABSTRACT Approaches to the diagnosis and treatment of attention-<ieficit hyperactivity disorder (ADHD) are undergoing a nuyor change as a result of iiifonmitinn from sturiies on the genetics of ADHD and the use of new neuroiniaging technologies. Moreover, phamiacogenomics, although stiil in its infancy, will provide a basis for much more sophist icatefi t reatment .strategies for ADHD, particularly once more information is available about the genetics of ADHD. Even at this poini in (ime, tliere is some pertinent information available that, although nol ready for application in clinical settings, nonetheless provides a broader perspective for the clinician. In terms of etiology, ADHD is a neuropsycluatric disorder. There is a genetic basis in about 809i) of the cases, involving a number of diffeient genes, and in about 20% of the cases, ADHD is the result of an acquired insult to the brain. Some individuals likely have both genetic and acquired forms. Although medication works well in many cases of ADHD, optimal treatment of ADHD requires integrated medical and behavioral treatment. The family plays a CRicial role in the management of children with ADHD. Because there is often a very high degree of comorbidity between ADHD and learning disabilities, teachers also have a great deal to contribute in the day-to-day management of these children. Early recognition and treatment prevent the development of more serious psychopathology in adolescence and adulthood. (/ ChiUl Neiirol 2004:19:7f)S-814).

Many children with a learning disability also have attention-deficit hyijcractivity disorder (ADHD), which can significantly impair the cliild's ability to absorb and make use of educational experiences and to function effectively in both academic and social environments. Awaieness of this association, which should lead to early diagnosis and appropriate treatment of ADHD, is an extremely important part of tlie management of the learning-disabled child. Appropriate management of ADHD helps the child deal with areas of deficit and use conipensatoty skills effectively. In this aiticle, I review some of the neurobiologic features of ADHD and its management. DIAGNOSTIC CRITERIA ADHD is a relatively common brain disorder, affecting as many as 10% of school-aged children. Currently, there is no "gold staiadard" or laboratory test to confirm the diagnosis of ADHD. Diagnosis is currently based on criteria from the Diagnostic mid Statistica! Manual of Menial Disonlers (DSM-IV), which lists nine behavioral characteristics (essentially "word pictures") for the inattentive type and

Rcceivpd August 20, 2004. Accepted for [Xiblication August 24. 2004. From the Western Institute for Neurodevelopmental Studies and Interventions, Boulder, ('O, Address correspondence to Dr Kytja K. S. Vopller, Western Institute for Neiirodevelopmenlal Studies and Intervention. 2501 Walnut Street, Suite 101, Boulder, CO 80302. Tel: 602-321-9725; fax: 303 443-4682; e-mail; k\oeller@ w orldnet. att. net.
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nine behavioral characteristics for the hyperactive-impulsive type.' To be diagnosofi with ADHD, at least six of the nine inattentive and/or hyperactive/impulsive criteria should be observed, both at home and at school. To meet the diagnostic criteria, the symptoms should significantly impair performance, be inconsistent with the child's developmental level, and be present for at least 6 months, and some symptoms should be apparent before age 7 years (although this last criterion has boon the subject of considerable controversy). However, determlniiig whether a patient meets a specific behavioral criterion (eg, "often has difficulty organizing tasks and activities") depends on the observers interpretation of terms such as "often," "difficulty," and "organizing." Parents (especially those who are divorced or separated) might disagree, with one parent seeing the child as active, impulsive, and disorganized and the other parent seeing the ciiild as "just having lots of energy." Sometimes parents see the child as having significant attentional and organizational problems, whereas the teacher perceives the child as "not trying" or vice versa. Nonetheless, there is often surprisingly good agreement between observers.^ In the last two decades, there has been a tremendous expansion of our knowledge about the neurobiology and natiual history of ADHD. In the DSM-IV, ADHD is conceptualized as falling into one of three categories: predominantly inattentive, predominantly hyperactive or impulsive, or combined. There is a continuing debate as to whether the diagnosis should be categorical (ie, making tight distinctions between those children w-ho meet criteria for specific numbers of symptoms) versus dimensional (ie, viewing ADHD as falling on a continuum). For example, in the categorical

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DSM-IV approach, a child who met the criteria for six of nltie .symptoms wotUtl l)e classified as having Ihe disorder but would not be so classified if he or she had only five of nine symptoms. It is likely that many of these debates will be resolved once there is grealer underetajKiing of the neurobiology and molecular genetics of this disorder. Some children with ADHD seem iinderaroiised, have difficulty initiating, are drowsy, and daydream, with variable attentiveness, and have been described as the "sluggish cognitive tempo" type.^ Although these symptoms had very high positive predictive power in the DSM-IV field trials, they did not have higli negative predictive power (ie, although the behaviors were strongly associated with inattention, their absence did not predict the absence of inattention). As a result, the sluggish cognitive tempo type of ADHD was not included in the DSM-IV diagnostic criteria.' Since the publication of the DSM-IV in 1994, information from neiirophysiologic imd genetic studies has provided support for this subtype. Based on a considerable body of research, the DSM-IV subtypes have been shown to differ in terms of age at onset, ratio of boys to girls, pattern of comorbid psycliiatric conditions, and neuropsychologic learning disability profiles. Age at Onset Based on the DSM-IV field trials, the symptoms of ADHD are apparent in most cases before the age of 7 yeai"s."' Although the median age at onset of the first symptom was 1 yeai, the median age at impairment did not occur until 3.5 years. The hyperactive or impulsive type etnerges earlier than the combuied tyi)e and significantly earlier than Ihe inattentive type. The mean age at onset of the hyperactive or impulsive type was 4.21 years and that of the combined type was 4.88 years. Most children with the hyperactive or impulsive and combined types of ADHD were considered impaired before age 7 years (98% and 82%, respectively). The inattentive type followed a different trajectory; the mean age at onset did not occur until 6.13 years, and only 57% became symptomatic before age 7 years. Only 85% of children with the inattentive-tyi^e ADHD manifested at least one symptom before they were 7 years old in comparison with 100% with the hyperactive or impulsive type and 96% with the combined type. Stated somewhat differently, 43% of the inattentive type met the criteria for impairment after age 7 years. Iti a large epideniiologic sample (the Great Smoky Mountains Study), a similar pattern was noted, with 25% of the youths with inattentive symptoms reporting onset after age 7 years, in contrast to 13% of the combined subtype, and SVa of the hyperactive or impulsive subtype reporting onset, before age 7 years.*' In our clinic, we have encountered adults who had not been diagnosed with ADHD tmtil they were well into their forties, after having struggled with their sytnptoms for mtich of their lives. Many sought care when their own children were diagnosed. Thus, although ADHD is a childhood-onset disorder, requiring a precise age at onset, particularly for the inattentive type, is probably not warranted." Early Identification It is apparent from tlie above that ADHD symptoms become appaienl in the preschool child. In fact, given the genetic nattire of the disorder (discussed below), it is not surprising that manifesta-

