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.

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

" Early Identification It is apparent from tlie above that ADHD symptoms become appaienl in the preschool child. As a result. and neuropsychologic learning disability profiles. 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. the male-tofemale prevalence ratio is much lower. are vulnerable to alcohol and di iig dependence.'-'-"'' ADHD in Boys and Girls There are more boys than girls diagnosed with ADHD. 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.21 years and that of the combined type was 4. girls do not manifest disniptive behaviors to the extent seen in boys. a similar pattern was noted.88 years. as well as in cognitive ftinctioning and academic performance. They have higher rales of disniptive beha\ior disorders. pattern of comorbid psycliiatric conditions.^ Although these symptoms had very high positive predictive power in the DSM-IV field trials. compared with unaffected girls. particularly for the inattentive type. 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. particuiaily the hyperactive or impulsive or combined type. On the one hand." Using standard clinical techniques. information from neiirophysiologic imd genetic studies has provided support for this subtype. ratio of boys to girls. respectively). Many sought care when their own children were diagnosed. However. they did not have higli negative predictive power (ie. In surveys dealing with children referred to clinics. In epideniiologic samples. and only 57% became symptomatic before age 7 years. can be reliably made in many children by the titne they are in preschool. and conduct problems. 3:1. Some children with ADHD seem iinderaroiised. and SVa of the hyperactive or impulsive subtype reporting onset. which then develops into ADHD of the combined lyjie during elementar>' school.'^ 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. they manifest more emotional distress. the DSM-IV subtypes have been shown to differ in terms of age at onset. Iti a large epideniiologic sample (the Great Smoky Mountains Study). although ADHD is a childhood-onset disorder. when appropriately tested. girls with ADHD aie significantly impaired on the Global Assessment of Fimctioning Scale. In a study of 156 children ranging in age from 3 to 5y2 years. IQ. set shifting and difficulty tolerating a delay in gratification—^together accounted for 70 to 80% of the variance. In fact. as well as poor school perfonnance. and then evolves hito the inattentive type of ADHD after the hyperactivity or impuLsivity . we have encountered adults who had not been diagnosed with ADHD tmtil they were well into their forties. planning. 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. their absence did not predict the absence of inattention). have higher rates of depression and anxiety. the sluggish cognitive tempo type of ADHD was not included in the DSM-IV diagnostic criteria. The inattentive type followed a different trajectory. although the behaviors were strongly associated with inattention. have difficulty initiating. and daydream. the ratio of boys to girls vai'ies from 6:1 to 12:1.symptoms fade and academic and social demands for autonomous functioning increase. in contrast to 13% of the combined subtype. Thus. The hyperactive or impulsive type etnerges earlier than the combuied tyi)e and significantly earlier than Ihe inattentive type. with 25% of the youths with inattentive symptoms reporting onset after age 7 years. which is correlated with heightened right frontal evoked potential responses and has good interobserver reliability. are drowsy.' Since the publication of the DSM-IV in 1994.Attention-Deficit Hyperactivity Disorder (ADHD) / Voeller 799 DSM-IV approach. with variable attentiveness. '•' Early treatment should also ameliorate later impairment in social beha\iors.^ 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'*). a cluster of executive ftmction deficits—working memory. Preschool children with ADHD. have also been shown \o have executive ftinction deficits. Most children with the hyperactive or impulsive and combined types of ADHD were considered impaired before age 7 years (98% and 82%. and have poor selfesteem and a limited sense of control.*' In our clinic. The mean age at onset of the hyperactive or impulsive type was 4. ADIID symptoms were correlated in a linear fashion with both of these factors. the symptoms of ADHD are apparent in most cases before the age of 7 yeai"s. Some researchers have suggested that ADHD follows a developmental pathway in which the earliest.5 years.'^'^ 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 ."' Compared with boys with ADHD. Stated somewhat differently. the median age at impairment did not occur until 3.'" On the other hand. stiggesting that ADHD ill giris lends to be underdiagnosed. given the genetic nattire of the disorder (discussed below). are highly vulnerable to stress. a child who met the criteria for six of nltie . girls show an equivalent degree of prefrontal executive function impairment. and have been described as the "sluggish cognitive tempo" type. it is not surprising that manifesta- tions of ADHD might be apparent in infancy."' Although the median age at onset of the first symptom was 1 yeai. is probably not warranted.'" Goldman et ai described an attentional task for 2-year-old children. and are at risk of academic failure. requiring a precise age at onset. the diagnosis of ADHD. Based on a considerable body of research. manifestations are hyperactivity or imptilsivity.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. 43% of the inattentive type met the criteria for impairment after age 7 years. wliich were also correlated with iige. before age 7 years. Age at Onset Based on the DSM-IV field trials.13 years. the mean age at onset did not occur until 6. after having struggled with their sytnptoms for mtich of their lives.

"'"^'' *^"^" In one study.^' Motor incoordination is often associated with ADHD''•' and can be an early and prominent feature in the preschool child who will develop ADHD symptoms. In a study drawn from a community sample. Neuroanatomy and Physiology of ADHD Behaviorally. a high level of inattention was heritable regardless of the degree of hyperactivity and impulsivity. In addition. In most.800 Journal of Child Neurology /Volume 19.'^'' The inattentive and hyi^eractive or impulsive types also diffei' in hcritability. we observed that of the 60 children selected because of severe phonologic awareness deficits.'•' 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.^^*' Boys with ADHD and learning disiibility tended lo have more serious executive function deficits titan boys who were not learning disabled. and Tourette syndrome are all such comorbidities. Cortical right prefrontal gray matter and left occipital gray and white matter were reduced in the subjects with ADHD and their siblings. Kadesjo and Gillberg in Scandinavia pointed out the syndromic nature of this combination—deficits in atlention. 1. Moreover.-'' In one tepoit. have been reported to be smaller in children with ADHD compared with controls. They suggested that both the inattentive and hyiieiactive or impulsive symptoms can relate to a latent. and perception (DAMP).^"^. well-designed longitudinal study involving 541 MRIs from children with ADHD and age. particularly untreateti ADHD. response inhibition deficits (inipuLsivity). On the other hand. niiyor affective disorder (depression or bipolar disorder).^ (Also see the ariicle by Suiidlieim and Voeller in this issue for further discussion of this association. restlessness or hyperactivity. "disinMbition. or apathy in some cases.) Other regions of the basal ganglia have also been reported to be reduced in volume in subjects with ADHD relative to . was associated with signifit ant neuropsychologic impainnent.in size observed in different studies because the age of the subjects varied considerably across these studies. higli levels of hyperactivity and impulsivity were tightly linked to the num- ber of inattention sympt onis manifested by the twin with ADHD.'" 3. aj e at risk for drug and alcohol abuse.""'' In one study comparing boys with ADHE). including subject and control group selection and the presence of certain comorbid disorders. and nonverbal learning disability) also often have associated ADHD. particularly the caudate nucleus. motor control. anxiety disorder. this study strongly supports the genetic basis of ADHD. pervasive developmental disorder. bilaterally.*''^'^^ Many magnetic resonance imaging (MRI) mon^honietric studies (ie. trait. 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). 80% met the criteria for ADHD. Brain regions involved in self-regulation (executive function) show differences from those of controls.'. and children with both specific language impairment and ADHD appealed to have greater difficulty with verbal short-term memory. There is a small but significant reduction (on the order of 5%) in mean total cerebral volume or intracranial volume. A large. their unaffected male siblings. Asperger's syndrome. depending on a number of methodologic variables.4% reduction compared with controls (a statistical trend).'"'""' (This might explain the variability. Various regions of the basal ganglia. many individuals with mental retaidation and autistic spcctrtmi disorders (ie. and with maturation. oppositional defiant disorder. as has been believed. Children with ADHD start out with smaller caudate nuclei than controls. and matched (controls. the results have been somewhat variable. the frontal lobes or subregions of the frontal lobes were found to be smaller in subjects with ADHD than in controls. Language disorders are frequently associated with ADHD. the inferior portions of dorsal prefrontal coriices and anterior temporal cortices. difficulty with self regulation. studies. Tcenagei-s witli AUHl). 2.^" *''^'''" 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).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 researchers found that the inattentlcjii dimension.This suggests that changes in cerebral volume need to reach a certain crucial level before they become obviously symptomatic. 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. 45% of children with ADHD had at least one element of langui^e inipainnent.'* However.Conduct disorder. ADHD is a disonler of self-regulation.'" The nx^or findings of these studies are summarized as follows. Frontal lobe volume is smaller in persons with ADHD. Their unaffected siblings had a 3. Number 10. which implicates some sort of dysfunction of thefrontal-subcorticaJsystem." with the inattentive symptoms referring more to the cognitive aspects and the hyperactive or inattentive symptoms relating to behaworal aspects. the subjects with ADHD had a significant (4%) reduction in intracranial volume. and that hyperactivity or impulsivity might result from some other factor. In a study of twins with ADHD. As a result.^'' Learning disabilities (dyslexia and dyscaiculia in particular) iu-e frequently associated with ADHD.-""^'' In the Remediation of Dyslexia study. Relatives of cliildreii with ADHD^"'^' are also at higher risk of neuropsychiatric disorders than relatives in the control families. Total cerebral volume is smaller in individuals with ADHD and in controls. Tliese studies iiave identified relatively consistent diffeiences in tlie brains of children with ADHD compared with those of normal controls. including obsessive-conipttlsive disorder. October 2004 extremely high rate of comorbid psychiatric disorders and Ls usually acconipiinietl by a learning disability. were reduced in subjects with ADHD. any difference in size between children with ADHD and controls becomes less apparent with increasing age.^) Language inipainnent in ADHD has been considered by some to reflect a common imderiying prefrontai executive function deficit.''^ This suggests the intriguing possibility that the essential dysfunction in ADHD involves inattention and disorganization rather than hyperactivity or impulsivity. there is a further decrease in size. autistic disorder. not the liyperactive or impulsive dimension.

