Nov. 30, 2022
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This article includes discussion of attention deficit hyperactivity disorder, ADHD, and hyperkinetic syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Attention deficit hyperactivity disorder (ADHD) is the most common entity seen by child neurologists and psychiatrists. It is a neurobehavioral syndrome that is defined by its behavioral phenotype and frequently coexists with other cognitive and behavioral disorders. ADHD is a lifelong disorder. A strong familial component to ADHD exists, although it is associated with many etiologies. Genetic studies show a number of statistically significant relationships that are of small effect size. Converging data from a number of sources implicate frontal-striatal-cerebellar dysfunction as a possible mechanism for ADHD. These sources, however, fail to identify a single explanation for ADHD. Psychostimulant medications remain the mainstay of therapy, but several nonstimulant medications have been shown to be effective agents.
• ADHD is a neurologic disorder that is defined by its behavioral characteristics.
• ADHD frequently is seen in conjunction with disorders in motor, language, or academic areas.
• ADHD may persist into adulthood, and although the hyperactivity becomes attenuated, distractibility, impulsivity, and pathological disorganization may persist.
• Stimulants are the mainstay of therapy and have a wide therapeutic margin.
Still and Tredgold are credited with the first modern descriptions of what is today known as "attention deficit hyperactivity disorder," or ADHD (17). They highlighted relevant features of ADHD and hypothesized a neurologic etiology. In the same era, other physicians were linking behavioral pathology to brain injuries.
In the 1930s, Strauss and colleagues described hyperactivity, distractibility, emotional lability, and perseveration in a group of survivors of encephalitis lethargica (286). These behaviors were posited to be de facto evidence of brain injury, and it was suggested that children who demonstrated these behaviors were brain damaged, even when there was no known injury (285). The minimal brain damage concept persisted until the 1960s, despite the circularity of the reasoning that led to its existence. The minimal brain damage concept gave way to the minimal brain dysfunction concept.
Ultimately, the focus shifted to the symptoms rather than etiology or mechanism. The hyperactive child syndrome was included in the Diagnostic and Statistical Manual of Mental Disorders as the hyperkinetic reaction of childhood. Inattention became the predominant feature in DSM-III; attention deficit disorder was said to exist with or without hyperactivity. The core symptoms of inattention, hyperactivity, and impulsivity were not considered 3 independent variables, and they were merged into a single syndrome that required inattention and hyperactivity-impulsivity in DSM-III-R. DSM-IV reflects the covariation of hyperactivity with impulsivity and independence of inattention. Consequently, 3 major syndromes evolved: (1) inattention and hyperactivity-impulsivity, (2) inattention alone, and (3) hyperactivity-impulsivity alone.
Some people have questioned the specificity of inattention (120). Barkley presented a model of ADHD that posits poor behavioral inhibition as the central deficit (18; 19); this results in the disturbance in 4 neuropsychologic functions: (1) nonverbal working memory, (2) internalized self-speech, (3) self-regulation of affect-motivation-arousal, and (4) behavioral analysis and synthesis (reconstitution). Other models of ADHD have been put forth: Executive Dysfunction, State Regulation, Delay Aversion, and Dynamic Developmental (142). Working memory deficits have received increased attention as a model for inattentive ADHD (06). Impulsivity has been related to deficits in temporal processing (245). The Scandinavians maintain a broader view of the disorder and combine deficits of attention, motor control, and perception as the acronym "DAMP" (167).
The core symptoms of ADHD disorder are developmentally inappropriate and maladaptive degrees of inattention, hyperactivity, and impulsivity, resulting in clinically significant impairment in social, academic, or occupational functioning. Symptoms begin before 12 years of age, are present in 2 or more settings (eg, home, school, or at work; with friends or relatives; in other activities), and persist for at least 6 months. Most children present in the early years of school but initial diagnosis in adults or preschoolers is not uncommon. Preschool presentations show a predominance of hyperactivity whereas adult presentations are more associated with inattention. Byrne and colleagues found that some symptoms contained in DSM-4 were infrequently endorsed by parents of preschoolers with ADHD and would be of little clinical utility (43). Other symptoms frequently endorsed by parents of typically developing preschoolers might result in overidentification (108). Others have found stability of the ADHD symptoms in preschoolers who were followed longitudinally, although the subtypes were not constant; hyperactive-impulsive preschoolers either “outgrew” their ADHD or became the combined type at follow-up (166).