tions of ADHD might be apparent in infancy. Infants with the dopamine receptor 4 (D^) polymoiphism (hat is associated in older children and adults with ADHD are reported to have disorgaitized attjichnient behavior.^ Older children and adults with ADHD have been shown to have executive function deficits (disctissed below and in the article by Powell and Voeller in this issue'*). Preschool children with ADHD, when appropriately tested, have also been shown \o have executive ftinction deficits. In a study of 156 children ranging in age from 3 to 5y2 years, a cluster of executive ftmction deficitsworking memory, planning, set shifting and difficulty tolerating a delay in gratification^together accounted for 70 to 80% of the variance. ADIID symptoms were correlated in a linear fashion with both of these factors, wliich were also correlated with iige, IQ, and conduct problems.'" Goldman et ai described an attentional task for 2-year-old children, which is correlated with heightened right frontal evoked potential responses and has good interobserver reliability." Using standard clinical techniques, the diagnosis of ADHD, particuiaily the hyperactive or impulsive or combined type, can be reliably made in many children by the titne they are in preschool.'^ It is important to identify and treat children with ADHD as early as possible because the parents of preschool children with ADHD fitid them very difficult to manage and extremely stressful. '' Early treatment should also ameliorate later impairment in social beha\iors, as well as poor school perfonnance. Some researchers have suggested that ADHD follows a developmental pathway in which the earliest, manifestations are hyperactivity or imptilsivity, which then develops into ADHD of the combined lyjie during elementar>' school, and then evolves hito the inattentive type of ADHD after the hyperactivity or impuLsivity .symptoms fade and academic and social demands for autonomous functioning increase.'-'-"'' ADHD in Boys and Girls There are more boys than girls diagnosed with ADHD. In surveys dealing with children referred to clinics, the ratio of boys to girls vai'ies from 6:1 to 12:1. In epideniiologic samples, the male-tofemale prevalence ratio is much lower, 3:1, stiggesting that ADHD ill giris lends to be underdiagnosed. On the one hand, girls do not manifest disniptive behaviors to the extent seen in boys; girls w ith ADHD have half of the rates of conduct disorder and oppositional defiant disorder but are much more likely to have significant social problems."' Compared with boys with ADHD, they manifest more emotional distress, have higher rates of depression and anxiety, are highly vulnerable to stress, and have poor selfesteem and a limited sense of control. However, girls show an equivalent degree of prefrontal executive function impairment.'" On the other hand, compared with unaffected girls, girls with ADHD aie significantly impaired on the Global Assessment of Fimctioning Scale, as well as in cognitive ftinctioning and academic performance. They have higher rales of disniptive beha\ior disorders, are vulnerable to alcohol and di iig dependence, and are at risk of academic failure.'^'^ Comorbid Conditions II is tai e to encounter a child with "pttre" ADHD without other emotional or learning problems because ADHD is associated with an

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extremely high rate of comorbid psychiatric disorders and Ls usually acconipiinietl by a learning disability. Relatives of cliildreii with ADHD^"'^' are also at higher risk of neuropsychiatric disorders than relatives in the control families.^"^- Conduct disorder, oppositional defiant disorder, niiyor affective disorder (depression or bipolar disorder), anxiety disorder, including obsessive-conipttlsive disorder, and Tourette syndrome are all such comorbidities. Tcenagei-s witli AUHl). particularly untreateti ADHD, aj e at risk for drug and alcohol abuse. In addition, many individuals with mental retaidation and autistic spcctrtmi disorders (ie, pervasive developmental disorder, autistic disorder, Asperger's syndrome, and nonverbal learning disability) also often have associated ADHD. Language disorders are frequently associated with ADHD.-'' In one tepoit, 45% of children with ADHD had at least one element of langui^e inipainnent, and children with both specific language impairment and ADHD appealed to have greater difficulty with verbal short-term memory.^ (Also see the ariicle by Suiidlieim and Voeller in this issue for further discussion of this association.^) Language inipainnent in ADHD has been considered by some to reflect a common imderiying prefrontai executive function deficit.^'' Learning disabilities (dyslexia and dyscaiculia in particular) iu-e frequently associated with ADHD.-""^'' In the Remediation of Dyslexia study, we observed that of the 60 children selected because of severe phonologic awareness deficits, 80% met the criteria for ADHD.^^*' Boys with ADHD and learning disiibility tended lo have more serious executive function deficits titan boys who were not learning disabled.^' Motor incoordination is often associated with ADHD''' and can be an early and prominent feature in the preschool child who will develop ADHD symptoms. Kadesjo and Gillberg in Scandinavia pointed out the syndromic nature of this combinationdeficits in atlention, motor control, and perception (DAMP).'' Neuropsychologic Profiles and ADHD Subtypes Neuropsychologic studies on children with ADHD have revealed a pattern of cognitive deficits consistent with prefrontal executive function deficits: inattention, difficulty with self regulation, response inhibition deficits (inipuLsivity), restlessness or hyperactivity, or apathy in some cases.'* However, depending on a number of methodologic variables, including subject and control group selection and the presence of certain comorbid disorders, the results have been somewhat variable. In a study drawn from a community sample, children were examined to fmd out if the inattentive and hyperactive or impulsive dimensions and subtyi^es based on the DSM-IV criteria were iissociated with different neuropsychologic profiles. The researchers found that the inattentlcjii dimension, not the liyperactive or impulsive dimension, was associated with signifit ant neuropsychologic impainnent. They suggested that both the inattentive and hyiieiactive or impulsive symptoms can relate to a latent, trait, "disinMbition," with the inattentive symptoms referring more to the cognitive aspects and the hyperactive or inattentive symptoms relating to behaworal aspects.'^'' The inattentive and hyi^eractive or impulsive types also diffei' in hcritability. In a study of twins with ADHD, a high level of inattention was heritable regardless of the degree of hyperactivity and impulsivity. On the other hand, higli levels of hyperactivity and impulsivity were tightly linked to the num-

ber of inattention sympt onis manifested by the twin with ADHD.''^ This suggests the intriguing possibility that the essential dysfunction in ADHD involves inattention and disorganization rather than hyperactivity or impulsivity, as has been believed, and that hyperactivity or impulsivity might result from some other factor. Neuroanatomy and Physiology of ADHD Behaviorally, ADHD is a disonler of self-regulation, which implicates some sort of dysfunction of thefrontal-subcorticaJsystem.*''^'^^ Many magnetic resonance imaging (MRI) mon^honietric studies (ie, studies involving measui-ements of various brain regions) have been t onducted using different techniques and different populations (iiiclutiing subjects from different regions of the globe). Tliese studies iiave identified relatively consistent diffeiences in tlie brains of children with ADHD compared with those of normal controls. A large, well-designed longitudinal study involving 541 MRIs from children with ADHD and age- and sex-matched conti'ols has provided evidence that ADHD is associated with an atypical pattern of brain development that appears in early childhood.'" The nx^or findings of these studies are summarized as follows; 1. Total cerebral volume is smaller in individuals with ADHD and in controls. There is a small but significant reduction (on the order of 5%) in mean total cerebral volume or intracranial volume.""'' In one study comparing boys with ADHE), their unaffected male siblings, and matched (controls, the subjects with ADHD had a significant (4%) reduction in intracranial volume. Their unaffected siblings had a 3.4% reduction compared with controls (a statistical trend). Cortical right prefrontal gray matter and left occipital gray and white matter were reduced in the subjects with ADHD and their siblings,'- This suggests that changes in cerebral volume need to reach a certain crucial level before they become obviously symptomatic. Moreover, this study strongly supports the genetic basis of ADHD. 2. Frontal lobe volume is smaller in persons with ADHD. Brain regions involved in self-regulation (executive function) show differences from those of controls. In most, studies, the frontal lobes or subregions of the frontal lobes were found to be smaller in subjects with ADHD than in controls."'"^'' *^"^" In one study, the inferior portions of dorsal prefrontal coriices and anterior temporal cortices, bilaterally, were reduced in subjects with ADHD.'" 3. Various regions of the basal ganglia, particularly the caudate nucleus, have been reported to be smaller in children with ADHD compared with controls.^" *''^'''" Studies on normal individuals have shown that the caudate decreases in size as the cluld matures (a manifestation of the normal "pruning" of nemons seen in many parts of the brain during development). Children with ADHD start out with smaller caudate nuclei than controls, and with maturation, there is a further decrease in size. As a result, any difference in size between children with ADHD and controls becomes less apparent with increasing age.'"'""' (This might explain the variability- in size observed in different studies because the age of the subjects varied considerably across these studies.) Other regions of the basal ganglia have also been reported to be reduced in volume in subjects with ADHD relative to