it would not be siiri^nsing to observe reduction in riglit frontal lobe volume. children on psychostimulant treatment actually had somewhat. "' hi summary. it still suggests that the dopaminergic system is dysfimctiona! in persons with ADHD.ion pattern than was seen in controls. rather. children with ADHD do not activate frontostriatal networks to the same extent seen in the children without ADHD but. 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. These findings suggest a couiplicated interaction between gender. and the findings were significant ouiy when computed witliout atljustments for multiple statistical comparisons)."'"^''' I lowever. 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. One example involves making two taps with a hand when the examiner makes one. both groups . 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. Although this is not consistent with the findings in other studies. often with greater involvement of areas of the right hemisphere. the riglit. when carefully examined. "•""''' In some studies. suggesting that the development of frontostriatal circuits was delayed in children with ADHD. Although tiiis study was not without uiethodologic problems (it involved a small number of subjects. hi normal child and adult populations. and honnonal effects. Given the important role that tlie right hemisphere plays in l-egiilating attention and the deficits seen in ADHD. those with ADHD have atypical pattenis of activation. 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. 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.^"'^'It is possible that the reduction in size is due to (he reduction of global brain volume. but the child with ADHD has much greater difficulty than oUier children of the same age. greater white-uiatter volumes than those who had not been treated. a decrease in the right frontal giaymatter volume was noted. Activity was decreased bilaterally in the posterior putamen aiid middle cingulate coitex. the right caudate nucleus is smaller tlian the left caufiate nucleus. and magnetic resonance spectroscopy (MRS).* 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. the "controls" were siblijigs of the ADHD subjects. In one study. children with ADHD made more errors than controls. fiuictional magnetic reson^ice imaging (fMRI) scans. frontal area is larger than the left frontal area. but it was noted tliat the degree of sexual maturation was probably a variable that had not been taken into consideration. Children have greater difficulty with these tasks thaji adults. based on the laige National histitute of MentiU Health study of children with ADHD.^^' [Note: Functional neuroimaging studies involve a nuinbei of different techniques: positron emission ton\ographic (PET) scans. Interestingly. childien with ADHD activated frontal ai'eas to a greater extent than controls. manifest a more diffuse acUvat. Tliesefindingswere not continued on a subsequent study.'^ In another functional MRI study involving children with ADHD and controls performing two somewhat different types of go/no-go tasks. 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. functional MRIs on children performing tasks that demand executive function control have somewhat different patterns of activation than are seen in those of adults.^"'^^"'^""'^' 6. Right hemisphere structures are affectefi more than left hemisphere Biructiires. or changes in volumes of certain subcortical stnictures were more prominent on the right.tj% lower tlian in boys witli ADHD. '•'•*'-^" 5. [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. but rather a very real brain dysfunction. ] In general. the subject makes none. single photon emission computerized tomography (HPECTj.1 to 50. it is possible that the task required the subjects with ADHD to exert more effort than controls.^" In iinothor PET study of adolescents in the age range of KJ to 14 years. the right caudate is laiger than the left caudate. subjects with ADHD had a higlier accumulation of dopa decarboxylase (indicating a high level of dopamine synthesis) in the right niidbrain than controls. (In this study.'' However.U1 sluiUes. Women with ADHD demonstrated better performance on the auditory attention task with increasing age.Atteiition-Deficil Hyppracludty Disorder (ADHD) / VocUer 801 4. as suggested by C^astellanos et al. in which tlie effects of sexual maturation were controlled. in the laige National Institute of Mental Health study. children with ADHD and controls were studied using functional MRI during a go/no-go task. This was not a consistent finding. but they generally involved many fewer t hildren and were not longitudinal.^" In normal adults. and then when the examiner makes one tap.''* This asymmetry was not necessarily obsei^ved in . ^^ In one task. It is one test of executive function in that it requires the ability to inhibit an established pattern of behavior. but it was noted in a number of studies."^' However."-} After receiving methyiphenidate (Ritalin). Functional Neuroimaging Studies I"\mctiona! neuroimaging studies have been used to study individuals with ADHD and controls and are consistent with the morphometric findings.''"* Bniin regions in which this lower activity was observed were the right frontal premotor cortex and right temporal cortex. These studies also revealed dysfunction of the prefrontal-subcortical system.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. age. A number of studies reported a reduction in the area of tJie anterior"-"'"-"'^ or posterior corpus callosum. Wlien cliildren are asked to peifonn a task that places demands on the frontal executive system.'"'" A study of adults (18. there is now much research suggesting that.

Diffei ent patterns are noted in sleep and wakefulness. it might be useful in determining the response to medication"^^ and possibly will be more meaningful once ADHD genetics are unraveled. Psychostimulant medications that increase the amount of central dopamine and norepinephrine are typically the most effective way to treat ADIID. At the present time. quantitative EEG patterns appear to demonstrate differences in children with ADHD and those witliout ADHD. However. Parents with ADHD have a better than 5(yA> chance of having a child with ADHD. 10.scent of the sluggish cognitive tempo type described by Laliey et al') and one consistent with a maturational lag. children with the inattentive type of EEG were fotmd to have two different EEG patlerns. and about 25% of cliildren witli ADHD liave i)ai ents who meet tlie fonnal diagnostic criteria for ADHD. neuroimaging studies reveal that children and adults with ADHD activate frontal subcortical stnictures to a lesser extent thiui control subjects. elect rophysiologic studies of children wilh ADHD reveal atypical brain wave patterns.hnrnal of Child Neurotogi/ /Volume 19. . one consistent with hypoarotisal (renuni. the ability to "keep something in mind" for a brief period of time. the subjects with ADHD activated the posterior right anterior cingulate more than the controls."'"^ Thus. dopamine can modulate neuronal activity related to motor activity that is guided by external cues and is goal directed. A control task was also employed.'^ 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. it can also be acquired. 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. and 12 years. in most cases. To sunmiarize. which suggest dysregulation of arousal and attention. ETIOLOGY OF ADHD ADHD is a highly heritable disorder. Methylphenidate increased frontal activation in both groups and increased striatal activation in the children with ADHD but decreased it in the controls. althotigh there are clearcut differences between the EEG patterns of children with ADHD jind those of controls. and beta). However. of familial origin. and the troherenc^e patterns across tJie three grtjups. motivation. diagnostic accuracy is not much better than the clinical assessment and requires specialized equipment and technical expertise. as well as the specific amotmts of activities of different frequencies (theta. they.*^' Twin studies have placed the heritability of ADHD in the range of SO'fii. Nuiiilx-r 10. theestimateof heritability was nearly 75%at each age. Moreover.*^ 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. However. as well as maintaining trained or conditioned responses and motivated (goal-directed) behaviors. This is consistent with the observed difficulty that these individuals have in motivation and aiousal. the ratios of these different frequencies. and motor jjlanning.^' 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.™ The ability of adults with ADHD to tolerate delays in gratification was studied using PET while they perfonneri the gambling t. however.^" Comparing the EEG patterns of children with ADHD and controls. like adults with ADHD. 1 These EEG patterns correctly classify over 909i) of cliildren with ADHD and normal controls.^'' Dopamine plays an important role in the function of the prefrontal-subcortical system. with hyperactivity at age 3 yeais behig somewhat less related to later inattention and inattention at age 7 years being quite stable. with panicular focus on the neurotransmittcrs dopamine and norepinephrine. more prominently in children witli tlie hyperactive or unjiulsive type than in those with the inattentive tyj^e. Given the possibility that there can be different EEG patterns seen in children with ADHD.^'^' Tliese EEG patterns suggest reduced cortical differentiation and specialization in ADHD. Norepinephrine neurons are triggered by novel and important stimuli and are quiescent during sleep. it is not possible to distinguish between these two tyjses of ADHD—they both look the same. and some individuals liave a combination of genetic and acquired ADHD. which are involved in emotional arousal and memory. 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. Norepinephrine (noradrenaline) is involved in maintaining alertness and attention. do not activate areas involved with emotion and memory to the sanie extent that controls do.ask. cognhion. ADHD can be considered a disorder of neurotransmitter function. The genetic factors explained 76% and 92% of the covariance between hyperactivity and inattention.802 . there is enough heterogeneity in the ADHD group to limit the diagnostic efficacy of this technology. [Note: EEGs are "brain wave" studies that record electrical activity of the brain by means of electrodes to the scalp." In stmmiary. There has been extensive research conducted that demonstrates that dopamine is critical in the regulation of learning.^-* Some SPEt'T studies liave identified decreased activity involving the temporal lobe and cerebellum in some children witli ADHD. 7.**' In summary. Genetics of ADHD ADHD is.^''' However. and both usually respond to treatment with tlie same psychostimulant medication. dopamine is the neurotransmitter that regulates the system that plays an important flmction in learning. this technique appears to have limited application at this time. Elec trophysiology Electroencephalographic (EEG) studies of children with ADHD reveal an excess of slow-wave (theta) activity consistent wil h decreased alertness and underarousal. (X'tulii'r :^( of cliildren made fewer errors.'"^ A decision-making gambling task developed for patients witli prefrontal deficits was administered to adults with ADHD."^^'" Dopamine also plays an important role in working memory. Increased slowing during wakefulness is consistent with a lower level of alertness or ilisttirbance of cerebral function. with a highly significant improvement in the ADHD group. group differences were found in the mean frequency of the total EEG. In siunmary. Although the pattern of activation in children with ADHD is somewhat more diffuse. alpha.

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. A number of different medications are now available for the treatment of ADHD.'-" Lyme disease has also been associated with a number of neuropsychiatric symptoms."^ Genetic studies of ADHD have focused on genes involved in the regulation of neurotransmitter function.'"'' Iron deficieiKry is associated witli disniption of the dopamine system and more extensive neurodevelopmental problems. Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) is linked to Tourette syndrome. It is not unusual to see individuals who have botli a genetic and an acquired form.""' Hyperbilinibinemia (jaundice) in the newborn period can evolve into an ADHD-like picture later in childhood. Many different processes are involved in neurotransmission. children who have suffered strokes. paternal criminality) that are present.and perinatal factors can result in ADHD. ADHD might be due to the interaction of several different genes involved in the function of several different neurotransmittere. These children also have a somewhat different set of associated psychiatric disorders than children with genetic ADHD and have disturbed attachment. 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."-"'' In one study comparing monozygotic twins who were discordant for ADHD. impulsivity.irticularly in tlie fetus or infant. possibly because of the disruption of dopamine regulation in the dorsolateral prefrontal cortex. The risk of ADHD is proportional to the number of adverse factors (eg."'' Similajiy. A specific discussion of the selection of a medication for a given child is beyond the scope of this article. during. individuals' genetic makeup will determine how they will respond to specific medications used to treat ADHD. phenylketonmia) caii aiso result in an ADHD-like picture in tlie infant. neonatal hyperbilirubinenia resuhed in severe and irrever-sible damage to the basal ganglia (spe( ifitaily the globus pallidus imd siibthalanuc nucleus). includmg those of ADHD. poverty.'"" One study found a fourfold higher risk of ADHD in the offspring of smokei"s. and hyperactivity in the child. even after controlling for maternal ADHD. Autoimmune disorders have also been implicated in triggering ADHD-Uke symptoms in susceptible patients. 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. It is unlikely (hat a single gene will be linked to ADHD: rather. diabetes.'^"'" Any injury to the brain that affects tlie prefrontal-subcortical circuits can result in an ADHD-like picture. Multiple pre. Such insults give rise to behaviors that are indistinguishable from the behaviors seen in ADHD of genetic origin. not infrequently manifest ADHD-like behaviors.'^^'^^ Children who grow up in chaotic environments often have difficulty regulatii^g altention. In one study. is rarely a cause of ADHD because most children in the United States receive diets with adequate iron. Thus. (Bilinibin is a mitochondrial poison and affects calcium homeostflsis. and the generic names and trade names are listed in Table 2. drives. Tliis has been shown in nonhuman primates'"^'"" and children with temporal lobe cysts. and emotion—all of which are crucial to survival. obsessive-compulsive disorder. impulsivity.""' One such factor is fetal alcohol syndrome. Injury to the medial temporal lobe during early development is also associated with ADHD-like behaviors later in development. Principle 1 The treatment of ADHD involves the selection of an appropriate medication at an appropriate dose in combination with behavioral tlierapy. 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 the past."'*'"' Even though women with ADHD are at increased risk of becoming smokers and the child's ADHD might be genetic. before effective treatments were developed. it has become apparent tliat even moderate levels of bilinibin in othei-wise healthy infants might not be as benign as previously believed. neai'lyhalfofthe children developed ADHD following stroke. mainly related to dopamine. caudate lesions were observed in the twin with ADHD.'"The dopamine system is exquisitely sensitive to hypoxia. resulting in neuronal death. These and a list of c andidate genes for ADHD ai'e summarized in Table 1."" Meningitis and encephalitis ai'e also associated witli ADHD-like behaviors. and emotionality.Attention-Deficit Hyperactivity Disorder (ADHD! / Voelter 803 goals. 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). any events pre. Acquired Brain Lesions and ADHD The liehaviors associated with ADHD can also iuise from environmeiilal factors that disnipt nonnal brain giowih.'-' TREATMENT OF ADHD This section focuses on some general principles of the treatment of the child with ADHD. and ADHD."" Metabolic disorders of the mother (eg.'^' The role that environmental factors play in ADHD should not be minimised. maternal psychopathology. and after birth. before. particularly those involving subcorticsil areas in the prefrontal-subcortical circuits. although some studies have also examined the role of norepinephrine and other neurotransmitters. Tlius.or postnatally that disnipt the flow of blood or oxygen to the brain might set the stage for later ADHD behaviors."**and there wiis a strong correlation between lesions of the putamen and ADHD symptomatology. p. Tiiis system appears to be impaired in children with ADHD who have difficulty regulating their own level of aleitness and awareness of important stimuli. exposure of the fetus to cigarette smoking confers an increased risk.'"'"' Maternal smoking has been linked with ADHD. which results in significant inattention. In addition.) However. 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.'"" It. but it is worth a brief review of the Multimodal Tieatment Study of Children With ADHD .