The diagnostic criteria have been modified when applied to older adolescents and adults. The DSM-5 recognizes that symptoms of inattention and hyperactivity may be less prominent in older adolescents and adults and decreased the number of symptoms that define inattention or hyperactivity from 6 to 5. However, cutoff scores of 4 for current symptoms of inattention and hyperactivity-impulsivity are sufficient to identify a college student as distinct from the norm (127). The WHO developed a 6-question screener to identify ADHD in adults in the general population. The sensitivity was 68.7%, specificity was 99.5%, and total classification accuracy was 97.9% (153).
Girls with ADHD do not differ from boys in respect to impulsivity, academic performance, social functioning, fine motor skills, parental education, or parental depression. Girls showed greater intellectual impairment, lower levels of hyperactivity, and lower rates of externalizing behaviors. In nonreferred populations, girls with the disorder had lower levels of inattention, internalizing behaviors, and peer aggression than boys with the disorder (102).
Criteria for the diagnosis of ADHD are codified in the DSM. Although DSM-5 did not change the DSM-4 symptoms that constituted inattention or hyperactivity, the new classification included examples that modified the symptoms (eg, symptom of inattention). The effect of these expanded examples on the diagnosis will have to be determined. The DSM-5 incorporates a number changes over the previous edition:
(1) The age of onset of impairing symptoms was raised from 7 to 12 years.
(2) Subtypes are replaced by presentations, in recognition that subtypes were not stable longitudinal constructs.
(3) Multiple informants are required for the diagnosis.
(4) Pervasive developmental disorder has been removed from the exclusion criteria.
ADHD is diagnosed based on the following symptoms:
(1) Inattention: 6 (or more) of the following symptoms (5 or more for older adolescents, over the age of 17 years, and adults)
(a) Often fails to give close attention to details or makes careless mistakes in schoolwork, at work, or during other activities (eg, overlooks or misses details, work is inaccurate).
(b) Often has difficulty sustaining attention in tasks or play activities (eg, has difficulty remaining focused during lectures, conversations, or lengthy reading).
(c) Often does not seem to listen when spoken to directly (eg, mind seems elsewhere, even in the absence of obvious distraction).
(d) Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (eg, starts tasks but quickly loses focus and is easily sidetracked).
(e) Often has difficulty organizing tasks and activities (eg, difficulty managing sequential tasks; difficulty keeping materials and belongings in order; messy, disorganized work; has poor time management; fails to meet deadlines).
(f) Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (eg, schoolwork or homework; for older adolescents and adults, preparing reports, completing forms, reviewing lengthy papers).
(g) Often loses things necessary for tasks or activities (eg, school materials, pencils, books, tools, wallets, keys, paperwork, eyeglasses, mobile telephones).
(h) Is often easily distracted by extraneous stimuli (for older adolescents and adults may include unrelated thoughts).
(i) Is often forgetful in daily activities (eg, doing chores, running errands; for older adolescents and adults returning calls, paying bills, keeping appointments).
(2) Hyperactivity and impulsivity: 6 (or more) of the following symptoms (5 or more for older adolescents, over the age of 17 years, and adults)
(a) Often fidgets with or taps hands or feet or squirms in seat.
(b) Often leaves seat in situations when remaining seated is expected. (eg, leaves his or her place in the classroom, in the office or other workplace, or in other situations that require remaining in place).
(c) Often runs about or climbs in situations where it is inappropriate. (In adolescents or adults may be limited to feeling restless).
(d) Often unable to play or engage in leisure activities quietly.
(e) Is often "on the go," acting as if "driven by a motor" (eg, is unable to be, or uncomfortable being still for extended time as in restaurants, meetings; may be experienced by others as being restless or difficult to keep up with).
(f) Often talks excessively.
(g) Often blurts out an answer before a question has been completed (eg, completes people's sentences, cannot wait for turn in conversation).
(h) Often has difficulty waiting his or her turn (eg, while waiting in line).
(i) Often interrupts or intrudes on others (eg, butts into conversations, games, or activities; may start using other people's things without asking or receiving permission; for adolescents and adults, they may intrude into or take over what others are doing (American Psychiatric Association 2013).