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4. Right hemisphere structures are affectefi more than left hemisphere Biructiires, hi normal child and adult populations, the riglit. frontal area is larger than the left frontal area. Given the important role that tlie right hemisphere plays in l-egiilating attention and the deficits seen in ADHD, it would not be siiri^nsing to observe reduction in riglit frontal lobe volume. This was not a consistent finding, but it was noted in a number of studies. """''' In some studies, a decrease in the right frontal giaymatter volume was noted, or changes in volumes of certain subcortical stnictures were more prominent on the right.^"'^'It is possible that the reduction in size is due to (he reduction of global brain volume, as suggested by C^astellanos et al.^" In normal adults, the right caudate is laiger than the left caudate."'"^''' I lowever, based on the laige National histitute of MentiU Health study of children with ADHD, the right caudate nucleus is smaller tlian the left caufiate nucleus.''* This asymmetry was not necessarily obsei^ved in ;U1 sluiUes, but they generally involved many fewer t hildren and were not longitudinal. ''*'-^" 5. There is a relative decrease in the size of the cerebeUuni. The cerebellum also participates in the regulation of executive function as a result of its reciprocal connections to the prefrontaJ cortex.* The decreased size of the cerebellum in children with ADHD was initially described by Castellaiios et al" and has been coiToborated in a number of other studies.^"'^^"'^""'^' 6. A number of studies reported a reduction in the area of tJie anterior"-"'"-"'^ or posterior corpus callosum."^' However, in the laige National Institute of Mental Health study, this was not confirmed.'' It is worth noting that treatment with psychostimulants was not responsible for the reduction in various brain areas because these findings were also noted in children who were drug naive. Interestingly, children on psychostimulant treatment actually had somewhat, greater white-uiatter volumes than those who had not been treated. "' hi summary, there is now much research suggesting that, when carefully examined, groups of children with ADHD have small but significant reductions in total brain volume and in the various regions of the bniin that are involved in the regulation of attention and impulsivity. This would suggest that the behaviors seen in children with ADHD are not simply the result of environmental factoi-s or some sort of distortion of perception on the part of parents and teachers, but rather a very real brain dysfunction. Functional Neuroimaging Studies I"\mctiona! neuroimaging studies have been used to study individuals with ADHD and controls and are consistent with the morphometric findings. These studies also revealed dysfunction of the prefrontal-subcortical system, often with greater involvement of areas of the right hemisphere.^^' [Note: Functional neuroimaging studies involve a nuinbei of different techniques: positron emission ton\ographic (PET) scans, fiuictional magnetic reson^ice imaging (fMRI) scans, single photon emission computerized tomography (HPECTj, and magnetic resonance spectroscopy (MRS). The conunon feature of these studies is that they enable us to examine the brain while it is performing various cognitive or behavioral tasks and provides a remarkable window in the understanding of

brain function.] A study of adolescents with ADHD using positron emission tomography (PET) with ['"Fl-fluorodeoxyglucose revealed that global cerebral glucose metabolism in tlie atlolescent girls with ADHD was 15% lower than in the contjol girls and 19.tj% lower tlian in boys witli ADHD.''"* Bniin regions in which this lower activity was observed were the right frontal premotor cortex and right temporal cortex. Activity was decreased bilaterally in the posterior putamen aiid middle cingulate coitex. Tliesefindingswere not continued on a subsequent study, but it was noted tliat the degree of sexual maturation was probably a variable that had not been taken into consideration.'"'" A study of adults (18.1 to 50.8 years of age) with ADHD by the same investigators demonstrated that global cerebral glucose metabohsm was reduced in women with ADHD but not in men with ADHD or in control men or wouien. Women with ADHD demonstrated better performance on the auditory attention task with increasing age. These findings suggest a couiplicated interaction between gender, age, and honnonal effects.^" In iinothor PET study of adolescents in the age range of KJ to 14 years, in which tlie effects of sexual maturation were controlled, subjects with ADHD had a higlier accumulation of dopa decarboxylase (indicating a high level of dopamine synthesis) in the right niidbrain than controls. Although tiiis study was not without uiethodologic problems (it involved a small number of subjects, the "controls" were siblijigs of the ADHD subjects, and the findings were significant ouiy when computed witliout atljustments for multiple statistical comparisons), it still suggests that the dopaminergic system is dysfimctiona! in persons with ADHD. Wlien cliildren are asked to peifonn a task that places demands on the frontal executive system, those with ADHD have atypical pattenis of activation. In one study, children with ADHD and controls were studied using functional MRI during a go/no-go task. [Note: Go/no-go tests involve establishing a pattern of response to a specific "go" signal and then inhibiting the response when a "nogo" signal is presented. It is one test of executive function in that it requires the ability to inhibit an established pattern of behavior. One example involves making two taps with a hand when the examiner makes one, and then when the examiner makes one tap, the subject makes none. Children have greater difficulty with these tasks thaji adults, but the child with ADHD has much greater difficulty than oUier children of the same age. ] In general, functional MRIs on children performing tasks that demand executive function control have somewhat different patterns of activation than are seen in those of adults.'' However, children with ADHD do not activate frontostriatal networks to the same extent seen in the children without ADHD but, rather, manifest a more diffuse acUvat.ion pattern than was seen in controls, suggesting that the development of frontostriatal circuits was delayed in children with ADHD.'^ In another functional MRI study involving children with ADHD and controls performing two somewhat different types of go/no-go tasks, children with ADHD made more errors than controls. ^^ In one task, childien with ADHD activated frontal ai'eas to a greater extent than controls. Although this is not consistent with the findings in other studies, it is possible that the task required the subjects with ADHD to exert more effort than controls. (In this study, other brain regions were not examined so that there was no opportimity to see the diffuse activation pattern described in the Durston et al study."-} After receiving methyiphenidate (Ritalin), both groups

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of cliildren made fewer errors, with a highly significant improvement in the ADHD group. Methylphenidate increased frontal activation in both groups and increased striatal activation in the children with ADHD but decreased it in the controls.^-* Some SPEt'T studies liave identified decreased activity involving the temporal lobe and cerebellum in some children witli ADHD.'^ This would support the observation that the dysfunction in ADHD involves nol only the trontal-subcorlical circuits but also the integration of temporal lobe and cerebellar function in emotion, cognhion, and motor jjlanning.'"^ A decision-making gambling task developed for patients witli prefrontal deficits was administered to adults with ADHD. Subjects were required to choose between immediate rewards with the risk of high long-term losses and lower immediate gains with lower long-term losses. The ability of adults with ADHD to tolerate delays in gratification was studied using PET while they perfonneri the gambling t.ask. A control task was also employed. Adults with ADHD did not activate the prefrontal cortex during the decisionmaking process to the same extent as did the controls and did not acti\ ate tlie anterior ciiigulate and liippocanipus, which are involved in emotional arousal and memory. However, the subjects with ADHD activated the posterior right anterior cingulate more than the controls." In stmmiary, neuroimaging studies reveal that children and adults with ADHD activate frontal subcortical stnictures to a lesser extent thiui control subjects. Although the pattern of activation in children with ADHD is somewhat more diffuse, they, like adults with ADHD, do not activate areas involved with emotion and memory to the sanie extent that controls do. This is consistent with the observed difficulty that these individuals have in motivation and aiousal. Elec trophysiology Electroencephalographic (EEG) studies of children with ADHD reveal an excess of slow-wave (theta) activity consistent wil h decreased alertness and underarousal. [Note: EEGs are "brain wave" studies that record electrical activity of the brain by means of electrodes to the scalp. Diffei ent patterns are noted in sleep and wakefulness. Increased slowing during wakefulness is consistent with a lower level of alertness or ilisttirbance of cerebral function. 1 These EEG patterns correctly classify over 909i) of cliildren with ADHD and normal controls.^''' However, althotigh there are clearcut differences between the EEG patterns of children with ADHD jind those of controls, there is enough heterogeneity in the ADHD group to limit the diagnostic efficacy of this technology.^" Comparing the EEG patterns of children with ADHD and controls, group differences were found in the mean frequency of the total EEG, as well as the specific amotmts of activities of different frequencies (theta, alpha, and beta), the ratios of these different frequencies, and the troherenc^e patterns across tJie three grtjups.^'^' Tliese EEG patterns suggest reduced cortical differentiation and specialization in ADHD, more prominently in children witli tlie hyperactive or unjiulsive type than in those with the inattentive tyj^e. Moreover, children with the inattentive type of EEG were fotmd to have two different EEG patlerns, one consistent with hypoarotisal (renuni.scent of the sluggish cognitive tempo type described by Laliey et al') and one consistent with a maturational lag.**'