> 0) O I/I ra 'x en .9 "D Q 03 .c in >— " o re > • <- o .. ft 03 Q . Q.J3 rO re a) o E o "o — 1 re C "• Q c O o t EL. O E o E E orepine atechol amine amine o ej 3 03 en ra C O Q c <D m a E o m Q a o Q a o E C/5 1 1 3 U C >.E " . 0 3 . October 2t)04 CT) CO Q "o X3 E 01 !c a a 'Ul c re Q cc II CO ^ ID O C X X in . Number 10.5? .9 . 5 p — > > «-• O) 03 U "D .^ E 03 .t ^Qi O c E E t~ Q.2 O o C t/5 en o • <e <. 05 O Q. ^^ 05 03 •D X! T W c/5 3 32 II < 2 5 udi c en 3.E E la *" £ _t: t re ^ c •£ O ^ ^ >.oj.E "O opamiri' iutamat [GRIN2/ lonoam (chrome a^ 0) o w E b C £^ re o o c ti> ^ ILU ILU . Oi e _ > Q Q Q o E O o 03 .OJ CO .— ra o to Q_ 3 n • " : = = » - t Q.— O _ . = re ra as o — Q . 9 S3 03 = oE ^ o X) O en 01 •o •*.E ra " ." 'droxy 1 scodin isine h' G in aptoso romos E o c n E n SOLUOJ > . o CO ~ o .J ing en .5 — ra c ^^ m 1- S •5 O en en C O .804 Journal of Child Neuivlogy I Volume 19.E Q.^t o .^ i E 2 -^ 1 1 ? •o cr some ra a o 11 Q cc Q O 0) > 05 O Q. (/3 k— ra o > c^ o a Ii 03 0 9.^ 0 §"0 en C — OJ OJ o 03 c ra "O C o E I 03 .H- Cfl o 0 3o a a C ^ " o. o o en OJ L. CO c o CL ort ing • ^i3 Q.^ J Z ~^ c i ra S §2J ¥ < Q J en Q. e-a: eu O X 'a. ."> E [. > cn o ro c lac . ^ ^ tivate itamin T> 0) 0) E o CO XI CD c f i Q Q o CJ E o re E _ U E o E o _E U < O < _ 05 5 E ej CO 2 E E 03 ci5 >. O 4— ^ LJ . *-• .C E E 'Q .

(20 dfine 1 drine: 'ostat irall (5 (NI tn drugs t(18..^ .Atlention-Deficil Hyperactivity Disorder (ADHD) / VoeUer 805 •£ DJ DJ S3: OJ o re E tee c re OJ ami c * * < 03 "o E o 2 o « E 5 -.. Q. re Q Q £ < ^ O Cl Tl OJ ^ E ro (0 =1 in 03 E 0 0 C^i d 0 in hin i_ c: 25. in 03 _ 2 E TO o re c re 0> m . rke OJ 1 tn 03 lec OJ tr •4.= iP ra c X o "o "x c Q. 3 E — 3 CJ Q.^ LD CD _^ I re .ELnT! r-.c ra O) (J ra E nj • aj~ E OJ LJ TO in 03 03 C 3 CO O" 03 amp hetamin amp hetamin O OJ X X X 03 re •o 'c o •z OJ Opi _a >. 0 ^^ 10. u in E _ d r- in E .. r — OJ a r" Opi .J •'-' H ra "D S c f~ OJ OJ ixture of phetami phetami letamine bas tabletto o o u o Q c I X 1— u O CJ "ra ro re "D "D • g 03 c 03 00 r- c OJ c OJ f— c OJ OJ OJ ra c <b c S "x UJ tu X LLJ X .p O J 4. OJ tu T! 03 or TO £ « >. c ra re en C ID c E 0 . E •c ra OJ tn 03 l/> CLX 03 I% scents' ehav reaso ble a epatot icity o snsiv X wvent e reatmt OJ ^ E. o. M OJ tn ra OJ 0 c T3 t r cu oj ^ 1^ sn "^ P t re — "D 2z ra -^ 0. > Q 03 c C 03 Q. TJ r03 OJ •a £ 5 Q. 03 C UJ ' Q . = -E a t : ^ ra S ^ (/3 "O f^ qj TO c ~ m ^ ^ — 5.c O J TO TO TS 03 ' c 03 03 ra tu dJ t.= tj o 0 XI 01 re I CO CO . • S ^ 'n ra E o •^ •. S '^ =! in E 0 in in <N UJ c "^ to £^ « ^ tr d c o p c Ibu CJ lepi Ibu 'ani • * - ra ~ ~ ^ •5 ra ra ra ^ tr cr tr 0 X X X •a — OJ OJ OJ • 0 > OJ OJ ai Q D 0 < ^ 0 ^ > pra 0 tr - - 50. l2 tn _ ^ C/5 (0 (0 dJ .J= 03 tn OJ cc o <I 0) > ^ " C O O P "tn ^ Jt. c • ^ a 0 nati' uire 3nta •D ra 03 d Q c — ^ n ra . — OJ ro 0 I— someti 100 mg J : in OJ d E ra m f^ :3 i r j a in -^ r-~ . re u 2 03 rhyt ra 0 "o olizt res.^ 03 03 C a.- rem. OJ OJ 3 o o o tn c E re E u X !U E 03 O3 > ra ^ tn TO — Q. . t— Q.£ • - JS 2 SJi? re o -o . euM o . Q. OJ OJ _c ro J2 0 3 C J C Q. Q.7 Q U 0 (N en 0 E CO Q ra UJOIS ro tn £ 100 iri ^—.c c OJ re OJ OJ o o X 'x 03 OJ £ E E ra u ra o o c OJ E <J X c 0 u X c 0 CJ -p OJ 0 X 03 c c E OJ . . o U OJ = ^I 'ra E " ^ re ^ _ O ^ ^ > •E OJ ci> — "oj ^O OJ JZ 5 E ? ^E lie E latio c E O (J o " b "re iatio (cet c ">.9£ 1 TO Q XOLUO 1 Q Q o ra T ) cc X OJ X) 'x £ OJ Q. 2 o 0 3 § o c 5i ra i« x: 2 m Q J Q. OJ •0 0 C a ZT 3 i f S -S OJ OJ o •:. b XJ 03 y a.

is acljusted Lipward durhig the 14 months of the study. Of the 289 subjects who entered this segment of the study. as well as the environment. child-focused treatment.4%.) Behavioral treatment administered to tlie combined medication and behavioral treatment group and the behavioral treatment only group involved parent training. particularly those who have been recently diagnosed and treated. (Parenthetically. They have had a number of yeai's to develop dysfunctional strategies and require close supervision and support and usually individual therapy.8%. trouble sleeping. the results of the MTA study support the use of medication in the treatment of ADHD. and in the afternoon dtiriiig a 28-day titration period. and the response to the treatment and side effects were monitored. and social skills training. oppositional oi' aggressive symptoms. which was cosponsored in 1992 by the National Institute of Mental Health aiid the US Depaitnient of Education. in summary. they were worse as the medication was wearing off). this might not be an easy or rapid process. This large. anti a school-based intervention organized and integrated witlun the school. and a dull or listless appearance. The combination of medicine and behavioral management was associated with a better 2-year outcome than the medication group alone. In short. and severe side effects in 2. Depending on the child's age and the associated learning and behavior problems. The parent needs to learn to act as an "accessory frontal lobe.'-'"' At the end of the 14-month period. with specific rewards.99^1. Niimbor 10. 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. No side effects were reported in 35. 5 days per week ai\d 9 hours per day. pose a special challenge. In the role of "accessory frontal lobe.9%. with a paraprofessional working with the child. moderate side effects in U.806 •Journal of Child Neurology I Volume 19. Combined treatment was superior to the behavioral treatment for internalizing problems. Interestingly. medication plus behavioral treatment. 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. A daily repoit cai-d was filled out by the teacher and went home with the child. as well as individualized academic skills practice and reinforcement of appropriate classroom behavior. and their families. helping a young child get organized for . Adolescents. and the optimal dose was selected after the records were reviewed blindly by experienced diniciaiis at a <iifferent site. and both the parents and the clinicians were unaware of the dosage or whether the child wsis receiving placebo or active drug. which is somewhat liigher than is often used. mild side effects in 49. ajid 25% in the conuiumity care group showed improvement." at the same time helping the child to develop increasing insight and competence in his or her own behavioral regulation.'"" When the children were re-evaluated at the end of 24 months. Although the child with ADHD does well when provided with structiue and predictability. suggesting a "negative halo" effect. worrying. 56% in the medical management grotip. 3-l% in the behavioral treatment group. headache. and children in elementary and middle school need contiiiuons monitoring and support for school work. tearfulness. The goal is to help the child become aLitononious in setf-regulation. October 2004 (MTA). Daily records oi' behavior and side effects were kept. teachers reported more side effects when cliildren were on placebo. well-designed study strongly supports the use of medication integrated with a behavioral program. after the initial evaluation. combined type. the difference (68% \% 56%) was relatively small but was significantly better compared with behavioral treatment alone and community care. and "community care" (ie. to be reinforced by the pai ents on a daily basis. irritability). 68% in the combined group. and teac hers saw fewer side effects with ijicreased dosage. In about half of those children who had severe side effects (depression. tiie side effects might have been tmrelated to the medication. The most common parent-reported side effect involved decreased appetite. stomachaches. and reading achievement scores. Very young children with ADHD require close parental supervision.'^'' Thus. at lunch. The optimal dose for most children was in the range of 1 mg/lcg/dose. behavioral treatment only. (3) integration of the school into tlie behavior program. and many of tiie side effects occurred as an "end of dose" phenomenon (ie. 256 completed it. but the rate of increase was less marked in the combined therapy group. For example.'-" The school-based treatment involved 10 to 16 sessions of biweekly teacher consultation and 12 weeks of part-time interventions.'"' This study provicjes a great deal of valuable information about the treatment of ADHD. to a much greater degree than would usually occur in a standard clinical or school setting. Medication ajid jilacebo folkiwed a random schedule. and (4) a daily report card completed by the teacher. hi the long mn." the parent must learn to anticipate problems and tievelop a tactful approac'h to dealing with them. The behavioral treatment was extremely intense and involved (I) parent traiiiing. The rate of side effects was quite low. delivered in group-based recreational settings. timeout. The child-focused program was based on the summer treatment pn:)gram developed by Pelham and Hoza and involved an 8-week progrjuu. Another interesting facet of tlie study was that the medication dose w. this ciui be something of an oxymoron in a busy household. The children were randomly assigned to four different treatment conditions: medication only. (2) individual work with the child. Parents proved to be more reliable monitors of side effects. 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 children were seen at monthly visits. After the optimal dose was determined. 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. the behavioral treatment was well designed and intensive. It was conducted at six different sites in North America and involved 579 boys and girls who met the DSMIV criteria for ADHD. 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. 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. which was then used by the parents to deliver consequences.

