Special Article

Attention-Deficit Hyperactivity Disorder (ADHD) Kytja K. S. VoeUer, MD

ABSTRACT Approaches to the diagnosis and treatment of attention-' 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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Journal of Child Neurology /Volume 19, Number 10, October 2004

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 combination—deficits 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

Atteiition-Deficil Hyppracludty Disorder (ADHD) / VocUer

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

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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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.hnrnal of Child Neurotogi/ /Volume 19, Nuiiilx-r 10, (X'tulii'r :^(

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 ADHD—they 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,

Attention-Deficit Hyperactivity Disorder (ADHD! / Voelter

goals, drives, and emotion—all 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 coriices—Ihe 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,

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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

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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 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-y2(m-A{)A(i2^m. II. 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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\)» J Hum Geiiel 2002;71:969-963. 208. TXiric D. Langley K, Mills S, et al: Follow-up of genetic linkage findings on chromosome 16pl3: Evidence of £is.sociation of jV-methyl-u aspaHate glulainate receptor 2A gene polymorphism with ADHD. Mol Ps,/r 209, Carioret RJ, Langbehn D. Ciispers K, et al: Associations of the .serotonin transporter promoter polymorpliism with aggressivity, attention deficit, and conduct disorder in an adoptee population. Compr Psy210, Hawi Z, Dring M, Kirley A, et al: Serotonergic system and attention deficit hyperactivity disorder (ADHDj: A potential .susceptibility locius at tlie 5-HT(IB) receptor genp in 273 nuclear families from a m\ilti-centre sample. Mot PsychUtlry 2002:7:718-725, 211, Kent L, Doeny W Hardy E. et ill: Evidence tbat variation at the serotonin transporter gene infiuenc-es susceptibility to attention deficit hyperactivity disorder (ADHD): Analysis and pooled analysis, Mol Psychiatry 2002;7:908-912. 212, Quist JF, Ban- CL, Schachar R, et al: The serotonin 5-HTlB receptor gene and attention deficit hyperactivity disorder. Mol Pnyehiatrjj 2003;8:98-102.

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 disabilities—dyslexia, nonverbal learning disorder, dyscaJctilia—and 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).