In summary, quantitative EEG patterns appear to demonstrate differences in children with ADHD and those witliout ADHD. However, diagnostic accuracy is not much better than the clinical assessment and requires specialized equipment and technical expertise. Given the possibility that there can be different EEG patterns seen in children with ADHD, this technique appears to have limited application at this time; however, it might be useful in determining the response to medication"^^ and possibly will be more meaningful once ADHD genetics are unraveled. In siunmary, elect rophysiologic studies of children wilh ADHD reveal atypical brain wave patterns, which suggest dysregulation of arousal and attention. ETIOLOGY OF ADHD ADHD is a highly heritable disorder. However, it can also be acquired, and some individuals liave a combination of genetic and acquired ADHD. At the present time, it is not possible to distinguish between these two tyjses of ADHDthey both look the same, and both usually respond to treatment with tlie same psychostimulant medication. Genetics of ADHD ADHD is, in most cases, of familial origin. Parents with ADHD have a better than 5(yA> chance of having a child with ADHD, and about 25% of cliildren witli ADHD liave i)ai ents who meet tlie fonnal diagnostic criteria for ADHD.*^' Twin studies have placed the heritability of ADHD in the range of SO'fii.^' In a longitudinal twin study examining the size of genetic and environmental effects on ADHD behaviors based on maternal report at the ages of 3, 7, 10, and 12 years, theestimateof heritability was nearly 75%at each age, with hyperactivity at age 3 yeais behig somewhat less related to later inattention and inattention at age 7 years being quite stable. The genetic factors explained 76% and 92% of the covariance between hyperactivity and inattention.*^ This provides another luie of support for the observation that behaviors related to ADHD (inattention to a greater extent than hyperactivity) do not improve with maturalion. ADHD can be considered a disorder of neurotransmitter function, with panicular focus on the neurotransmittcrs dopamine and norepinephrine. There has been extensive research conducted that demonstrates that dopamine is critical in the regulation of learning, as well as maintaining trained or conditioned responses and motivated (goal-directed) behaviors."^^'" Dopamine also plays an important role in working memory, the ability to "keep something in mind" for a brief period of time."'"^ Thus, dopamine can modulate neuronal activity related to motor activity that is guided by external cues and is goal directed.^'' Dopamine plays an important role in the function of the prefrontal-subcortical system. Norepinephrine (noradrenaline) is involved in maintaining alertness and attention. Norepinephrine neurons are triggered by novel and important stimuli and are quiescent during sleep. Psychostimulant medications that increase the amount of central dopamine and norepinephrine are typically the most effective way to treat ADIID. To sunmiarize, dopamine is the neurotransmitter that regulates the system that plays an important flmction in learning, motivation,

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goals, drives, and emotionall of which are crucial to survival. Norepinephrine is the neurotransmitter involved in the detection of t hose st iimili that are important or novel and maintains the organism in a state of alei-tnpss and readiness as needed to process these stimuli. Tiiis system appears to be impaired in children with ADHD who have difficulty regulating their own level of aleitness and awareness of important stimuli."^ Genetic studies of ADHD have focused on genes involved in the regulation of neurotransmitter function, mainly related to dopamine, although some studies have also examined the role of norepinephrine and other neurotransmitters. Many different processes are involved in neurotransmission. These and a list of c andidate genes for ADHD ai'e summarized in Table 1. It is unlikely (hat a single gene will be linked to ADHD: rather, ADHD might be due to the interaction of several different genes involved in the function of several different neurotransmittere. In addition, individuals' genetic makeup will determine how they will respond to specific medications used to treat ADHD. Thus, we are at the beginning of a process that will not only make it possible to carry out more sophisticated diagnostic processes but will also make it possible to develop more sophisticated and effective approaches to treatment. Acquired Brain Lesions and ADHD The liehaviors associated with ADHD can also iuise from environmeiilal factors that disnipt nonnal brain giowih, before, during, and after birth. Such insults give rise to behaviors that are indistinguishable from the behaviors seen in ADHD of genetic origin. It is not unusual to see individuals who have botli a genetic and an acquired form. Multiple pre- and perinatal factors can result in ADHD.""' One such factor is fetal alcohol syndrome, which results in significant inattention, impulsivity, and hyperactivity in the child. Exposure of the fetus to alcohol is associated with a reduction in the volimic of the prefrontal and temporal coriicesIhe brain areas involved in regulation of attention and control of impulsivity.'"'"' Maternal smoking has been linked with ADHD."'*'"' Even though women with ADHD are at increased risk of becoming smokers and the child's ADHD might be genetic, exposure of the fetus to cigarette smoking confers an increased risk.'"" One study found a fourfold higher risk of ADHD in the offspring of smokei"s, even after controlling for maternal ADHD."" Metabolic disorders of the mother (eg, diabetes, phenylketonmia) caii aiso result in an ADHD-like picture in tlie infant.'"The dopamine system is exquisitely sensitive to hypoxia, p;irticularly in tlie fetus or infant. Tlius, any events pre- or postnatally that disnipt the flow of blood or oxygen to the brain might set the stage for later ADHD behaviors. This observation is supported both by laboratoiy studies""'"^ and a study of ex-prematme infants who had docimiented cerebral ischemia at birth and were re-examined in early adolescence.'"'' Iron deficieiKry is associated witli disniption of the dopamine system and more extensive neurodevelopmental problems.'"" It. is rarely a cause of ADHD because most children in the United States receive diets with adequate iron. Injury to the medial temporal lobe during early development is also associated with ADHD-like behaviors later in development,

possibly because of the disruption of dopamine regulation in the dorsolateral prefrontal cortex. Tliis has been shown in nonhuman primates'"^'"" and children with temporal lobe cysts.""' Hyperbilinibinemia (jaundice) in the newborn period can evolve into an ADHD-like picture later in childhood. In the past, before effective treatments were developed, neonatal hyperbilirubinenia resuhed in severe and irrever-sible damage to the basal ganglia (spe( ifitaily the globus pallidus imd siibthalanuc nucleus). (Bilinibin is a mitochondrial poison and affects calcium homeostflsis, resulting in neuronal death.) However, it has become apparent tliat even moderate levels of bilinibin in othei-wise healthy infants might not be as benign as previously believed.'^"'" Any injury to the brain that affects tlie prefrontal-subcortical circuits can result in an ADHD-like picture. Traumatic iiyury often involves damage to the tips of the frontal lobes or shearing of white matter tracts and often results in ADHD-like behaviors."-"'' In one study comparing monozygotic twins who were discordant for ADHD, caudate lesions were observed in the twin with ADHD."'' Similajiy, children who have suffered strokes, particularly those involving subcorticsil areas in the prefrontal-subcortical circuits, not infrequently manifest ADHD-like behaviors. In one study, neai'lyhalfofthe children developed ADHD following stroke,"**and there wiis a strong correlation between lesions of the putamen and ADHD symptomatology."" Meningitis and encephalitis ai'e also associated witli ADHD-like behaviors. Autoimmune disorders have also been implicated in triggering ADHD-Uke symptoms in susceptible patients. Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) is linked to Tourette syndrome, obsessive-compulsive disorder, and ADHD.'-" Lyme disease has also been associated with a number of neuropsychiatric symptoms, includmg those of ADHD.'^' The role that environmental factors play in ADHD should not be minimised. Eaily deprivation can result ui ADHD symptoms in later childhood {increased rates of attention deficit and hyjieractivity have been observed in children who were raised in institutions). These children also have a somewhat different set of associated psychiatric disorders than children with genetic ADHD and have disturbed attachment.'^^'^^ Children who grow up in chaotic environments often have difficulty regulatii^g altention, impulsivity, and emotionality. The risk of ADHD is proportional to the number of adverse factors (eg, poverty, maternal psychopathology, paternal criminality) that are present.'-' TREATMENT OF ADHD This section focuses on some general principles of the treatment of the child with ADHD. Principle 1 The treatment of ADHD involves the selection of an appropriate medication at an appropriate dose in combination with behavioral tlierapy. A number of different medications are now available for the treatment of ADHD, and the generic names and trade names are listed in Table 2. A specific discussion of the selection of a medication for a given child is beyond the scope of this article, but it is worth a brief review of the Multimodal Tieatment Study of Children With ADHD

804

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Journal of Child Neurology I Volume 19, Niimbor 10, October 2004