and.) Although medication often decreases the severity of the problem of getting ready for school. Given that many children with ADHD (on or off medication) have difficulty settling down to sleep. Mothers who described themselves as having moderate levels of iaiattention had the most negative parentchild interactions. different homes) can be extremely disorganizing. and treatment should be put in motion for remediating the learning disorder. it is important that whoever takes over.knows what the routines and expectations are. once she was staited on medication for her own ADHD symptoms. which often makes it extremely difficult for parents to regulate their own behaviors enough to adhere to such routines. keep in touch with the school on a daily basis. Even when there are several children in a liousehold. then.'™ Providing the child with opportunities to n\ove around after workijig on a project for a given length of time is helpful. ajid vice versa. L nfoitiinately. 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. Principle 4 Making sure that the child gets enougli to eat. and make sure that positive rewards occurred when he completed his work. the parent needs to provide support until the medication has laken effect in the morning. Because ADHD is such a strongly genetic condition. Parents often view this as stubbornness or manipulation. this whole process requires split-second timing and teaniwork to prepare dinner." this should be treated as a serious problem and addressed immediately. (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. Even after parent training." It had been made clear to him that if he just "tried harder" and "did something different. After several months. When a child tells a parent or a teacher tl\at he or she cannot do something "because of the ADHD. so we will work out a system together that will make it easier. a lengthy and predictable bedtime routine t)ften needs to be in place to help the child calm down. Some children requii'e 10 hours of sleep. One mother complained that lier son was unable to keep track of his homework. it was apparent that she could not do this in a consistent manner. one or both parents can also have ADHD. Making sure tiiat they have eaten breakfast and have a snack in the afternoon is also helpful because psychostimulant medication can suppress hunger. on tlie rare occasions when he did complete tlieni. a baby-sitter's home. perform the backpack check. 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). there are occasions when the situation improves only after the parent's own attention problems are medically treated. Bedthne is another problematic time. chronic sleep deprivation is not conducive to learning. tliey tended to overreact. many houseliolds have difficulty in managing these routines. many pai ents have difficulty finding time for their own exercise program." "ADHD. Wlien both parents work and arrive home after 5 pm. if necessary. supervise homework. the child usually employs this as a way of not carrying out an unpleasant task. Tlie more a parent or teacher buys into the . Principle 5 Encourage self-awareness and autonomy. 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. and they might not be aware that they need to eat." 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. However. maintaining routines and anticipatoiy management strategies requires considerable managerial skill. This pattern had gone on through elementary school. again requiring close supervision. a child should be carefully evaluated for a learning disorder. so that the boy (then age 12 years) was not particularly motivated to change his modus operandi. Given tlie high degree of coinoil)idity between ADHD and learning disorders. Helping children with ADHD understand themselves so that they can function effectively is important. Principle 3 Treatment of ADHD is not the same as treating a learning disorder. To effectively deal with this problem. was able to provide the required stnicture much more effectively. gets enough sleep.'^ Although parent training is often very helpful. he always had the sense that whatever he was doing was "never enough. forgot his assignments. his mother needed to monitor him closely. This requires making snre that the child gets up early enough and receives medication and. If a parent is busy or absent. This emphasizes the need to lay out a very clear and explicit program. let alone developing one for their children. and. wash the dishes. It takes creative parenting to make sure that the child gets enough sleep and remains on schedule over the v\'eekeiids. often forgot to turn them in. whereas her 5-year-old daughter was able to do this autonoinously and consistently. A standard complaint is that the child with ADHD dawdles while getting dressed and delays the family's departure. and get the child to bed on time. She recognized that some of these difficulties were due to her own inattention and. which facilitates memory and learning.Attention-DeHcit Hyperactiv-ily Disorder (ADHD) / VoeUer 807 school in the morning is often stressful for nuuiy families. Having a child with ADHD si>end time in multiple envuonments (school. Altliough medication might help a sleepy child stay awake during school. However." he would perform better. an after-school program."). but it iLsually works better for cluldren to eat if they are hungry. and has sufficient exercise is a crucial part of the treatment. let alone provide the systematic support that the child requires. he had no idea what "trying harder" and "doing something different" meant. fathers with this profile reported lax paienting both before and after parent training. if tlie parents iire divorced. and the logistics of getting the child to bed on time while completing the rest of the evening routine are formidable. Telling them that they are "hyper. In a study that examined the pai-enting styles of parents who described themselves as inattentive and impulsive. 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. 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.

is useful in the treatment of drugabushig adolescents. a series of natural consequences might ensue. possibly because nicotine enbajices attention. Some Information About Medications for ADHD Pai eiiLs ajid teachers sometimes state tliat a cliilit cannot liave ADHD because the child is not "hyper. and the most effective treatment involves psychostimulants and behavioral treatment. and sometimes letting a child experience a "natural consequence" helps reinforce the routine. Children with ADHD cannot monitor theii. the more the chiltl will use this excuse.'" A nuuiber of different types and fonnulations of medication are now on the market. but the medication works well in both situations.backpack?") aie more helpful Ihiui allowing the due date to creep up or to let the child foiget the final version. Children witli ADHD benefit enoniiously from daily communication between the parent and teacher. Children with ADHD. the child leanis that it is not very important to perform this routine. it is almost impossible to improve the situation." or if he tells his parents convincingly (but untruthfully) (hat he "has no homework. the root cause involves dysfunctional brain circuits. the stuue day).in those who are untreated. '•^' They also tend to be drawn into deviant peer relationships. which ai'e strongly associated with drug abuse. Be forewarned: ti-aining these behaviors takes a long time and requires great persistence on the part of parents. so frequent pieasant and focused reminders when they are tirifting away from the program are helpful. might also be helpful. are at nmch greater risk of drug abuse than children without ADHD. andfindit liai'd to imagine tiiat a cliild wbo is slow-moving. and are especially vulnerable to these undesirable social influences. '"^ . clironically disorganized. Number 10." As discussetl above. Principle 6 A child's compliance with a routine should be closely monitored. unaware of his or her surroundings would benefit from the sanie medication used to treat a c'hild with riuupanf hyperactivity and inipulsivity. and pro\1de immediate feedback to the pai'ent if homework is either not turned in or is substandai d. antl reminders as well as consequences should be provided. Although the vast m^ority of children respond to methylphenidate or dextroaniphetamine. it requires a herculean efforl for the parent to correct the situation. or a combination of both mechanisms. October 2004 "I caii't do it because I have ADHD" roiiline. which is used to treat narcolepsy or daytime drowsijiess in adults with partially treated sleep g^nea.) Natural consequences are usually better than "unnatiu-al" consequences. A child learns quickly that if the homework assignment is written illegibly or is "forgotten. The parent then becomes responsible for delivering piompt rewards or negative conse((uences. one study demonstrated that treatment with psychostimulants in liigh school appeared to protect against hallucinogen abuse by adulthood.''" In fact. particularly those who are not treated with psychostimulants. if the child's teacher does not respond with an immediate consequence if the homework is not turned in. and the solution is to "tlirow medicine at it" ratlier than look for "the root cause.er (methylpbenidate) or increasing dopaiuine release into the synaptic cleft (dextroaniphetamine). If there is minimal feedback from the teacher. Thus." or the necessary workbooks or other materials are not brought home. When it comes to long-range projects.'•'''' 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." 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). However. "Have you put the report in youi.808 Journal of Cliild Neurology I Volume 19. tricyclic antidepressants) might be useful in treating children who have failed psychostimtilani treatment. if a child does not perfonii the nightly routine of checking the backpack and forgets homework. Medications that increase norepinephrine (eg. If a child has done well working on such a long range project. di-eaniy. with the focus on fixing responsibility on the child and teacliing tlae cliild to monitor his or her own homework.se the risk of dmg abuse in later life. (However." Some believe that psychostimulant treatment is designed tx) "slow tlie child down. or it does not occur in a very timely fashion (ie. but tiien forgets to turn it in on time. available data would suggest that it is quite the reverse. and somewliat. might need to remind and monitor what materials the child is taking home. 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". Modafinil.". Psychostimulant medication appears to activate neural networks. i>arents need to Vie aware that it is extremely difficult for a child with ADHD to anticipate and plan a long-tenn project. I have worked with children who have perfected the art of "flying under the radar.''*^ They start smoking at an eai'lier age than peers. further increasing the risk of dmg abuse.own behavior well. which are either genetic or acquired. Pemoiine. parents often state that ADHD is diagnosed too frequently. At 7 o'clock in tlie evening. Principle 7 Teacher involvement is crucial. it required almost 24 months for this child to beghi to change his behavior. The teacher is a very important player in this situation. which has the potential for liver damage and requires repeated blood tests. Parental Concerns When the diagnosis of ADHD is made and medication is recommended. Rewaiding compliance witli routines worky better than pimisliing noncomplianre. This strongly reinforces homework avoidance.Bupropion and atomoxetine (both of wliicli increase centiai dopamine and norepinephrine) are also medications that might be helpful in this situation. such a "natural consequence" might be unnecessarily harsh. What are the risks of not treating ADHD? Although parents are often concerned that starting a child on psychosthiiulant medication will jncrea. this means that the teacher must check the homework list. Medications used to treat ADHD act by inhibiting the dopamine transport. When tlie parent and teachers began to communicate very closely and a tight behavioral prognmi was set up. then the homework cannot be completed. an o( casional child does not. subserving performance of specific tasks.

VaiiBrakle J: Preschool children 13. and executive fimctions: Constructing a unilying theory of ADHD. contTolied trial with a coinnumity sample.. JAbvorm Child Psyriwl 199^:23:729-749. Bifdemiaii J: Toward a broader itefinitioii of the age-ofoaset criterion for attention-deficit. Mol Ptiyrhi'itn/ 2002. 3.-4 (i./ Child Nnirol 2004. 9.25:227-250. sustained attention. 12. 14(3 Because a nmnber of different genes are involved in the ADHD phenotype. 7. whereas perfonnance on these tasks was enhanced by dextroamphetamine in subjects with a diffei-ent (tJie ValA'al) plienotype. Pnychul Bull 19!t7. et al: Validity of age-of-onset criterion for ADHD: Aroport from the DSM-IV field trials. Nelson CA: Measurement of vigilance in 2year-old c-hildrcn. JAm Acad Ckild Adolcsc Psyrhiatr// im7. Tliompson M. Laliey BB. Washington. Castellanos FX.m:l2U-l22\./ Am Anid Child f'syrhittlry i987. soc ial. Uhey BB. psychosocial. Some parents worry thai stalling children on a psychostimulajit medication will commit them to lifelong use. hi contrast.in its niechanisni to cocaine. V'otilor K: f'rt'frontal I'xcciitivo function syndromes in children. Lahey BB. Iiitt'rac tion of tht' exon III 4a-l)p repeat and the -521 CfT promoter polymorphisms.3C:1204-l^]0. Adalexc Psi/fiiinlnj 1994. 2. . hyperactivity disorder. nonetheless. are at greater risk of behavior disorders'*' and psychiatric disordei-s (mtyor depression and pei"sonaiity disorders). Milherger S. Daly D.1 Rucklidge JJ. impairing. cocaine remains bound to the dopamine transporter for very brief periods of time. 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. Mc'Goey KE.1. DC.^'iQ-^^40. Doyle A: Diagnoses of attenlion-dpficit hyi)praf tivity disorder from parpiit rei)or(s predid dia^oses l. therefore. Barkley RA: Behavioral inhibition.have a much higher rate of traffic violations than peers. Knee D. et al: Executive function oculomotor tasks in girls with ADHD.'" A SPECT study of children with this genotyi>e. 1994. Although no parent wants to see Ms or her child on medication.. American Psychiatric Assofiatkui: DimjiiDstic and Stalisticni ManuaJ u/Mf'iital Disorders. . Greene RW. -/ 4m Arad Child Adolrsc Psychiatry 1997. and correlates. I. 4th ed. are dangeroii. Goldman DZ. Angold A: Implications of early versus lato oiispt of attention-detlcil/liyppractivity disorder symptoms. Hart EL. "^' and. 5. Applegate B.1 Am Acini Child. J Am Acad Child Adolesr Psychiatry 2000. . Tolli I. methylphenidate remains bound to the dopamine transporter for several hours. inethylphenidate is not a very good addictive medication unless it is administered intravenously.Adolesc P.40:704-7lO.I. Willotighby MT. Halt EL. Mick E.7 P. 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. 14.7:27-. Biedemian J. Faraone SV. Sonuga-Barke E. with attention-defirit/hyperactivity disorder Impaii-ments in beliavioral.40:. Arn J Fsyvhialry 19«7. Lo<^ber R. rt . The real issue is to weigh the risks of treatment against the risks of nontrealnient.Adolcsc Psych i<il>-y2(m-A{)A(i2^m. In addition. Faraone SV. There are many medicines that.U: Validity of DSM-IV attentiondeficiL/liyperat'tivity disorder for younger children.s imt at the appropriate dose are lifesaving (eg. Munir K. had significantly higl\er regional cerebral blood flows in the medial frontal and left basiilgimglia regions than children wlio did iiol have this genotype. 4.. 8. Children with ADHD who are honiozygous for the 10-repeat allele at the dopamine transporter 1 (DATl) gene show a poor response to niethyiphenidate. POWPII KB. A few examples will suffice. understanding these c'omplex interactions will take much furthei" investigation.sv/c/. et ill: Fiirtiter e\-i(ience for the role of the (fopaniiiie 04 rer^^plor (DRD4) gene in alliirhnient disorganization. J4mAc«(/C/n7(/ Adolenc Psychiatry 1998 . Pelliimi WE. Bie<ieinian . Laliey BB.("/r/y2<K)(): 157:1077-108.(lisorders: Symptom utility estimates.121:65-94. Biedemian J. children with endocrine disorders or asthma need lo lake medicine). R^erences 1.Attention-Deficit Hyperactivity Disorder (ADHD) / Vocllcr Despite c o n r e r n s regarding its addictive potential.. Applegato B. ADHD is no different. are more likely to abuse drugs tlian children with ADHD who are treated. -/ Am Acad Child Adol. Nenioda Z.'^. et al: Developmental chaiigf ui allt-ntion-deficit hjperactivity disorder in boys: A foirr-yeai' longiludinal study. repeated doses have very little effect. children with diabetes require insulin. 6. who showed some response to inethylphenidate. Marvasti FF. et al: Family study of girls witli attention defuiliiyijeraclmly disorder. DuPaiil GJ.1 Am Acaii Child AdolcNr Pnychialnj 1993. Dev Neuropsychol 2004. Stein MA. gender comparisons. II. with about 60X1 of dopajnine transporters blocked. Faraone SV. Lakatos K. repeated high intravenous doses have euphoric effects and set the stage for abuse.37:696-702.3^:529-539. ThLs is siiTiilai.'"*'' 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.50. Coslello EJ. Altiioiigh most patients respond well to psychostimulants.'5O8-515. American Psychiatric Association. . et al: Social impairment in girls with ADHD: Puttcnis. It is a chronic. Barkley RA.'"' Wlien niethylphenidate is aiiniiiustered by nioiitli at a standiuxi clinical dose.)ase(:l on toaclipr repons.ahey BB.J. Biedemian . Frick P. Attention deficit disorder with aji(i wilhoiit hyiipractivity: C"otiniarison of behavioral duiractcristics of cliiuc-refnTcd children.2(J: 718-723. Taiuiock R: Psychiatric./ Atn Acad Child Adolesc Psychiatry 2O0l. impairing disijrder Ihat is perhaps not as lile-threatening as diabetes but is. et al: DSM-IV field trials for the disni|>tive beha\ioi. Schaughency E. 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.'!ic Psyrhinfiy 200i. untreated. 10. a small group has atypical responses or is at increased risk of ntidesirable side effects. if adminislered incorrectly.JS. and school fiincUoning.:i 1. c:iirraii PJ. particularly a (•hroni<' medication. et al: l*arent-based therapies for preschool attention-deficit/hyi)eractiv1ty disorder: A randomized. Ei kert TL. Hynd G. Methylphenidate binds to the dopamine transpoiter aiid increases dopamine levels iti the brain. 19:785-797. therefore./Am Arad Child Adolesr Psycliinliy 2000:^9ArA-i-iril9. insulin or digitalis). Shapiro EG. there are some situations in which a cliild needs In Uike medication mvi continue it thiougliout life (eg. et al. etiphoric effects arc not present''" Dextroaniphetaniine has a somewhat more complicated mechanism of action.:39:G44-6.'iychia try 2tmA0.!44:3a0-333.'''" 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. What iire the risks of nontreatmenl'? Children with ADHD who aie not treated are likely never to live up to their potential in school.. JAm Arnd Child . -/ A m Acad Ch ild . aiid cognitive functioning of female adolescents uith ADHD. Ducharme JL.