The symptoms of ADHD are not solely a manifestation of oppositional behavior, defiance, hostility, or a failure to understand tasks or instructions. The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder (eg, mood disorder, anxiety disorder, dissociative disorder, personality disorder, substance intoxication, or withdrawal).
One of the difficulties in making the diagnosis of ADHD is how to integrate the data that comes from the multiple sources. Disparate reporting is not uncommon between parents, between parents and teachers, or among teachers (when there are multiple informants). Some investigators have scored a symptom present if it is reported by any of the informants. Others have opted to score a symptom present if there is agreement by the reporters. A study proposed summing symptoms at the domain level or overall diagnostic category and averaging across reporters as a means of decreasing variability due to rating bias and standardizing diagnostic practice (190). A study suggested that a teacher rating was not necessarily essential if the parent rating scales were positive because teacher reports confirm the positive findings in a large percentage of cases (27).
Dysfunction in areas other than activity level and attention may presage ADHD. Infants and preschool children who will develop the disorder, as a group, show more sleep disturbance (216; 296), motor disorders (117; 163), and language disorders. Regulatory problems in infancy are associated with later ADHD if the child has the DRDr-7r allele (25).
A study questioned whether adult-onset ADHD was a distinct entity. In a longitudinal study of a cohort from Dunedin, Moffitt and colleagues found that only 5% of children with ADHD manifested the full DSM-5 syndrome in adulthood, and that of the adults who met ADHD criteria, save for the age of onset by 12 years, almost 90% were de novo cases (204). Both the childhood and adult onset groups showed psychosocial impairment, but adults showed general intellectual ability that was comparable to those without ADHD and negligible neuropsychological impairments. Reimherr and colleagues identified a subset of adults with ADHD who had high levels of emotional symptoms and suggested 2 types of adult ADHD—1 with inattentive presentation and the other with emotional dysregulation presentation (240). The latter presentation was associated with higher rates of impairment.
Frequently, children with ADHD have associated symptoms that are not essential to the diagnosis (148). These symptoms include fine neuromotor abnormalities (242), gross neuromotor abnormalities, clumsiness, tics, learning problems, speech and language delays, sleep disorders (320), enuresis, encopresis, functional constipation (197), asthma (30), immaturity, disorganization, poor peer interactions, oppositionality, emotional distress, and antisocial behaviors. Mood instability (eg, mood changeability, volatility, irritability, hot temper, low frustration tolerance) is often seen in ADHD and may not be affective in origin (271). They may be more troubling than the hyperactivity or inattention and may be the motivation for seeking assistance.
ADHD is common in children with epilepsy. Hermann and colleagues found that prevalence of ADHD in new-onset epilepsy was 31% versus 6% in a control population (130). They also found that ADHD in childhood epilepsy is associated with lower global intelligence, significantly increased rates of academic underachievement, poorer executive function, and increased prevalence of oppositional disorders.
The prognosis of ADHD depends on the age at diagnosis, the associated disorders, the IQ, and such external characteristics as the length of follow-up, the referral or population cohort, and the discipline providing follow-up (eg, pediatrics or psychiatry) (185). In a population study, McGee and colleagues found that 75% of pervasively hyperactive preschoolers had continuing symptoms at 15 years of age, but half of the hyperactives who did not have preschool hyperactivity had resolution of their syndrome between 7 and 11 years of age (194). By contrast, Weiss and Hechtman found that almost one third of patients with hyperactivity who were followed 15 years after diagnosis through a psychiatric clinic had at least a single symptom of restlessness, poor concentration, impulsivity, or explosiveness that was moderately or severely impairing (306). Almost one half of this cohort had no DSM-III diagnosis at follow-up, but almost one quarter had the diagnosis of antisocial personality disorder.
A similar study of young adults (mean age 26 years) by Mannuzza and colleagues reported lower educational and occupational achievements, somewhat lower rates of ADHD symptoms (11%) and antisocial personality (18%), and higher rates of drug abuse disorder (16%) (186). A subsequent study confirmed these findings but did not find higher rates of anxiety or affective disorders at outcome (187). Another study found increased rates of arrest, conviction, and incarceration when compared to controls but noted no improvement in outcome for multimodality treatment over drug treatment only (251). Adult criminality was predicted by socioeconomic status, IQ, and antisocial acts in childhood.