(MTA), which was cosponsored in 1992 by the National Institute of Mental Health aiid the US Depaitnient of Education.'"' This study provicjes a great deal of valuable information about the treatment of ADHD. It was conducted at six different sites in North America and involved 579 boys and girls who met the DSMIV criteria for ADHD, combined type, and their families. The children were randomly assigned to four different treatment conditions: medication only, medication plus behavioral treatment, behavioral treatment only, and "community care" (ie, after the initial evaluation, faiiiilies were provided with a report summarizing the iissessiuent results and a list of mental heaiOi resoLirc(> in tJieir community and were then followed as part of the study). The medication management protocol (used for the medication only and the combined treatment groLips) involved a sophisticated titration phase: the child was tried on a range of doses (including placebo) given at hreakfast, at lunch, and in the afternoon dtiriiig a 28-day titration period. Medication ajid jilacebo folkiwed a random schedule, and both the parents and the clinicians were unaware of the dosage or whether the child wsis receiving placebo or active drug. Daily records oi' behavior and side effects were kept, and the optimal dose was selected after the records were reviewed blindly by experienced diniciaiis at a <iifferent site. Of the 289 subjects who entered this segment of the study, 256 completed it. After the optimal dose was determined, the children were seen at monthly visits, and the response to the treatment and side effects were monitored. No side effects were reported in 35.9%, mild side effects in 49.8%, moderate side effects in U.4%, and severe side effects in 2.99^1. In about half of those children who had severe side effects (depression, worrying, irritability), tiie side effects might have been tmrelated to the medication. Interestingly, teachers reported more side effects when cliildren were on placebo, suggesting a "negative halo" effect, and teac hers saw fewer side effects with ijicreased dosage. Parents proved to be more reliable monitors of side effects, and many of tiie side effects occurred as an "end of dose" phenomenon (ie, they were worse as the medication was wearing off). The most common parent-reported side effect involved decreased appetite, stomachaches, tearfulness, trouble sleeping, headache, and a dull or listless appearance. (Parenthetically, it should be noted that some of these "side effects" are present in cMdren with ADHD even before medication is started and can often be remedied by an adjustment in timing and dose.) Behavioral treatment administered to tlie combined medication and behavioral treatment group and the behavioral treatment only group involved parent training, child-focused treatment, anti a school-based intervention organized and integrated witlun the school. The child-focused program was based on the summer treatment pn:)gram developed by Pelham and Hoza and involved an 8-week progrjuu, 5 days per week ai\d 9 hours per day, delivered in group-based recreational settings, with specific rewards, timeout, and social skills training, as well as individualized academic skills practice and reinforcement of appropriate classroom behavior.'-" The school-based treatment involved 10 to 16 sessions of biweekly teacher consultation and 12 weeks of part-time interventions, with a paraprofessional working with the child. A daily repoit cai-d was filled out by the teacher and went home with the child, to be reinforced by the pai ents on a daily basis. In short, the behavioral treatment was well designed and intensive, to a much

greater degree than would usually occur in a standard clinical or school setting.'-'"' At the end of the 14-month period, the results indicated that the medication management alone and combined medication and behavioral treatment gioup showed a considerably more robust response than the behavioral treatment alone and community care groups. Combined treatment was superior to the behavioral treatment for internalizing problems, oppositional oi' aggressive symptoms, and reading achievement scores. Another interesting facet of tlie study was that the medication dose w;is acljusted Lipward durhig the 14 months of the study, but the rate of increase was less marked in the combined therapy group. The optimal dose for most children was in the range of 1 mg/lcg/dose, which is somewhat liigher than is often used.'"" When the children were re-evaluated at the end of 24 months, 68% in the combined group, 56% in the medical management grotip, 3-l% in the behavioral treatment group, ajid 25% in the conuiumity care group showed improvement.'^'' Thus, in summary, the results of the MTA study support the use of medication in the treatment of ADHD. The rate of side effects was quite low. The combination of medicine and behavioral management was associated with a better 2-year outcome than the medication group alone, hi the long mn, the difference (68% \% 56%) was relatively small but was significantly better compared with behavioral treatment alone and community care. The behavioral treatment was extremely intense and involved (I) parent traiiiing, (2) individual work with the child, (3) integration of the school into tlie behavior program, and (4) a daily report card completed by the teacher, which was then used by the parents to deliver consequences. This large, well-designed study strongly supports the use of medication integrated with a behavioral program. Principle 2 Adequate behavioral therapy involves intensive and prolonged pareTil involvement and cooperation from the teacher With regaid to the parents' role in the management of ADHD, there is little question that the optimal management of a child with ADHD requires an enormous time and energy commitment on the part of parents to maintain an exti emely liigh degree of consistency and structure. The goal is to help the child become aLitononious in setf-regulation. The parent needs to learn to act as an "accessory frontal lobe," at the same time helping the child to develop increasing insight and competence in his or her own behavioral regulation. Depending on the child's age and the associated learning and behavior problems, as well as the environment, this might not be an easy or rapid process. Very young children with ADHD require close parental supervision, and children in elementary and middle school need contiiiuons monitoring and support for school work. Adolescents, particularly those who have been recently diagnosed and treated, pose a special challenge. They have had a number of yeai's to develop dysfunctional strategies and require close supervision and support and usually individual therapy. Although the child with ADHD does well when provided with structiue and predictability, this ciui be something of an oxymoron in a busy household. In the role of "accessory frontal lobe," the parent must learn to anticipate problems and tievelop a tactful approac'h to dealing with them. For example, helping a young child get organized for

Attention-DeHcit Hyperactiv-ily Disorder (ADHD) / VoeUer

807

school in the morning is often stressful for nuuiy families, A standard complaint is that the child with ADHD dawdles while getting dressed and delays the family's departure. (The frustrated mother of one of my patients reported that her 10-year-old daughter seemed to be luiable to get dressed and gel downstaii"s in time to eat breakfast, whereas her 5-year-old daughter was able to do this autonoinously and consistently.) Although medication often decreases the severity of the problem of getting ready for school, the parent needs to provide support until the medication has laken effect in the morning. This requires making snre that the child gets up early enough and receives medication and, then, if necessary, is monitorefi during the dressing process (this does not mean dressing the child but ratlier helping the child stay on track and complete the process on his or her owii). This also means that the parent needs to be up early enough to manage this process. It is important to make sure that the child has organized the backpack lor school the night before, again requiring close supervision. Bedthne is another problematic time. Given that many children with ADHD (on or off medication) have difficulty settling down to sleep, a lengthy and predictable bedtime routine t)ften needs to be in place to help the child calm down. Wlien both parents work and arrive home after 5 pm, this whole process requires split-second timing and teaniwork to prepare dinner, wash the dishes, supervise homework, perform the backpack check, and get the child to bed on time. If a parent is busy or absent, it is important that whoever takes over- knows what the routines and expectations are. Having a child with ADHD si>end time in multiple envuonments (school, an after-school program, a baby-sitter's home, and, if tlie parents iire divorced, different homes) can be extremely disorganizing. Even when there are several children in a liousehold, maintaining routines and anticipatoiy management strategies requires considerable managerial skill. L nfoitiinately, many houseliolds have difficulty in managing these routines. Because ADHD is such a strongly genetic condition, one or both parents can also have ADHD, which often makes it extremely difficult for parents to regulate their own behaviors enough to adhere to such routines, let alone provide the systematic support that the child requires, In a study that examined the pai-enting styles of parents who described themselves as inattentive and impulsive, fathers with this profile reported lax paienting both before and after parent training. Even after parent training, tliey tended to overreact. Mothers who described themselves as having moderate levels of iaiattention had the most negative parentchild interactions.'^ Although parent training is often very helpful, there are occasions when the situation improves only after the parent's own attention problems are medically treated. One mother complained that lier son was unable to keep track of his homework, forgot his assignments, and, on tlie rare occasions when he did complete tlieni, often forgot to turn them in. This pattern had gone on through elementary school, so that the boy (then age 12 years) was not particularly motivated to change his modus operandi. To effectively deal with this problem, his mother needed to monitor him closely, keep in touch with the school on a daily basis, and make sure that positive rewards occurred when he completed his work. After several months, it was apparent that she could not do this in a consistent manner. She recognized that some of these difficulties were