Konstantai-eas MM. . Saliakian BJ: Specific language impaiiinent with or without liyperactiviiy: NeiHTjpsycholo^cal evidence for fronrostriatal dysfiaic-tion. Voeller KKS: Neurological factors imderlyiiig the comorbidity of attentional dysfimction and dyslexia. Voeller KKS: Psychiatiic uiiplications of language dlsoi-ders and learning disabilities: Risks and miuiagement. et al: Quantitative morphology of the caudate nucleus in attention deficit liyi>eractivity disorder. Durston S. England. prefrontal cortex. matter deficits in hyperkinet ic disorder: MlSl evidence for anatomical abnormality in an attentional network. laterality and gender. Alexander AW. Neu45. cerebrum observed in vivo during adolescence. Buchanan RW. Bullmore ET. Peterson BS. Molloy E. Ann Neimtl 1978. Sprich S: Comorbidity of attention deficit hyiM'iactivity disorder with conduct. Miinii" K.931: 33-49. niid Bp. Biedemian J./))7dPsy(7(o/2000:28:149-159. 29. Lee PP.128-155. Hesselink JR. Arch Geri Psychiatry 1977:34: . Cmnming.31:1425-1435. et al: Attention deCcit-hyperactivity dis50. 49:921-926.2(J:844-848.ind wiiite 54. Hynd G W. Hesslinger B. Biedennaxi J. Brain mori)ho!ogy in schizophrenia: Effects of diagnosis. Giedd JN. Nadeau SE: A possible pathophysiologic substrate of attention deficit hyperactivity syndrome. Cambridge University Press. anxiety. October 2004 21.IK. 2001.. 46. Eckburg P. in Beitfhman JH. J Ch ild Ncii ml 1996. Casteilanos FX./. York Press. 31. Junqu C. Rndel RG: Anomalies of motor development in hyjieractive boys. Rpader MJ: Basal ganglia volumes in children with attention-deficit hyijeractivity disorder. in Lichter DG.i . Willciitt. Casey ai. Denckia MB. Psyeh/il M'rf2001. Voeller KKS: Altention-deficit/hyperactivity disorder as a frontal-subcortical disorder.i7. 26.lL(eds): Fmntai-Siibrnrlieal Ciiviiits in Psychiatric and Nemvloyiral Disoirlers. 35.s in children and adolescents witb attentiondeficit/hyperactivity disorder. et al: Volumetric MRl analysis comparing subjects liaving attention-deficit hyjjeractivity disorder with normal controls. MD. Brain 1991:114: 2037-2049. and caudate stnictures. Denckia MB. ami OiriicalPerspectives. Tebartz van Elst L. Berquin PC. Nat Nevrosci 2003:6:309-^:315. Am J Psychia(77/1995:152:704-714. 59.1 Chikl Neiira/2004:19:814-820. DeFries JC: Etiology of inallention and hyperactivity/impulsivity in a commtmity sample of twins witii learning difficulties. 42. . Jacobsen LK. 32. and other disonlers.48:589-6O1. Cambridge. Overmeyer S. et al: Cerebellum in attentiondeficit hyperactivity disorder A morphometric MRI study. t'ilipek PA. Campbell RA.:i(3:374^'i8:i. in Duanc DD (ed): Heading and Allcntioii Disorders: Neurobiological Corrrlates. Seninid-Clikeman M. Sohnat-k HG. lSri-212. Psychiatry Rea 2002:116:63-81.4()?! orm. Frederikse M. Reiss AL. Gillberg C: Attention deficits and clumsiness in Swedisb 7-year-old children. Neurology 1H97. J Leani DisflbiV 2001:34:33-58. 24. 40. Hill DE. EG: A comparison of the neuropsychologicalprofilesof f he DSM-IVsubty|X's of ADHD. Yeo RA.'^40. Stott ('M. Jeniigan TL./ Am Acad Chitd Adolesc Psychiatry 1992. Biedennan J. Kates WR.hnvior Disordeis: Dfi. 47. J Child Neurol 1993:8:339-347. Peterson BS. Dev Med Child NeumI 1998:40:796-804. et al: MRI parceilation of the frontal lobe in boys wilh attention deficit hy^ieractivity disorder or Tourette syndrome.52:785-794. et al: Mapping cortical change across the human life span.53.13:4.IN. Chitd Psyrhol 2001:20:. 43. Singer HS. J Learn Disabil 1991./ Child Neurol 1998.I. Castellanos FX. Sundheiin STFV. Science 1994:266:458-461. Ann N yAcad Sei 2001. . 28. Gipdd . Neurology 1998:50:1087-1093. Semnid-Clikemaii M. Marsh WL. Number 10. 11: 112-115. Am Jl^yehiatry 1994. Giedd JN. Novey ES. Mostofsky SH. Cantwell 1): Psyctiialnc disorder in diiidren with speech and ianguage retardation: A critical review. Lorys AR. :134. . Tbie! T. Mostofsky SH. J Ani Ac<nK:hild Adotesr Psychiatry im7-. A)ii . et al: Humaji basal ganglia voluiue 58. Strick PL: Anatomiciil evidence for cerebellar and basal ganglia involvement L n higher cognitive function. Neurotogy 1996:47:477-482.a] trajectories of brain volume abnonnalitue.sum morphology in attention deficit hyperactivity disorder: Morpliometric analysis of MRI. Giiilford Press.i4-439. JAMA 2002:288:1740-1748. 23. Am J Psychiatry li)94:i5l-Mii-ma. Goodyei" IM. Cohen A: Language deficit with aftention-deficit tUsorder: A proviilent comorbidity. Pt al: Magnetic rosonajice imaging correlates of attention-deficit/hyperactivity disorder in ciilldren. .46»o)fn r. Tirosh E.1 PsychhiU-y 1991:148:564-577. \'oeller KKS. 1999. Arch Neurol 1990:47:919-926. et al: Quantitative brain magnetic resonance imaging in ationtion-dellcit hyperactivity disorder. Dri. Biologica}. Cohen NJ. Castellanos FX. asynunetries on magnetic resonance images. I leni KL. Momiteaus MC. J. 25. S(>ninid-Clikemaii M. et ai: Implication of right frontostriatal circuitry in response inhibition and altcntion-deficit/liyperRc1i\iry dmmcipr. 61. 22. . Pennington BF. Baumgardner TL. Blunienthal J. 39. 56. Sprich-Biickminster S. 1996. et al: Brain morphology in developmental dyslexia and attention deficit disorder/byperactivity. 38. Cooper KL.42:368-375. J Am Acad Child Adnlesr Psychiatry 2004:43: :!3:i-:i40. Brcier A. Castellanos FX: Brain imaging of attention deficifhyperactivity disorder. Mostofsky SH. Castetlanos FX. et al: Smaller prefrontal andpremotor volumes in boys with attention-deficit/liyperactivity disorder. 34. New York.151:1791-179(i. Knee D: Psychiatric comorbidity in patients with attention detlrit disorder: Acontrollod study. Swayze V 11.810 Journal of Child Neurology I Voliutie 19. 41. Mataro M.31:439^48. Semnid-Clikenian M. Castellanos FX. et al: Frontoorbital volume reductions in adult patients witii attention deficit hyperactivity disorder.3:231-233. et al: Corpus callosum moqihology in children witb Totirette syndrome and attention deficit hyperactivity disorder. et al: Magnetic resonance oys with attention-deficit/hyperactivity disorder and tbeir unaffected siblings. TMal PA: Maturation of human 51. SeidmaJi LJ. Learning. l-ockhart P.Mrd Ch Ud \'euml 2OO0. Cbhabildas N. et al: Intensive remedial instnirtion for chiklren witJi severe reatiing disiibilities: Immediate anti !ong-temi outcomes from two instructional approaches. Iiulshoff Pol HE. Nciiropsyvhohign 2001:I5:I)44-. Kates WR. 27.i3. Torgesen .24:141-146. Denckia MB: Evaluation of cerebellar size in attention-deficit hyperactivity disorder. Hynd GW. Kadesjo B. . et al: Comorbidity between ADDH and learning disability: A review atid report in a clinically referred sample.356. .-Hoptuenlxii. Tannock R (eds): LanffHage. Cohen DJ. Reiss AL. Giedd JN.37I. 36. TVauner DA. Suckling J. et al: Quantitative morphology of the coipus callosum ui attention deficit. Baltimore. Middleton FA. et al: Learning disabilities and executive dysfunction in boys willi attention-deficit/liyijeractivity disorder.. Tannock R. Magnetic Reson hnag- 57. O'Leary DS.">29-. Neiimsci Lett 2002:328:319-321. Giedd JN. Giedd JN. Sowell ER. 63. et al: Brain niorijhology and schizophrenia: A magnetic resonance imaging study of limbic. Flaum M. 52. 60. Biedemian J. 64. Biol Psychiatry 2002. 62. 30. Lorys AR. Williams D./ Child Nenml 1998:13:493-497. Willcutt E(i. J Chitd Neuml 1991:6:S74-S80. 44. 48. order and asymmetry of the caudate nucleus. Newcom J. 49. An-h Gen Psychiatry 1992. Thompson PM.583-591. et al: Distributed grey . Steiiigard RI. Scharhar R: Exectitive dysfmit-litin as an underlying nieciv anism of behavior and language problems in attention deficit hyi>practivity disorder. depressive. Aivh Neumt 1997:54:96:3-969. Waiiner RK. hyperactivity disorder. Airh Gen Psychiatry 1996:53:607-616. ct al: Develop me nt. et al: Magnetic resonance imaging measurement of the caudate nucleus in adolescents witb attention-deflcil hyperactivity disorder iuid its relationship with neiiropsychologicat and behavioral measures. Heihiian KM.-l/o Acad CfiiM Adnlesr Psyrhinlry 1987. Elkashef A. Pt ai. Aylward EH. Shaip W. Garcia-Siuicbez C. Hynd GW. Casey B. Riddle UA. Penniiigton BF. et :il: Coipus callo.