A follow-up study of hyperactive (n=149) and control (n=72) children who were initially evaluated in 1978 to 1980 were interviewed in 1992 to 1996, at a mean age of 20 (21). The hyperactive group did less well than the controls on all measures. They had lower educational attainment, higher rates of failing to complete high school, more firings from jobs, lower job performance, and greater employer-rated ADHD and oppositional defiant disorder symptoms. The hyperactive group had fewer close friends, more trouble keeping friends, and more social problems as rated by parents. Many more of the hyperactive group had become parents (38% vs. 4%). The authors concluded that ADHD is not a benign developmental disorder of childhood and that clinical interventions need to center on a wide range of adaptive impairments.
A more optimistic review confirmed the clinical observation that hyperactivity wanes with age. It went on to note that 20% of children with persistent ADHD performed poorly in emotional, educational and social adjustment domains, but 20% did well in all 3 domains. Sixty percent had intermediate outcomes. The authors concluded that persistence of ADHD is not associated with a uniform functional outcome (277).
In a 16-year follow-up of 140 boys with DSM-III-R ADHD and 120 without DSM-III-R ADHD, Biederman and colleagues found that the ADHD subjects were significantly more impaired in pyschosocial, educational, and neuropsychological functioning. They noted a high level of persisting neuropsychological deficits, even in those whose core ADHD symptoms declined (33).
When a European cohort of children (N = 347, mean age 11.4 years) with ADHD were followed over 6 years, it was found that the majority of the participants (86.5%) had persistence of ADHD diagnosis. Symptom severity at baseline and family history were associated with poorer outcome (297). In another longitudinal study examining ADHD severity over 10 years from childhood into adulthood, it was found that a group who had the severe persistent ADHD had the highest rate of comorbid major depressive disorder and oppositional defiant disorder (289). Caye and colleagues performed a systematic review and metaanalysis of literature for risk markers predicting the persistence of ADHD into adulthood (48). In their review, a severe presentation of ADHD, treatment for ADHD, comorbid conduct disorder, and comorbid major depressive disorder presented in childhood were significantly associated with persistence of symptoms into adulthood.
In addition to studies that report the adult outcome of children who were previously diagnosed as ADHD, there has been substantial attention to adults who manifest attention deficit but were not previously diagnosed (92). Adults with the disorder are impulsive, inattentive, and restless. They have similar comorbidity to children with the disorder and often have clinically significant impairments. Studies of biological features show correspondences between child and adult cases of ADHD.
The relation between symptoms and impairments was explored and found not to be consistent across time (325). Multivariate analysis was used to determine which of the ADHD symptom dimensions was most associated with impairment in academic, social, or behavioral domains in early childhood, middle childhood, or adolescence. For social functioning, hyperactivity/impulsivity is more predictive for early childhood but inattention is more predictive in adolescence. For behavioral functioning in the classroom, hyperactivity/impulsivity decreases across the 3 time epochs and inattention increases. Academic function was most related to inattention.
JL, a 6.5-year-old, right-handed male, was referred for evaluation of inattention, increased activity, and declining school performance in first grade. JL had problems with school since the beginning; he had poor fine motor skills before even beginning kindergarten. JL was considered to be "high spirited" in kindergarten and had difficulty following instructions, following rules of games, and sitting for story time. The prior year had been more difficult; JL could not sit in his seat as well as other children, would shout out answers, and would "zone out." He was not having trouble with reading but could not work independently. When working in a group, he was always "minding other people's business." Teachers and parents provided accommodations for JL's difficulties, but he did not seem to be "closing the gap." A conference was held to consider placement in a transitional first grade the following year.
Past history and family history were unremarkable. History of developmental milestone attainment was notable for mild delays in fine motor achievement. He had delayed onset of handedness and delayed attainment of shoe-tying skills. Behavior had always been marked by high intensity, need for external structure, and immaturity. JL was beginning to call himself "stupid," and his parents were concerned about his self-esteem. His mother endorsed 8 DSM-IV symptoms of inattention and 9 symptoms of hyperactivity-impulsivity. Convergent data were available from school reports. General physical examination was unremarkable. Neurologic examination was notable for silliness, excessive fidgetiness, distractibility, synkinesias, and diffuse, mild hypotonia. A diagnosis of "attention deficit hyperactivity disorder combined type" was made, and a diagnosis of developmental coordination disorder was entertained.