due to her own inattention and, once she was staited on medication for her own ADHD symptoms, was able to provide the required stnicture much more effectively. Principle 3 Treatment of ADHD is not the same as treating a learning disorder, ajid vice versa. Given tlie high degree of coinoil)idity between ADHD and learning disorders, a child should be carefully evaluated for a learning disorder, and treatment should be put in motion for remediating the learning disorder. Principle 4 Making sure that the child gets enougli to eat, gets enough sleep, and has sufficient exercise is a crucial part of the treatment. Altliough medication might help a sleepy child stay awake during school, chronic sleep deprivation is not conducive to learning. It takes creative parenting to make sure that the child gets enough sleep and remains on schedule over the v\'eekeiids. Some children requii'e 10 hours of sleep, and the logistics of getting the child to bed on time while completing the rest of the evening routine are formidable. Eating is another problem: some children on medication are simply not hungiy at dbmer and start foraging lor food about the time tliey are expected to go to bed. Parents often view this as stubbornness or manipulation, but it iLsually works better for cluldren to eat if they are hungry. Making sure tiiat they have eaten breakfast and have a snack in the afternoon is also helpful because psychostimulant medication can suppress hunger, and they might not be aware that they need to eat. Vigorous exercise on a daily basis is extremely helpful not only for the cardiovascular benefits but also because exercise helps increase arousal and enhances brain-derived neurotrophic factor, which facilitates memory and learning.' Providing the child with opportunities to n\ove around after workijig on a project for a given length of time is helpful. However, many pai ents have difficulty finding time for their own exercise program, let alone developing one for their children. Principle 5 Encourage self-awareness and autonomy. Helping children with ADHD understand themselves so that they can function effectively is important. Telling them that they are "hyper," "ADHD," or "disorganized" (particularly if this is communicated in moments of anger) is much less helpful than defining the dysfunctional behavior in very concrete terms ("You have trouble keeping track of your homework, so we will work out a system together that will make it easier,"). One 40-year-old man who had asked to be evaluated iifter his son was diagnosed with ADHD pointed out that when he was growing up, he always had the sense that whatever he was doing was "never enough." It had been made clear to him that if he just "tried harder" and "did something different," he would perform better. However, he had no idea what "trying harder" and "doing something different" meant. This emphasizes the need to lay out a very clear and explicit program. When a child tells a parent or a teacher tl\at he or she cannot do something "because of the ADHD," this should be treated as a serious problem and addressed immediately; the child usually employs this as a way of not carrying out an unpleasant task. Tlie more a parent or teacher buys into the

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Journal of Cliild Neurology I Volume 19, Number 10, October 2004

"I caii't do it because I have ADHD" roiiline, the more the chiltl will use this excuse. Principle 6 A child's compliance with a routine should be closely monitored, antl reminders as well as consequences should be provided. Children with ADHD cannot monitor theii- own behavior well, so frequent pieasant and focused reminders when they are tirifting away from the program are helpful. Rewaiding compliance witli routines worky better than pimisliing noncomplianre, and sometimes letting a child experience a "natural consequence" helps reinforce the routine. Thus, if a child does not perfonii the nightly routine of checking the backpack and forgets homework, a series of natural consequences might ensue. (However, if the child's teacher does not respond with an immediate consequence if the homework is not turned in, the child leanis that it is not very important to perform this routine.) Natural consequences are usually better than "unnatiu-al" consequences. When it comes to long-range projects, i>arents need to Vie aware that it is extremely difficult for a child with ADHD to anticipate and plan a long-tenn project, so moniloriiig homework and providing tactful reminders and assistance ("Let's plan out how you're going to tackle your book report that is due next month"; "Have you put the report in youi- backpack?") aie more helpful Ihiui allowing the due date to creep up or to let the child foiget the final version. If a child has done well working on such a long range project, but tiien forgets to turn it in on time, such a "natural consequence" might be unnecessarily harsh. Principle 7 Teacher involvement is crucial. The teacher is a very important player in this situation. If there is minimal feedback from the teacher, or it does not occur in a very timely fashion (ie, the stuue day), it is almost impossible to improve the situation. A child learns quickly that if the homework assignment is written illegibly or is "forgotten," or if he tells his parents convincingly (but untruthfully) (hat he "has no homework," or the necessary workbooks or other materials are not brought home, then the homework cannot be completed. At 7 o'clock in tlie evening, it requires a herculean efforl for the parent to correct the situation. This strongly reinforces homework avoidance. Children witli ADHD benefit enoniiously from daily communication between the parent and teacher, with the focus on fixing responsibility on the child and teacliing tlae cliild to monitor his or her own homework. However, this means that the teacher must check the homework list, might need to remind and monitor what materials the child is taking home, and pro\1de immediate feedback to the pai'ent if homework is either not turned in or is substandai d. The parent then becomes responsible for delivering piompt rewards or negative conse((uences. Be forewarned: ti-aining these behaviors takes a long time and requires great persistence on the part of parents. I have worked with children who have perfected the art of "flying under the radar." One normally intelligent but language-disordered 12year-old boy was able to generate such a cioud of confusion around homework that he almost never had to ck) it (his family had no idea of tlie status of his homework). When tlie parent and teachers began to communicate very closely and a tight behavioral

prognmi was set up, it required almost 24 months for this child to beghi to change his behavior. Some Information About Medications for ADHD Pai eiiLs ajid teachers sometimes state tliat a cliilit cannot liave ADHD because the child is not "hyper." Some believe that psychostimulant treatment is designed tx) "slow tlie child down, andfindit liai'd to imagine tiiat a cliild wbo is slow-moving, di-eaniy. clironically disorganized, and somewliat. unaware of his or her surroundings would benefit from the sanie medication used to treat a c'hild with riuupanf hyperactivity and inipulsivity, but the medication works well in both situations. Psychostimulant medication appears to activate neural networks, subserving performance of specific tasks.'" A nuuiber of different types and fonnulations of medication are now on the market. Medications used to treat ADHD act by inhibiting the dopamine transport,er (methylpbenidate) or increasing dopaiuine release into the synaptic cleft (dextroaniphetamine), or a combination of both mechanisms. Although the vast m^ority of children respond to methylphenidate or dextroaniphetamine, an o( casional child does not. Medications that increase norepinephrine (eg, tricyclic antidepressants) might be useful in treating children who have failed psychostimtilani treatment."- Bupropion and atomoxetine (both of wliicli increase centiai dopamine and norepinephrine) are also medications that might be helpful in this situation. Pemoiine, which has the potential for liver damage and requires repeated blood tests, is useful in the treatment of drugabushig adolescents. Modafinil, which is used to treat narcolepsy or daytime drowsijiess in adults with partially treated sleep g^nea, might also be helpful. Parental Concerns When the diagnosis of ADHD is made and medication is recommended, parents often state that ADHD is diagnosed too frequently, and the solution is to "tlirow medicine at it" ratlier than look for "the root cause." As discussetl above, the root cause involves dysfunctional brain circuits, which are either genetic or acquired, and the most effective treatment involves psychostimulants and behavioral treatment. What are the risks of not treating ADHD? Although parents are often concerned that starting a child on psychosthiiulant medication will jncrea.se the risk of dmg abuse in later life, available data would suggest that it is quite the reverse. Children with ADHD, particularly those who are not treated with psychostimulants, are at nmch greater risk of drug abuse than children without ADHD.''*^ They start smoking at an eai'lier age than peers, possibly because nicotine enbajices attention. '^' They also tend to be drawn into deviant peer relationships, which ai'e strongly associated with drug abuse, and are especially vulnerable to these undesirable social influences, further increasing the risk of dmg abuse.''''' Appropriate treatment with psychostimulants has been shown to reduce the risk of later drug and alcohol abiise in children with ADHD.'*' Children with ADHD who are on stimulant therapy are three to four times less likely to abuse drugs th;in those who are untreated.''" In fact, one study demonstrated that treatment with psychostimulants in liigh school appeared to protect against hallucinogen abuse by adulthood. '"^