14:343-351. Kolachana BS.'erpbrai glucose metabolism in adolascpnt girls with attention-dt'tirii/liyiieractivity disorder. (. 94. Bruce CJ.SV7 USA 199S./ ChildFsychot Psychiaiiy 2004.l 1989.ild Adolfsc Psychiotry 1999 . Olson L: Development of monoamine systems ai^er neonatal iuioxia in rat.'lrndO(*7(. Cliv Nfu2:113:1036-1044. Thomas KM. 83. 104. 95.6: 205-210. 1:887-900. Neumpsychology 2003. 19:91-96. et al: ADHD: Increased dopamine receptor availability linked to adention defieir and low neonatal cerebral blood fiow. Saunders RC.dysfunction in schizophrenia. Filipek PA. King AC. Faraone SV. 67. Orgill AA. -/ Nfiin)phy. Aw. Kinies AS. Heath AC. Clin Neiira/200I. McGee CL. Riley EP. Goldman-Rakic PS: Working memory. JAm Acnd C^. Nenivlogy 1997. et al: Regional brain s abnormalities persist into adolescent e after heavy prenatal alcohol exposure. Ryding E. Tliomason ME.I. .irthy R. AH n u Rev A'wfr 2003:23:4158. 76.sy(:-/?m/i:y 1994:33:858-868. 82. 97. 96. J Nennisri 1981. Pryds O. J Am Acad Cltild Adolpsv Pst/rhifiliy/ i997MV. 93. 105. Ausiiii G. pt al: (.im:lOC. 13:900-913. Neunian IiJ. Bany R). Obel C. 106.ention problems in children. Nissenkorii A. Nordalil TE. Ernst M. 84. et al: Maternal smoking and hyi>eractivity ui 8-year-old clukiren. J Am Acad Cliild Adolesr Psi/rhUifr(/1994. Farone SV. Aosald T. Jones J: Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: FiiuJings from a high-risk sample of siblings.95:14494-14499.IoneK G. et al: EE(i evidence for a new conceptualisation of attention deficit hyperactivity tlisorder. 68.265:412—415. J Neu7T>pliysi. Brtihn P. Phillips RL.s in 87.160:1028-1040.im'U0i5. LorbeHjoyni M. Selikowitz M: EEG coherence in attention-deficit/liyperacttvity disorder: A compai^ative study of two DSM-IV ty])ps.153:1138-1142. 80. Connor JR: Iron status and neural functioning. McC. J \'riirnplii/siot 1990:63:1385-1400. Biol Psychiati-y 1996. Todd RD. et al: Immatiu'e frontal lobe contributions to cognitive control in children: Evidence from fMRI. Coh<'n RM.5-63. Bloom FE: Central catecholaminp neuron systems: Anatomy and physiology of the dopamine systems. Barry RJ.o! 1986.striatal dopamine.J. 107.\V(«. Matsumiua M.} Am AvatI Child Adolesc Psychiatry 2003:42:826-833. Bloom FE: Norepinephrine containing locus coeruletis neurons in behaving rats exhibit jironoimced responses to non-noxious enviromnental stimuli. 81. 70. behaviour syntptonis. (Jraybiel AM. . Dainasio AH. EmsT. Pettigrew D. cognition and neurologic:il soft signs in cliildren witli attention-deficit hyperarti\ity disorder (ADHD). Chabot Rl. Decker MJ. Kimura M: Effect of the nigrostriatal dopamine system on acquired neural responses in thp striatimi of behaving monkeys. et al: Terimetiinn 99ni etJiylcysteinatf dimcr single-photon emission coniptiteii toinogi^aphy (SPECT) dtiiiiig intellectual stress test in childi^en and adolescents with pure vei-sus comorbid attention-deficit hyperactivity disorder (ADHD). 73.(31:331-349.41: 65-75. Kirkorian (J. Beard JL. Sowell ER: Teratogenic effects of alcohol: A decade of brain imaging. 102.iross M. 92. 103. Millichap JG: Temporal lobe arachnoid cyst-attention deficit disorder syndrome: Role of the electroencephalograph in diagnosis. 100. Liebenauer LL.577-. et a!: Neural substrates of decision making in adults with attention deficit hyperactivity disorder. et al: Differential patterns of striatal acdvatlon in young cliildren with and without ADHD. Faraone SV. Funaliashi S.. Biol Psychiatry 2003. Goklnian-Rakic F*S: Mnemonic coding of \isual spare in tlie inonkey's dorsoiateral prefrontal cortex. 2002:33:301-311. Zanietkin AJ. 10:299-316. London ED. Kotimaa A.53:87t-878.63:1401-1412. et al: Attention-deficit hyperaclivit>' liisorder: Magnetic resnnaiic-e imaging nioiplionietric analysis of the corpus fallosum.U2:20E)8-2105. Liebenauer LL. Cognition 1994. Moilanen I. Kubota K: (?atecholanunergic effects on neuronal activity related to a delayed response task in monkey prefrontal coiiex. ME. Rye DB: Neonatal inrerminent hypoxia impairs dopamine signaling and executive functioning. et al: Evaluation of ADHD typology in tlu'pp contrasting samples: A latent cLiss approach.588. a%e 3 to 12. et al: Reduced brain metabolism in hyperacUvegii-ls. J AV'inusr/ 1993. Apicella P. Sawaguchi T. 75. et al: Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and assoc iated behaviors: Review of the current evidence. J Clin Ch ild Psychol 1998. A' EngI J Med 1990. Durston S. Bmin Res Bull 1993.33:875-881. Walembprg N. Tli()nipst>n PM. fiO. et al: Behavioral and electrophysiologic prf'dlctors of trpatmcnt response to stiniulanis in children with attention disorders. Zanietkin A.I.il: Cerebral glucose metabolism in adults with hyperactivity of childhood onset. Taanila A.38:2. Selikowitz M: EEG-defmpd subtypes of children with attpntion-dericit/liyi>erariiviiy di.323:1361-1366.48:1435-1439. Daniasio H. Sleep Breath 2002. 99.pntion tipflcil hyfieractivity disorder A functional ntagnetic vesonancestudy. 72. Antshel KM. Bal A: Separation of the motivational and motor consequences of 6-hydroxydopamine lesions of the mesolinibic or nigrostrialal systpni in rats. Bchav Brain Res 1987:23:221-229. brain glucose met. Ljungberg T Responses of monkey dopamine neurons to rewaJ'd and conditioned stinuiH liuring successive steps of learning a delayed response task. et . et al: Is mateniiil smoking during p re giiancy a risk facior for attention deficit hyperactivity disorder in children? Am J Psychiatry 1!)96. Milberger S.45. Barrj' RI. Dev Med Child Neurol 2OO4. 86. Rosa P. Mishldn M: Behavioral disturbances in the developing rhesus monkey following neonatal lesions of inferior temporai cortex (area TE) resemble those ui attention deficit hyrieractivity r. Bunge SA. et al: Pregnancy.4c/((/*f(p</m7» 2000:89:830-835. Bechara X. (. Dudukovic NM. 98.46:48-52. Ix)ngitudinal resulls from a study of twins. 109. Crawford G. Aston-. et al: Associations between cerebral blood-flow measured by single photon emission computed tomogr^^jhy (SPECT). Milberger S. Ernst M. Biol Psychiatry/ 1997. et aL SpkntivpeOivtsofnipthylphenidate in att. Merjanian PM.7 A»i. Tottenham NT../ Neuropsychiairy CAin Neurosci 1994:6:348-357. Biedemian J.46:179-I8.Aioui Rev Neiirosci 1978. Bachevaller J. ("laike AR. 101. Clai'ke AR. Ixm Hf". 79. (i9.50:7-15.17:458-468. Hudziak JJ. Bartels M. 88. 74. Hcnriksfn L. Sowell ER. .l~l070. Serfontein G: Quantitative electro en cephalograp hie profiles of children with attention deficit disorder.127C:35-C41. Biederniaji J. liiuiet KM. 78. Moore RY. Dalsgaard S.4ra(/.ftT>r. Themlund G..sorder. McCarthy R.27:352-a38. Science 1994.'habot Rl.3.si(. VaidyaCJ. Milberger S. . delivery and infancy complications and attention deficit hyperactivily tlisoRler Issues of gene-environment interaction. Ltiii HC.Attention-Deficit Hyperactivity Disorder (ADHD) / Voelter 811 65. . Matlson SN. 108. 89. 90. J Child Neurol 1999. Luthman J./ Child Neurol 2004. et a]: Striatal dysfunction iii attention deficit and h>n)erkiiietic disorder Anii NcumI 198E). Cliild AdolescPsychiatr Ctin Noiih Ain 2001. Weinberger DR: Neonatal lesions of the medial temporal lobe disnipt prefrontal cortical regulation of . Natuiv 1998. Antlerson SW: Insensitivity to future consequences following damage lo human pR'frontal coitex.32:159-170. Cohen RM: Age-related rhange. Schultz W: Responses of rnidbrain tiop<unine neuiT)ns to behavioral I rigger stimuli in iho monkey. M.il: Heritability of att. Biedemiaji J. JNeiiropsi/rhidln/ (I'm NeiiroHci 1098:10:108-177. Gustafssoii P.4(to/rarP. .str 1989:15:302. McCarthy R.393:169-171.'i. Biedemiiui J. Ernst M. . Lindqvist E. eleftro-encephalogrtim (EE(i).aboiisni In adults with attentioii-deficit/liyperactivity disorder and control subjects. Waisbren SE: Timing is eveiything: executive functions in children exposed to elevated levels of phenytalaiiine. Schultz W.40:951-963. 12:856-805. et . Atn J Psychiatry 2003. Ctiii Ncumphysiol 2002:113:579-585. Riet\'eki M. Seninid-Clikeman M. Cereb CoJlftr 2002. Pajjp M. Am J Med Genet 2004. J Psychiatry 200S-. 91. Faraone SV.1:129-I69. Doyle AE: The nature and heritability of attention- deficit/hyperactivity disorder. Clai-ko AR. Sf>c Neiirosci At>. 85.