JL undertook a therapeutic trial of stimulant medication. Accommodations were outlined for difficulties with handwriting. His parents were referred to a parent group for children with ADHD. JL started taking martial arts. When medication was started, JL was moody and evidenced decreased appetite for the first week. Over the next month, his dose was titrated, moodiness diminished, and appetite improved. Neither tics nor insomnia were observed. JL responded well to medication. His school performance and socialization improved. His pediatrician performed continued developmental surveillance.
The cause of ADHD is unknown. ADHD is likely to be a "final common pathway" with multiple causes. In addition to genetic etiologies, ADHD has been seen as a consequence of acquired brain disorders (infectious, traumatic, or toxic), in conjunction with seizure disorders. The prevalence of ADHD is related to a number of prenatal "risk factors," maternal smoking, maternal prepregnancy obesity (298), maternal genitourinary infection and preeclampsia (184), and prenatal emotional distress (196; 324). Linnet and colleagues reviewed 24 studies of maternal smoking and found that they consistently supported a greater risk of ADHD-related disorders (175). Rutter and Solantaus, quoting 3 types of natural experiments—assisted conception design, comparison of different pregnancies, and the Children of Twins design—challenged this association (248).
ADHD is also increased in children who were of low birthweight (174). A large population study from Norway found an association between early preterm birth and increased ADHD symptoms in preschoolers, and interestingly, this association was stronger in females (13). Slower prenatal growth may also be related to ADHD; it has been associated with higher ADHD symptom scores, even after correcting for maternal smoking (128). Similarly, the Finnish population study showed the risk of ADHD is increased by poor fetal growth and by each declining week of gestation. This increase in risk remained elevated even in late-preterm and early term infants in this population (287). Maternal hypothyroxinemia in early pregnancy has been associated with higher scores for ADHD symptoms in children at 8 years of age in a population cohort in the Netherlands, after adjustments for child and maternal factors (203).
Disordered sleep has been reported by parents of children with ADHD, but the majority of these findings have not been supported by objective sleep data. Experimentally restricting sleep had a direct effect on classroom performance and attention, as rated by teachers, but did not result in hyperactivity (90). Support was voiced for increased nighttime activity, reduced rapid eye movements, and significant daytime somnolence in unmedicated children with ADHD when compared to controls. A systematic literature search of interventional studies that examined the effect of obstructive sleep apnea on change in ADHD symptoms concluded that 1) attentional deficits have been reported in up to 95% of obstructive sleep apnea patients and 2) obstructive sleep apnea is common in ADHD, with an incidence of 20 to 30% (321).
Environmental factors associated with ADHD have been reviewed (99; 292) and include lead, manganese, organophosphates, polychlorinated biphenyls, and phthalates. Low child zinc and omega-3 levels were also associated with ADHD. Artificial food colorings were found to have a deleterious effect on children's behavior but this was not felt to be specific to ADHD (11). Abnormal serum ferritin (less than 30 ng/ml) was more common in a French cohort of children with ADHD than in controls, and the mean serum ferritin was significantly lower in the children with ADHD (157). Iron supplementation improved the mean Clinical Global Impression-Severity significantly in nonanemic children with low-serum ferritin and ADHD (158).
Television watching has been reported to be associated with ADHD. Although statistically significant relationship was found between time of television watching in kindergarten and ADHD in first grade, the effect size was small and not thought to represent a meaningful relationship (280). A study that used multivariate analysis did not find television and videogame use to be significant predictors of childhood attention problems (94). A longitudinal study of a large cohort of adolescents (N=2587) found statistically significant association between higher frequency of digital media use at baseline and subsequent symptoms of ADHD (235). In this study, media use included modern digital platforms (eg, social networking, streaming, texting) in addition to traditional television watching and videogame use.
Children repeatedly exposed to procedures requiring general anaesthesia before 2 years of age were found to be at increased risk (hazard ratio 1.95) for the later development of ADHD, even after adjusting for comorbidities (279).
A wide variety of genetic, neuroimaging, and neuropsychologic approaches have been employed to elucidate the pathogenesis and pathophysiology of ADHD. These studies are confounded by the heterogeneity of ADHD (etiology, expression, and limits); small population sizes; comorbid conditions; varying effects of family, age or gender; and difficulty determining whether the noted associations are causal or the result of ADHD or treatment.