Attention-Deficit Hyperactivity Disorder (ADHD) / Vocllcr

Despite c o n r e r n s regarding its addictive potential, inethylphenidate is not a very good addictive medication unless it is administered intravenously. Methylphenidate binds to the dopamine transpoiter aiid increases dopamine levels iti the brain, ThLs is siiTiilai- in its niechanisni to cocaine, but the euphoric effects and addictive potential of cocaine occur because it is administered in ways that rejsull in a very rapid increase in blood level, with about 60X1 of dopajnine transporters blocked. In addition, cocaine remains bound to the dopamine transporter for very brief periods of time; therefore, repeated high intravenous doses have euphoric effects and set the stage for abuse, hi contrast, methylphenidate remains bound to the dopamine transporter for several hours; therefore, repeated doses have very little effect.'"' Wlien niethylphenidate is aiiniiiustered by nioiitli at a standiuxi clinical dose, etiphoric effects arc not present''" Dextroaniphetaniine has a somewhat more complicated mechanism of action. There are many medicines that, if adminislered incorrectly, are dangeroii.s imt at the appropriate dose are lifesaving (eg, insulin or digitalis). Some parents worry thai stalling children on a psychostimulajit medication will commit them to lifelong use. Although no parent wants to see Ms or her child on medication, particularly a (hroni<' medication, there are some situations in which a cliild needs In Uike medication mvi continue it thiougliout life (eg, children with diabetes require insulin, children with endocrine disorders or asthma need lo lake medicine), ADHD is no different. It is a chronic, impairing disijrder Ihat is perhaps not as lile-threatening as diabetes but is, nonetheless, impairing. The real issue is to weigh the risks of treatment against the risks of nontrealnient. What iire the risks of nontreatmenl'? Children with ADHD who aie not treated are likely never to live up to their potential in school, are at greater risk of behavior disorders'*' and psychiatric disordei-s (mtyor depression and pei"sonaiity disorders),'^- have a much higher rate of traffic violations than peers, "^' and, untreated, are more likely to abuse drugs tlian children with ADHD who are treated.'''" Pharmacogenomics: A Glance at Medicine Management of ADHD in the Future The recent infomiation regarding the genetic basis of ADHD opens up the possibility Ihaf more sophisticated phannacologic management of this disorder will become possible. Altiioiigh most patients respond well to psychostimulants, a small group has atypical responses or is at increased risk of ntidesirable side effects. Hnderstajidhig the genetic basis of ADHD and how different drugs affect the central nervous system will make it possible to effectively select an appropriate medic ation, A few examples will suffice. Children with ADHD who are honiozygous for the 10-repeat allele at the dopamine transporter 1 (DATl) gene show a poor response to niethyiphenidate,'" A SPECT study of children with this genotyi>e, who showed some response to inethylphenidate, had significantly higl\er regional cerebral blood flows in the medial frontal and left basiilgimglia regions than children wlio did iiol have this genotype.'"*'' Individuals with two catecho! O-met hyltraiisferase Met/Met alleies (resulting in slower elimination of dopamine from synapses) performed less well on tiisks assessing iirefrontal executive function when treated with dextroamphetamine, whereas perfonnance on

these tasks was enhanced by dextroamphetamine in subjects with a diffei-ent (tJie ValA'al) plienotype, 14(3 Because a nmnber of different genes are involved in the ADHD phenotype, understanding these c'omplex interactions will take much furthei" investigation. R^erences
1. American Psychiatric Assofiatkui: DimjiiDstic and Stalisticni ManuaJ u/Mf'iital Disorders. 4th ed. Washington, DC, American Psychiatric Association, 1994, 2. Biedemian J, Faraone SV, Milherger S, Doyle A: Diagnoses of attenlion-dpficit hyi)praf tivity disorder from parpiit rei)or(s predid dia^oses l.)ase(:l on toaclipr repons,.1 Am Acaii Child AdolcNr Pnychialnj 1993; 3. I,ahey BB, Schaughency E, Hynd G, et al; Attention deficit disorder with aji(i wilhoiit hyiipractivity: C"otiniarison of behavioral duiractcristics of cliiuc-refnTcd children, ./ Am Anid Child f'syrhittlry i987;2(J: 718-723. 4, Frick P.I, Laliey BB, Applegate B, et al: DSM-IV field trials for the disni|>tive beha\ioi- (lisorders: Symptom utility estimates. .1 Am Acini Child, Adalexc Psi/fiiinlnj 1994;3^:529-539. 5, Applegato B, Laliey BB, Hart EL, et al: Validity of age-of-onset criterion for ADHD: Aroport from the DSM-IV field trials, JAm Acad Ckild Adolcsc Psyrhiatr// im7;m:l2U-l22\. 6. Willotighby MT, c:iirraii PJ. Coslello EJ, Angold A: Implications of early versus lato oiispt of attention-detlcil/liyppractivity disorder symptoms../Am Arad Child Adolesr Psycliinliy 2000:^9ArA-i-iril9. 7. Barkley RA, Bifdemiaii J: Toward a broader itefinitioii of the age-ofoaset criterion for attention-deficit, hyperactivity disorder. -/ 4m Arad Child Adolrsc Psychiatry 1997;3C:1204-l^]0. 8, Lakatos K. Nenioda Z, Tolli I, et ill: Fiirtiter e\-i(ience for the role of the (fopaniiiie 04 rer^^plor (DRD4) gene in alliirhnient disorganization; Iiitt'rac tion of tht' exon III 4a-l)p repeat and the -521 CfT promoter polymorphisms, Mol Ptiyrhi'itn/ 2002;7:27-;:i 1. 9, POWPII KB, V'otilor K: f'rt'frontal I'xcciitivo function syndromes in children,./ Child Nnirol 2004; 19:785-797. 10, Sonuga-Barke E.JS, Daly D, Tliompson M, et al: l*arent-based therapies for preschool attention-deficit/hyi)eractiv1ty disorder: A randomized, contTolied trial with a coinnumity sample. JAm Arnd Child .Adolcsc Psych i<il>-y2(m-A{)A(i2^m. II. Goldman DZ, Shapiro EG. Nelson CA: Measurement of vigilance in 2year-old c-hildrcn. Dev Neuropsychol 2004;25:227-250, 12. Uhey BB, Pelliimi WE. Stein MA. rt ;U: Validity of DSM-IV attentiondeficiL/liyperat'tivity disorder for younger children, J4mAc(/C/n7(/ Adolenc Psychiatry 1998 ;37:696-702. DuPaiil GJ. Mc'Goey KE. Ei kert TL, VaiiBrakle J: Preschool children 13. with attention-defirit/hyperactivity disorder Impaii-ments in beliavioral, soc ial, and school fiincUoning../ Atn Acad Child Adolesc Psychiatry 2O0l;40:.'5O8-515. 14. Barkley RA: Behavioral inhibition, sustained attention, and executive fimctions: Constructing a unilying theory of ADHD, Pnychul Bull 19!t7;121:65-94, Halt EL, Lahey BB, Lo<^ber R. et al: Developmental chaiigf ui allt-ntion-deficit hjperactivity disorder in boys: A foirr-yeai' longiludinal study. JAbvorm Child Psyriwl 199^:23:729-749. Greene RW, Bie<ieinian .J. Faraone SV, et al: Social impairment in girls with ADHD: Puttcnis, gender comparisons, and correlates, -/ Am Acad Child Adol,'!ic Psyrhinfiy 200i;40:704-7lO. Castellanos FX. Marvasti FF. Ducharme JL, et al: Executive function oculomotor tasks in girls with ADHD, J Am Acad Child Adolesr Psychiatry 2000;:39:G44-6.50. Faraone SV. Biedemian .1, Mick E. et al: Family study of girls witli attention defuiliiyijeraclmly disorder. .-4 (i;.7 P.sv/c/;("/r/y2<K)(): 157:1077-108.1 Rucklidge JJ, Taiuiock R: Psychiatric, psychosocial, aiid cognitive functioning of female adolescents uith ADHD, -/ A m Acad Ch ild .Adolesc P.'iychia try 2tmA0.^'iQ-^^40. Biedemian J, Munir K. Knee D, et al: High rate of alt'fctivf dLsordei*s in probands v\il h attention deficit disorder and in their relatives: A contj'oHed family study. Arn J Fsyvhialry 197;!44:3a0-333.