Mattay VS. Fowler JS. Wright V. Harvey E. Gunawai dene S: Does stimulant therapy of attention-deticit/hyiieractivity disorder beget later substance abuse? A meta-analytic review of the literature. Max JE. Kreppner JM. 139. Hogaii AK. Mathews K. Schwartz KP: Response preseveration <md delayed re.579. Castillo ('S.213:389-394.study of desiprainine in the treatment of ADD: I. 130. 133. American Psychiatric Association Pre. JAm Acnd Child . Shari^ WS. Bloom DR. 143. Ewing-Cobbs L. and treatment utilization. 127. Milberger S. 136. Danforth JS. Faraone SV.'U'l/fifvi/ Psyciiol 1988:97:371-:173. JAbnorm Psyehot 2003:112:497-507. et al: A double-blind placebo controlled . 17:293-302. 1996. Fera F.\n examination of deviant peer group affiliation as a risk factor. Chen C./ Almorm Child P. Biederinan J. (!)'t'oiinor TG.64{Suppl 11): 19-23. Peteison BS. Wang Y. 124. Mattay VS. Bai'klcy R. Wilens TE.III.s with aiul without ADHD. Psychiatr Ctin North Am 1998. BaiTett . Number 10.. Levin HS. Rohde LA.52:464-470. 134. 120.48:87-89. Stein MA. Daly G. hyperaili\'ity disorder Am J Psychiatry 2003:160:169:3-1696. Efficacy. et al: A family-based and case-control association study of the dopaniine D4 receptor gisiie and di. Fitzgerald M. O'Connor TG: Specificily and heterogeneity in cliildren's responses to profomid institutional privation. Engesser-Cesar C. 113. Szobot C. et al: Family-based ajid case-control association studies of DRD4 and DATl polymoiphisms in Chinese attention . Hoza B: Intensive treatment: A summer trpat. Fletcher KE: Adolescents with ADHD: Patterns of beliavioral atljustment. McKee TE. 141. J Am. Molina BS. Barkley RA. Cotman CW: The timecoiuse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. 1996. and the role of executive fimctioning.?io(/'/fps 2001:50:701-705. Cireenhill LL. Neuivsci ljf>tt 131. Biedennan J.100:6186-6191. and attention dellcit/liyperaclivity disorflere. Muhleman D: Association of the androgen receptor gene (AR) witli ADHD and conduci disorder. Fischer M.\.57::364-. Aivh Geii Psychiatry 2()OO. 125. t29. Quay HC. -/ Int Neiimpsychol Soc 2003. J Alti^n Di.Mot Psychintry 1999. Soorani-Luasing I. Barkley RA. Davatzikos i. 122.'389-1592. 137. Heron S.528. Krasowski MD.8:655-672. 142. 112. Marshal Ml'. Chen A. et a!: Lifetime and novel psychiatric disorders after pediatric traumatic brain injury.1. Holmes . Bennan KF. Manes FF. DBII and DRD5 to affected cluldren.sord 20O3. Pelham WE. Swanson JM. Dupaul (11. 117. Pelham WE Jn Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. ajid tht' role of childliood conduct problems and teen CD. et al: Ptitainen lesions and the development of attenlion-tieficit/liyperactivity symptomatology.30:752-7r>l.social IWatmails for Child.stance abuse. Qian Q. Swanson .s. Zhou R.siLSceptibility loci in attention defuit hyperactivity disorder: Preferential tTaiisnus. 132. JAbiwrm.311-340. atid Adolescent Disorders: Empirically Bast'd Slrateyif.2:311-31.ssion tomography rCBF study . Lancaster JL. Psychol Addict Behae 2003. Hadders-AlRra M: Are moderate degrees of hyperbitimbinemia in healthy tenii nooitates r<'ally safe for the brain? Ppt.7 A'pi/n>. 135. pt aJ: At ten tion-deficit hyperactivity symptomatology al'ter traumatic brain uijiir>': A prospective study. Neuroimage 2003. 128. ^rrft Gen Psychiatry 1995. 118. comorbidity. et al: Preliminary findings of antistreptococcal antibody liters and basal ganglia volumes in tic. Child Adolesc Psychiatry 2001. et al: Anatomic brain almormalities in monozygotic twins dLscortiant for attention deficit. adverse outcomes.'2003:27:615-621. Sliai')iro SK. in Hibbs E. JAm Acad.30:4a3--175. Fallon BA: The imderdiagnosis of neuropsyciuatric L^nne disease in chUdren and adults. Anastopoulos AD. Wu S. Castellanos FX.J-8. Le( kman JF.37:841-847.JM. 149. Gill M: Moping . Molina BS. Miiltimodai TVeatment Study of Children with ADHD. Pivc Natt Acad . Cook EH Jr. 150. et al: Association of attentiondeficit disorder and the dopamine transport(^r gene. WoltilHA. Mol Psychiatry 2000 fi:ri23-oM). .40:180-187.\ 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 .>erdctivity disorder aiid neurocognitive correlates after childhood stroke.40:108-179. Pediatrics 2003.ss. J Am Acad ChiJd Adolesc Psychiatry 1991. et al: Confirmation of association between attention deficit hy|)eractivity discirder jmd a dopmnine transporter polymorphism. Goldberg TE. et al: Catechol O-methylt rajisferase Val 158-Met genot^i^e and individual variation in the brain response to aniplieiamiiie. 114. Rutter M: Can inattention/overactivity be an institutional deprivation syndrome? .'tin Psychiatry 2003. 119. Gerring JP: Application of a data-mining method based on bayesian networks to lesion-deficit analysis.812 Journal of Child Neurology I \o\\m\e 19.40:572-. Fletcher K: Young adult follow-up of hyperactive children: Self-reporK-d psychiatric.i/f7. JAmAead Child Adolesc F. Smallish L.IE.'iychol 2001:29:513-. Daly G. el al: Preniorbid prevalence of ADHD and development of secondary ADHD after closed head ii\jury. Max JE.disorders.sfor Clinical Practice. Arndt S. J (. Biedemian J.52:45(i-563. Gottesman RF.41:5fi3-571. Gill M. October 2004 110.>piimine transporter gene in attention deficit hyperactivity disorder. Volkow ND: Serum and brain concentrations of methylphenidate: Implications for use and abuse.sjionding in undersocialized aggressive conduct disorder./ A m Acad Child Adotcsc Psychintnj 2002. Kraenier HC. JAm Acad Child Adolesc Psychiatry 200l. 12:i. Mol Psychiatry 1997.eta]: Is metliylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Faraone SV. 140. el <il: linpiunncnt and deportment responses to different methylphenidate doses in childien with ADHD: The MTA titration trial. Max . VolkowND.mont program for children witli ADHD.16:4816-4822. Peireau VM. J Am Acad Child Adolesc Psychiatry 2001. Hinshaw SP.7:31-42. Jensen P(eds):/'. Synnpse 2003. response to methylphenidate and cerebral blooti How in attentiondeficif hyperactivity disorder: A pilot study. "Hicker D.4:192-19f). Adlard PA.10:l. 115 Herekovits EH. et al: Attention deficit hyi. Payton A.J72. 138. Biedemian J.' S A 2003. et al: Family-environment risk factore for attention-deficit hyperactivity disorder: A test of Rutter's indicators of adversity. Milberger S.sychiatry 1989:28:777-784.sc. (iuevTemont D('. KreppniT JM. Fischer M. Herskovits EH. Neuroreport I999. et al: Parenting of children with attention-deficityi\vperacti\'ity disorder (ADHD): The role of parental ADHD symptomatology.19:1664-1673. Gerring JP. Vitiello B. •lAm Acad Child Adolesc Psychiatry 199S. Am J Hum Genet 1995:56:993-998. Child Psychnt 2002. New York. Bush T: Driving in young adults with attention deficit liyperartivity disorder Knowledge. et al: ADHD is associated with early initiation of cigiirette smoking in children and adolescents. Acad Child Adulesc Psychiatry 1997:36:37-44.lll:179-ia5. Arch Gen Psy12(i. Rutter ML. 146. 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.4/r/i Gen Psychiatry 1995.-/.«. Comings DE.SV. DingY-S. 144. Swaiison JM.sior) of paitu)tal alleies at DAT!. Hawi Z. . By J Psychiatry 2001. Faraone SV. t. Brady KD.9:815-829. Baldessarini RJ. obsessive-compulsive. Roman T.!. 147. Neumsd Biobehav fl«. 148.idolcsc Psyvhiotm i998. Megalooikonomoti V. Radiology 19!»9.(U(Suppl 11 ):. 145.: A 14-montli randomizeti clinical trial of treatment strategies for attention-delicifliyperactivity disoi'der. IK). et ai: Dextroamphetamine enhances "neural network-specific" physiological signals: A positi-on-emi. Murphy KR. Biedennan J: Pharmacotheij^y for attention-deficifhyperactivity disorder (ADHD) decreases the lisk for substance abuse: Findings from alongitudinal follow-up of yonth. The MTA C'ooperative Group. t)strein JL. Barkley RA: <'liildliood stimulant treatment and risk for later sub. academic functioning. J Int Neumpsychol Soc 2()02. perfonnance. 179:97-103.21:693-703. Fox IT. et al: Dopamine transpoiier gene. 111. Pelham WE Jr: Childhood ADHD and adolescent substance use: .37:( 147-656. J Clix Psychiatry 200:3. 151. 121.