Genetics. ADHD has been the subject of intensive genetic study. Familial studies, twin studies, latent class analysis, linkage analysis, genome-wide association studies, quantitative trait locus approaches, endophenotype analysis, and knockout models in animals have all been employed.
ADHD has a high level of heritability (approximately 0.75) (277). Studies of twins, siblings, half-siblings, adoptees, and families all point to a strong genetic component in this condition (93; 164). Approximately 25% of first-degree relatives of attention deficit probands are thought to have attention deficits (28). Second-degree relatives are also at a significantly higher risk for ADHD than controls (91).
Studies of specific candidate genes have shown statistically significant correlations that may give insight into the neurobiology of ADHD. Candidate genes involved in dopaminergic neurotransmission system (eg, DRD4, DRD5, DAT1/SLC6A3, DBH, DDC), genes associated with the noradrenergic (eg, NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (5-HTT/SL:C6A4, HTR1B, HTR2A, TPH2) have received considerable interest. Even though statistically significant relationships exist, candidate genes account for only about 3% to 4% of the total phenotypic variance in ADHD.
Mill and colleagues posited that the diagnosis of ADHD might be the extreme end of a set of traits that are quantitatively distributed in the general population (201). A subsequent study found that an ADHD polygenic score based on common genetic variants previously found to be associated with risk of a clinical diagnosis of ADHD was associated with ADHD traits measures at ages 7 and 10 years in the general population (191).
A prospective study of twins from England and Wales showed that interindividual differences in the changes of ADHD symptoms of hyperactivity/impulsivity between ages 8 and 16 years were under strong additive genetic influences independent of factors that account for variation in the baseline level of symptoms (226). The authors hypothesized that different sets of genes may be associated with the developmental course of ADHD symptoms, accounting for persistence versus decline of ADHD symptoms in different individuals.
Large, rare chromosomal deletions and duplications (copy number variants) are increased in ADHD compared to controls. The findings were stronger for those with comorbid intellectual disability, but the differences persisted. An excess of chromosomal 16p13.11 duplications was noted in the ADHD group, and this finding was replicated in an Icelandic sample (314). A subsequent study supported the enrichment of large, rare copy number variants in ADHD and implicated a duplication at 15q13.3, which spans the CHRNA7 gene (313). This study, however, did not confirm the previously noted duplications at 16p13.11.
Additional genes associated with neurotransmission and neuronal plasticity include SNAP25, CHRNA4, NMDA, NGF, NTF4/5, and GDNF (14). Earlier studies that found associations with BDNF and NTF3 have not been replicated in adult populations (97). A number of novel candidate genes have been identified–LPHN3, BAIAP2, CLOCK, and NOS1–but require independent replication (97).
Durston and coworkers investigated the link between genetic and neuroimaging studies and found that dopamine genes have been found to be expressed differentially in the brain (81; 80). DAT1 is expressed predominantly in the basal ganglia and preferentially influences the caudate volumes. DRD4 is expressed predominantly in the prefrontal cortex and preferentially influences prefrontal gray matter. In a preliminary study of 20 sibling pairs discordant for ADHD and 9 controls, Durston and colleagues evaluated the effects of DAT1 genotype in the striatum and cerebellum using an fMRI go/no go task (82). She found that DAT1 genotype influenced MR for individuals at familial risk for ADHD (affected and unaffected siblings) but not controls in the striatum, but this effect was not seen in the vermis. The observation that the effect was also seen in unaffected siblings suggests that the 10R allele of the DAT1 gene is not sufficient to convey genetic risk in isolation and suggests moderating influences on the vulnerability to the DAT1 10R allele.
Rommelse and coworkers did not find an association between DAT1 and neuropsychological performance (243). This was confirmed, and the author concluded that the DAT1 gene may have a modulating effect rather than a direct influence on cognitive functioning (151). The review reported that high reaction time variability was associated with absence of the 7-R allele of the DRD4 gene and that speed of processing, set shifting, and cognitive impulsiveness were altered in 7-R carriers. Dadds and colleagues examined the association between epigenetic regulation of the DRD4 gene and ADHD symptom severity and found that higher methylation level of the DRD4 gene was associated with severe ADHD symptoms (67). Specifically, increased methylation of the DRD4 gene was associated with higher levels of cognitive/attention problems and not with hyperactivity/impulsivity.