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Journal of Child Neurology I Voliutie 19, Number 10, October 2004

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110, Sliai')iro SK, Quay HC, Hogaii AK. Schwartz KP: Response preseveration <md delayed re.sjionding in undersocialized aggressive conduct disorder.-/.'U'l/fifvi/ Psyciiol 1988:97:371-:173, 111. Soorani-Luasing I, WoltilHA, Hadders-AlRra M: Are moderate degrees of hyperbitimbinemia in healthy tenii nooitates r<'ally safe for the brain? Ppt;?io(/'/fps 2001:50:701-705, 112. Bloom DR, Levin HS, Ewing-Cobbs L, et a!: Lifetime and novel psychiatric disorders after pediatric traumatic brain injury, JAm Acad. Child Adolesc Psychiatry 2001;40:572-.579. 113. Gerring JP. Brady KD, Chen A, el al: Preniorbid prevalence of ADHD and development of secondary ADHD after closed head ii\jury, JAm Acnd Child .idolcsc Psyvhiotm i998;37:( 147-656. 114. Herskovits EH, Megalooikonomoti V. Davatzikos i.\ et al: Is the spatial distribution of biTiui lesions associated with closed-head iryiuy predictive of subsequent development of attention-detlcit/hyiieractivity disorder? Analysis willi brain-image d a t a b a s e . Radiology 19!9;213:389-394, 115 Herekovits EH. Gerring JP: Application of a data-mining method based on bayesian networks to lesion-deficit analysis, Neuroimage 2003;19:1664-1673. IK), Max JE, Arndt S, Castillo ('S. pt aJ: At ten tion-deficit hyperactivity symptomatology al'ter traumatic brain uijiir>': A prospective study. lAm Acad Child Adolesc Psychiatry 199S;37:841-847, 117, Castellanos FX, Shari^ WS, Gottesman RF, et al: Anatomic brain almormalities in monozygotic twins dLscortiant for attention deficit, hyperaili\'ity disorder Am J Psychiatry 2003:160:169:3-1696. 118, Max .IE. Mathews K, Manes FF. et al: Attention deficit hyi.>erdctivity disorder aiid neurocognitive correlates after childhood stroke, -/ Int Neiimpsychol Soc 2003;9:815-829, 119, Max JE, Fox IT. Lancaster JL, et al: Ptitainen lesions and the development of attenlion-tieficit/liyperactivity symptomatology,./ A m Acad Child Adotcsc Psychintnj 2002;41:5fi3-571, 120. Peteison BS. Le( kman JF, "Hicker D, et al: Preliminary findings of antistreptococcal antibody liters and basal ganglia volumes in tic, obsessive-compulsive, and attention dellcit/liyperaclivity disorflere. Aivh Geii Psychiatry 2()OO;57::364-;J72, 121. Fallon BA: The imderdiagnosis of neuropsyciuatric L^nne disease in chUdren and adults. Psychiatr Ctin North Am 1998;21:693-703. 122. Kreppner JM, (!)'t'oiinor TG. Rutter M: Can inattention/overactivity be an institutional deprivation syndrome? ./ Almorm Child P.'iychol 2001:29:513-.528. 12:i. Rutter ML. KreppniT JM, O'Connor TG: Specificily and heterogeneity in cliildren's responses to profomid institutional privation. By J Psychiatry 2001; 179:97-103. 124. Biedemian J, Milberger S, Faraone SV. et al: Family-environment risk factore for attention-deficit hyperactivity disorder: A test of Rutter's indicators of adversity, ^rrft Gen Psychiatry 1995;52:464-470, 125. The MTA C'ooperative Group.: A 14-montli randomizeti clinical trial of treatment strategies for attention-delicifliyperactivity disoi'der, Miiltimodai TVeatment Study of Children with ADHD. Arch Gen Psy12(i, Pelham WE, Hoza B: Intensive treatment: A summer trpat.mont program for children witli ADHD, in Hibbs E, Jensen P(eds):/'.s,i/f7;.social IWatmails for Child, atid Adolescent Disorders: Empirically Bast'd Slrateyif.sfor Clinical Practice. New York. American Psychiatric Association Pre.ss, 1996,311-340. 127, Cireenhill LL. Swaiison JM, Vitiello B, el <il: linpiunncnt and deportment responses to different methylphenidate doses in childien with ADHD: The MTA titration trial. JAm Acad Child Adolesc Psychiatry 200l;40:180-187. 128. Swanson .JM, Kraenier HC, Hinshaw SP, et al: Clinical relevance of tlie primary findings of tlie MTA: Su<'cessnitesb<i5edonseveri(y of ADHD iuid ODD symptoms at Ihe end of ti-eatmeni, J Am Acad Child Adolesc Psychiatry 2001;40:108-179, t29. Harvey E, Danforth JS, McKee TE. et al: Parenting of children with attention-deficityi\vperacti\'ity disorder (ADHD): The role of parental ADHD symptomatology, J Alti^n Di.sord 20O3;7:31-42, 130, Adlard PA. Peireau VM. Engesser-Cesar C, Cotman CW: The timecoiuse of induction of brain-derived neurotrophic factor mRNA and protein

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194. Roniaii T, Sclimitz M, Polanczyk GV, et. ah Further evidence for the association between attentioii-deficit/hyperactivity disorder and the dopaniine-beta-hydroxylase gene. Am JMed Genrl. 20(12; 114:1 fvl-158. 195. Sniitb KM, Daly M, Fischer M. et a!: Assot-iatioii of tlie dopainitic beta hy(]roxylase gene with attentinii dpfirit hyperactivdty dis<mier: Genetic analysis of the Miiwauicet' kmgiludinal study. Am J Mcd Getict 20();3;119B:77-85. Wigg K, Zai G. Schachar R, et al: Attention deficit hyperaetivity disorder ajid the gene for dopamine beta-hydroxylase. Am J Psychiatry 2002;159:104G-1048, 197. lnkster B, Muglia P, Jain U, Kennedy JL: Linkage disequilibrium analysis of the dopaniiiie beta-hydroxylase gene in persistent attention itfllcil hyjieraciivity disorder, PsydiialrGeriel 2004:14:117-120. 198. Payt,on A, Holmes J, Barrett JH, et al: Examining for association between candidate gene polymorphisms in the dopamiiie pathway iuid attention-deficit liyperactivity disorder; A family-based study. Am J Mcd Genel 2001:105:4(34-470. 199, Eisrnberg J, Mei-Tal <i, Steinberg A, rt al: Haplotypc relative risk study of catpehol-0-nietl\yltransferase (COMT) and attention deficit hyijeractivity disorder (.\UHD): Association of tlie high-enzyme activity Val allele with ADHD iiiipiilsive-l\yperactive phenotype. Am JMed Genet 1999:88:497-502, 200, Ban- CL, W i ^ K, MaJone M, pt al: Linkage sttnly of catechol-0-methy!tiansferase and attention-tleticit hyperactivity disorder. Am JMcd Geiiet 1999:88:710-713. 201. Hawi 2, Millar N, Daly G, et al: No association between catocbol-0methyltraiisferase (C'OMT) gone polynioqihism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. Am J Mcd Getict 2000;9fi:282-284, 202. Manor 1, Kotler M, Sever Y, et al: Failiu-e to replicate an association between tlie catecho 1-0-niethyitransferase polymoipliisni and attention deficit hyperactivity disorder in a second, independently recruited Israeli cohort. Am J Mcd Genet 2000:96:858-860. 203. Tahir E, Curran S, Yazgan Y, et al: No association between low- and high-activity catecholaniine-methyl-transferase (COMT) and atten-

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Special Article

Psychiatric Implications of Language Disorders and Learning Disabilities: Risks and Management
Suzanne T. P. V, Sundheim, MD; Kytja K, S. VoeUer, MD

ABSTRACT
This article reviews the relationship between different learning disabilities, language disorders, and the psychiatric disorders that are commonly associated with learning disabilities and language disorder: atlention-deficit hyperactivity disorder (ADHD), anxiety disordei-s, (iepression. and cotiduct or atitisocial personality disorder. The complex associations between language disorders ancl specific learning disabilitiesdyslexia, nonverbal learning disorder, dyscaJctiliaand the various psycliiatric disorders are discussed. Clinical vignettes are presented to highlight the impact of these disorders on a child's social and psychological development and the importance of early recognition and treatment, (J Chiid Ncvrol 2004;19:814-S26).