et al: Identification of a polymorphism in the promoter region of DRD4 associated wirh the human novelty seeking personality trait. Psychosoni Med 2003:65:471-476. Brophy K. Am J Med Genet 2000. 184. 153. Mol Psychiatry 2001. Mill . Ban.58:1052-1057. Am J Med Genet 2001:105:387-393. 170.'"i907. 182. Zametkin A. et al: No association of the dopamine transporter gene 3| 165] VNTR po!ymon)hism with . et al: Tlie association between tlie dopamine D4 recept. Mol Psychiatry 2000. Kirley A. 18:3. P'araone SV.. Kennedy MA. et al: Haplotyi)e analysis of SNAP-25 suggests a role in llie aetiology of ADHD. Mol Psychiatry 2004:9:SOl-S10. Hawi Z. et al: The dopamine D4 receptor and the liyi)eracti\ ity phenotype: A developmental-epidemiologic-at study.mls S.5:548-551.Mol Psychiatry 1998:3:38-41. 167. Virkkunen M. Francks C. Am J Med Genet 200]:10. Konecki D.1. Kiriey A. Kustanovich V.18:. Wigg K.-dpficit/liyperactivity di.65:1157-11G5.') risk alleles in attention-deficit hyperactivity dis.s. Am. El-F'add^hM. 185. Fifield WJ.. Jonsson EG. 161. Malone M. Am J Med Genet 20O4:l27B:68-72. Mill J.5:64-(i9. et al: E\idence tJiat the dopiunine D4 receptor is a susceptibility gene in attention deficit hyjieractixity disorder.)-917. 157. 193. Malhotra AK. Castelianos FX.-4m J Med Gene! 2001:105:745-748. 155. . Rooney W./ Am Acad Child Adolesc Psychiatry •2000:39:im7-lM2. Bailey JN. 156.ention-deflcit/hjperactivity disorder (ADHD) in a lugh-risk community sample: A longitudinal study from birth to 11 years oi a^e. Kustanovich V. Laucht M. Feng Y. Rogan PK. Nothen MM. 176.105: 471-478.uid scores on a contuiuous perfoniiance test (TOVA).54:097-699. Fisher SE. Mol Psychiatry 2003. et ai: Pedigree disequilibrium test (PDT) replicates iissociation and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. et al: Joint analysis of the DRD5 marker concludes association wilh attention-deficit/hyjieractivity disorder confined to The predominajit iy inattentive and combined subtypes. et. et a t No association between novelty seeking and the type 4 dopamine receptor gene (DRD4) in two New Zealand s.7:S&i-^i)l. et al: DOPA decarboxylase activity in attention deficit hyperaciivity disorder adults. 169.196-404. Todd RD. 159. 171. Ebstein RP. Caspi A. 160.5:531-536. Ernst M. 163.5:405-409. Ishii J.7:9i. 1.st M. Mol Psychiatry 2000. et al: High midbrain [18F]DOPA accumulation In children with attention deficit. 191. et al: TVansmission diseqtiilibrium testing of dopamine-related candidate gt. Am J Psychiatry 1998. . Sanysil S. Arcos-Burgos M.l 1996:12:81-84.order.i-1196. Mol Psychiatry 2003:8:299-^08. Hawi Z. Li L. Umansky R.sorder. Mol Psychiatry 1998:3:427-430.ne ljolymorphisins in ADHD: C'onfiiTnation of association of ADHD with DRD^ iuid DRD5. et al: QTL association analysis of the DRD4 exon 3 VNTR polymoiphisni in a population sample of children screened with a parent rating scale for ADHD symptoms. et at: A genomewide scan for loci involved in attention. Palmer CG. Mol Psychiatry 2004. Hawi Z.1. Nat Gene. McCracken . Biedennan .155:98-101. et ai: Synaptosomal-associated protein 25 (SNAP-25) and allention deficit hjperactivity disorder (AfJHD): Evidence of linkage . Mol Psychiatf-y 2000. Elovainio M. Crawford L. Am J Med Genet 2004. Mol Psychiatry 1996. et al: Modulation of intracelliilar tyclic AMP levels by different human dopamine D4 receptor variant. etal: Association of dopamine D4 receptor (DRDA) gene witli att.CL.21:3-16. et al: Dopa decarboxylase getie polymorphisms and attention deficit hyperactivity di. Benjamin J. Maras A.J.5:.4m J Med Genet 1995:60:573-579. Kennedy JL. McClay J. et a\: Association and linkage ofDRD4 and DRD5 with attention deficit h>peracti\ity di. Mick E. et al: A. Biedennan J: Meta-analysis of the assoc:iation t>ptwec>n the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Kennedy JL: Dopamine D4 receptor gene: Novelty or nonsense? Neuivpsychophannacology I999. Doyle AE. et al: A. 179. McCarroti M.548-35(i. et al: Linkage of the dopamuie D4 receptor gene and attention-deficit/hyperacti\1ty disorder. Nankai M.md association in Ihe Irish population. Swanson . Hawi Z. Patterson C. 189. 174. Lowe N.6:420-424. Wigal SB.5:432-4. Hess EJ. et al: Dopamine D4 gene 7repeat allele and attention deficit hyperactivity disorder. et al: Population and familial association between the 04 dopamine receptor gene and meastires of novelty seeking. . Lowe N. 175.4*1/ J Hum Ge}iet 2002:70:l!8.mission of SNAP-2.ylm J Psyrhiafi-y 1997:1. Rich. 190. Sever Y. McGough JJ. Lobos EA. Polanczjk (1. Novick O. Roberts W. Kirley A.ssociation of the dopamine D5 rect^pt or with attention deficit hyjieractivity disorder (ADHD) . Am J Psychiiitry 2001:1. J Neurosci 1998. J Neural Transm 2004:111:88^889. Sunohara GA.5901-. et al: Biased paternal trans.DHD subtyi)es in a population sample of twins. 186. LaHoste GJ.8:309-315. al: Attention-deficit hyjjeractivity disorder and the gene for the dopamine D5 receptor. Neuman RJ. . 166. Kivimaki M. J Ncu rochem 1995. Ciirran S. Schinitz M.L Matochik JA. et al: Dopamine D4 receptor (D4DR) exon III p(ilymor}>hi.58. Am J Psychiatry 1999:156:1209-1215.. 188. Manor 1.sorder (ADHD): No e\idence for association in the Irisb population. Todd RD. Weiffenbach B. Kirley A.snLS. Foley D. Manor I. et at: No association of the dopamine DRD4 receptor (DRD4') gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population. 162.. Okuyama Y.C'L. 154. Smalley SL.IM. Kirley A.TT. Hawi Z.A. Mol Psychiatry 2004. Am -/ Med Gniet 2000:96:268-272. et al: Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hy])eractivity disorder. et al: Failure to replicale an excess of the long dopajnine D4 exon III repeat polymorplusm in ADHD in a family-based study. et al: Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Curran S. liyperactiNity disortler. 152. Mol Psychiatry 2000.9:711-717.4m J Mad Genet 2004. Mol Psychiatiy 2000. 165. 164. Matochik JA. Langloy K Kirov G. Feng Y.or (D4DR) 16 amino acid repeat polymorphism and novelty seeking. Merrimaji B. et al: Lack of association of dopamine D4 receptor gene polymonihisms with ADHD subtypes In a population sample of twins. 181. et al: Absence of linkage of apparently single gene mediated ADHD witli the human synteiiic region of the mouse mutant coloboma. Kotlcr M. iVrt/ Genet 1996:12:78-80. Sullivan PF. Domoto M.127B:73-77. Sliam P. et al: Association betwc-en the type 4 dopamine receptor gene polymorphism and novelty seeking.sm associated with the human personality trait of novelty seeking. et al: Linkage disequilibrium mapping at DA'n.58. 177. G alpha Z in ADHD. 172. Jong YJ. Em. "Rthir E. Keltikangas-Jarvinen L. Richards S. et al: Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene poIymoiphi. McCracken JT. . 187. Mol Psych iatn/2002. et al: Direct analysis of the genes encoding G proieiris G alpha T2. Swanson JM. 1:388-391. A [fluorine-18]fluorodopa positron emission tomographic study.Asghiiri V. Fai-aone SV. .9:252-259.96:278-28I. Smalley SL. 178. et al: Evidence fi>r linkage of a (andem duplication polymorphism upstream of the dopamine D4 receptor gene {DRD4) with attention deDcit liyperactiwty disorder (ADHD). Turic D.128B:84-89. Roman T. Am J Psychiatry 1999:156:768-770. 168. Corbex M. Knight J.ssociatioii of Ilie dopamine receptor D4 (DRD4J gene with a refined phenotype of attention deficil hyperactivity disorder (ADHD): A family-based approach. Gustavsson JP. Wigg K(. 192. Cirakoglu B. G alpha o. Mol Psychiatry 1996:1:121-124. McGough J. Sunohara GA. et al: Attention-deficit iiyperactivity disorder: A study of association with both tlie dopamine transporter gene and the dopamine D4 receptor gene. et al: Polymorphisms in the dopamine D5 receptor {DRDS) gene and ADHD. Ban.unples. Ishiguro H. 180. Yazgan Y. Sunohara GA. Am J Hum Genet 2004:74:. Zametkin AJ. 17. Lobos EA.J Med Genet 2004:12r. Paterson AD. DRD5 and DBH luirrows the search for ADHD susceptibility alleles at these loci. Mill J.4m J Med Genet 2001.B:38--12. Eisenberg J.Attention-Deficit Hyperactivity Disorder (ADHD) / Voeller 813 deficit hyi)eractivity disorder patients suggest long repeats contribute to genetic risk for the disorder. Mill JS. Mot Psychiatry 2002.sorder (ADHD) in a sample of Turkish chikiren. Buchwaldt S.

et al: Linkage studies between attention-deficit hyi)eracti\ity disorder and the monoamine oxidase genes. 198. Jiang S. MaJone M. Ban. Kennedy JL: Linkage disequilibrium analysis of the dopaniiiie beta-hydroxylase gene in persistent attention itfllcil hyjieraciivity disorder. VoeUer. 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. in a region implicated in autism.serotonin transporter promoter polymorpliism with aggressivity. Am JMcd Geiiet 1999:88:710-713. October 2004 194. MD ABSTRACT This article reviews the relationship between different learning disabilities. >\)» J Hum Geiiel 2002. Miiiassian SU et al: Genetic linkage of attention-deficit/liyijcraclivity disorder on chromosome 16pl3. Xin R. Am J Med Genet 2000:9(i:285-288. Schachar R. Daly G.sorder in the l(jpi. Sever Y. Mei-Tal <i. Eisrnberg J. Jain U. et al: Glutamate receptor. 208. 211. Mol Pnyehiatrjj 2003. Payt. Am J Mcd Getict 20(). Curran S. Doeny W Hardy E./r 209. P. 20(12. Langbehn D.susceptibility locius at tlie 5-HT(IB) receptor genp in 273 nuclear families from a m\ilti-centre sample. Hawi Z. Am J Med Genet 2003.159:104G-1048. Crosbie J. Tiiric D. Kotler 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. pt al: Linkage sttnly of catechol-0-methy!tiansferase and attention-tleticit hyperactivity disorder.3.119B:77-85. Kent L. and conduct disorder in an adoptee population. Mot PsychUtlry 2002:7:718-725.and high-activity catecholaniine-methyl-transferase (COMT) and atten- tion deficit hyjieractivity disorder (ADHD) in a sample of Turkish children. et al: Follow-up of genetic linkage findings on chromosome 16pl3: Evidence of £is. Wigg K.angley K.CL. 201. Mills S. t.9fi:282-284. Special Article Psychiatric Implications of Language Disorders and Learning Disabilities: Risks and Management Suzanne T.7:908-912. ionotropic. TXiric D. MD. Fischer M. Muglia P. Dring M.814 Journal of Child Neuyvlogy /Vohime 19. 204. Number 10. attention deficit. et al: Attention deficit hyperaetivity disorder ajid the gene for dopamine beta-hydroxylase.71:969-963. et al: Failiu-e to replicate an association between tlie catecho 1-0-niethyitransferase polymoipliisni and attention deficit hyperactivity disorder in a second. 200. ah Further evidence for the association between attentioii-deficit/hyperactivity disorder and the dopaniine-beta-hydroxylase gene. nonverbal learning disorder. Yazgan Y. 116B:84-89. and cotiduct or atitisocial personality disorder. Daly M. Roniaii T. Mol Psychiatry 2002. Ciispers K. Langley K. Zai G. Mot Psychialni 2004. el al: Associalion analysis of monoamino oxidase A and attention deficit. Mol Ps. Schachar R. hyperactivtiy disorder. anxiety disordei-s. 197. et al: The serotonin 5-HTlB receptor gene and attention deficit hyperactivity disorder. Am J Mcd Genel 2001:105:4(34-470. 205. Barrett JH. et. Polanczyk GV. Holmes J. Sniitb KM.sociation of jV-methyl-u aspaHate glulainate receptor 2A gene polymorphism with ADHD. 20(i. rt al: Haplotypc relative risk study of catpehol-0-nietl\yltransferase (COMT) and attention deficit hyijeractivity disorder (. Steinberg A. Carioret RJ. Quist JF. PsydiialrGeriel 2004:14:117-120. Smalley SL.19:814-S26). Hawi 2. Adanis J. 203.CL. Millar N. Am J Med Genet 2001:105:78:^788. independently recruited Israeli cohort. V. 195.8:98-102.\UHD): Association of tlie high-enzyme activity Val allele with ADHD iiiipiilsive-l\yperactive phenotype. lnkster B. et al: Associations of the . T V met liyl ivaspartate 2A (GRIN2A) gene as a positional candidate for attention-deticityiiyperactivity di. 212. Compr Psy210. Lin S. Am J Mcd Genet 2000:96:858-860. Am J Psychiatry 2002. A family-based study. Kustanovich V. Am JMed Genet 1999:88:497-502. and the psychiatric disorders that are commonly associated with learning disabilities and language disorder: atlention-deficit hyperactivity disorder (ADHD). et al: No association between low. Lawson DC. et al: Serotonergic system and attention deficit hyperactivity disorder (ADHDj: A potential . Am JMed Genrl. The complex associations between language disorders ancl specific learning disabilities—dyslexia. Kytja K. S. Am J Mcd Getict 2000. language disorders. W i ^ K. (J Chiid Ncvrol 2004. Tahir E. Manor 1. et al: Examining for association between candidate gene polymorphisms in the dopamiiie pathway iuid attention-deficit liyperactivity disorder. Sundheim. et al: No association between catocbol-0methyltraiisferase (C'OMT) gone polynioqihism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. et ill: Evidence tbat variation at the serotonin transporter gene infiuenc-es susceptibility to attention deficit hyperactivity disorder (ADHD): Analysis and pooled analysis.on A. 199.9:494-499. Sclimitz M. 114:1 fvl-158. dyscaJctilia—and the various psycliiatric disorders are discussed. 202. Wigg K. . Kirley A. (iepression.( region. 207. Ban.

Sign up to vote on this title
UsefulNot useful