Neuroimaging. The full range of neuroimaging techniques has been used to define the neuronal substrate of ADHD. MRI (volumetric, fMRI, diffusion tensor imaging, spectroscopy), magnetoencephalography, emission tomography (PET, SPECT), EEG, and near infrared spectroscopy are some of the techniques that have been applied. These techniques are complementary but often yield inconsistent findings. Willis and Weiler have reviewed the MRI and EEG data. No study of brain structure or function has reached the level of diagnostic certainty (315). This has led some to caution about the reliability of the finding and, consequently, the strength of the association between attention deficit and the neuroimaging findings (24). Varying results may be due to differences in technique, population selection criteria, associated and additional disorders, treatment, and familial variation. When children with ADHD were compared to their unaffected siblings, it was found that the volumetric reductions in cortical gray and white matter in subjects with ADHD were also present in their unaffected siblings (83). Another study showed that reduction in caudate and putamen volume was seen in both subjects with ADHD and their unaffected siblings compared to that of typically developing control individuals (115).
Reviews of structural neuroimaging studies reported that the most replicated alterations in ADHD in childhood include smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum and concluded that the brain is altered in a more widespread manner and that ADHD is not limited to frontal-subcortical etiology (106; 79; 161; 182; 65). A metaanalysis encompassing 21 studies (565 subjects with ADHD and 583 controls) found that total cerebral volume was most studied followed by regions of the corpus callosum, caudate, and cerebellum. The standard mean differences were largest for the posterior inferior cerebellar vermis followed by the splenium, right and total cerebral volume, and the right caudate (295). The volume of the posterior inferior cerebellar vermis was significantly smaller in children with ADHD and predicted a significant amount of the variance in parent-reported hyperactivity, inattention, and restlessness/hyperactivity (35). A study of preschool children showed significant reduction of volume in both caudate nuclei and that left caudate volume predicted hyperactivity/impulsivity (180).
In a longitudinal study of the brain structure of children with ADHD, 152 children and 139 controls had serial MRI scans (47). Children with ADHD had smaller total brain volumes and smaller cerebellar volumes. Previously unmedicated children with ADHD also demonstrated significantly smaller total cerebral volumes. Over time, the differences in total and regional cerebral volumes and in the cerebellum persisted. Differences in caudate volume that were seen in childhood diminished during adolescence. The authors also correlated anatomy with behavior; frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures.
Another longitudinal study provided neuroanatomic evidence that supported the theory of delayed cortical maturation in ADHD (264). In 223 children with ADHD and 223 controls, the development of the cortical thickness was estimated over a 2- to 3-years’ period, and the authors found that the peak cortical thickness was delayed in children with ADHD for most of the cortical points by a time window of approximately 3 years. The differences in the frontal lobes showed a delay of 5 years in the middle frontal cortex and a delay of about 2 years for the posterior and medial prefrontal cortices. The second most delayed region was in the peak of cortical thickness in the bilateral middle and superior temporal cortex with a delay of about 4 years. The 7 repeat microsatellite in the DRD4 gene (but not DAT1 or DRD1) was associated with cortical thinning in regions important in attentional control and showed a distinct trajectory of cortical development that showed normalization of the right parietal cortex (266). A subsequent study of children with and without diagnosed ADHD found an inverse relationship between the levels of hyperactivity/impulsivity and rate of cortical thinning (265). Thinner cortex at baseline and slower cortical thinning with aging were related to higher scores on the Attention Problems subscale of the Child Behavior Checklist (77).
Shaw and colleagues extended their finding of delayed cortical thickness and found delays in the maturing cortical surface area, particularly in the right prefrontal cortex (268). The median age by which 50% of cortical vertices attained peak area was 1.9 years later in children with ADHD (14.6 years vs. 12.7 years).They concluded that their findings supported mechanisms controlling the maturation of multiple cortical dimensions, in contrast to dyslexia and autism where delays in cortical thickness or surface area are noted.
Structural abnormalities on imaging support a dimensional view of ADHD. Neuroanatomical abnormalities on structural imaging that were shared between ADHD probands and their unaffected first degree relatives were also associated with impairments in sustained attention in both groups (227).
Finally, drug therapy may affect volumetric findings. Semrud-Clikeman and colleagues compared children with ADHD combined type who were treated with stimulants to treatment-naïve children with ADHD combined type and typically developing children. They found that both ADHD groups had decreased caudate volume when compared to controls. They also found that the right anterior cingulate cortex was smaller for treatment-naïve children when compared to children who received stimulants or who were controls. Similar differences were noted for the left but did not achieve statistical significance (260). Others have reported that the anatomic changes seen in children with ADHD are attenuated with stimulant treatment (278).
Using diffusion tensor imaging, Silk and coworkers confirmed anomalous white matter development in cortical regions that have been previously found to be dysfunctional or hypoactive in fMRI studies (270). They found greater fractional anisotropy in white matter regions underlying inferior parietal, occipitoparietal, inferior frontal, and inferior temporal cortex and suggest that the difference seen in ADHD may relate to a lesser degree of neural branching within key white matter pathways (270). Tractography methods show these regions to form part of the white matter pathways connecting prefrontal and parieto-occipital areas with the striatum and the cerebellum. Another study using voxel-wise analysis found increased fractional anisotropy in the right superior frontal gyrus and posterior thalamic radiation and left dorsal posterior cingulate gyrus, lingual gyrus, and parahippocampal gyrus (225). Region of interest analysis revealed increased fractional anisotropy in the left sagittal striatum and related it to ADHD symptom severity. Subsequent studies have shown associations between integrity of the frontostriatal tracts and measures of ADHD symptoms and executive functions in children with ADHD (262). ADHD combined type was associated with abnormalities in the fronto-subcortical circuit, fronto-limbic pathway, and temporo-occipital areas whereas ADHD inattentive type was related to abnormalities in the temporo-occipital areas (171).
Functional studies have yielded varying results and must be viewed as preliminary. Zametkin and colleagues, using PET scan studies, found global and regional reductions in glucose metabolism (particularly in premotor cortex and superior prefrontal cortex) in adults who had been hyperactive since childhood (323). Xenon-133 inhalation and emission tomography showed decreased regional blood flow in striatal areas (178); however, global or absolute measures of metabolism using PET scans and fludeoxyglucose F18 did not statistically differentiate normal adolescents from those with ADHD (322). Girls with the disorder had significantly lower global metabolism, as measured by positron emission tomography, than did boys with the disorder, normal girls, or normal boys (88). In addition, PET scans did not show metabolic effects of chronic stimulant treatment even though behavioral data demonstrated effectiveness (193). The dissociation between behavioral and functional imaging data also has been reported in fMRI studies (155).
Magnetoencephalography was used to evaluate children with ADHD. Subjects were found to have significantly lower Lempel-Ziv complexity scores, with the maximum difference in the anterior region. Combining age and anterior complexity values yielded a sensitivity of 93% and specificity of 79% (95). A simplified version of the Wisconsin Card Sorting Test was used in a study of magnetoencephalography that measured event-related brain activity. In control children, set-shifting cures evoked a higher degree of activation in the medial temporal lobe, with medial temporal lobe activation predicting later activity in the left anterior cingulate cortex. This was diminished in children with ADHD. Children with ADHD also showed early activity in regions barely activated in control children (eg, left inferior parietal lobe and posterior superior temporal gyrus). The data support theories of frontal dysfunction but also suggest that deficits in higher level functions might be secondary to disruptions in earlier limbic processes (211).
The range of task-related fMRI studies is wide. Inhibition and attention, reward-related processing, vigilant attention and reaction time variability, timing, emotional regulation, and arousal are some of the constructs that have been studied (22). The Default Mode Network encompassing the precuneus/posterior cingulate cortex, medial prefrontal cortex, and dorsal anterior cingulate cortex has drawn interest in resting-state studies but the results are mixed.
The most consistent functional MRI evidence shows that patients with ADHD have reduced activation in the striatum, but dysfunction is also noted in the frontal lobes (on tasks that tap inhibitory control) and temporal and parietal areas (during tasks that examine attentional processes) (218). Baseline functional neuroimaging studies have indicated pronounced hypoperfusion and hypometabolism in prefrontal and caudate regions, and abnormal responses have been noted in these regions to cognitive challenges requiring attentional and executive functions (118). SPECT has demonstrated a significant negative correlation between the density of dopamine transporter gene (DAT) in the striatum and cerebral blood flow in the cingulate gyrus, frontal lobe, temporal lobe, and cerebellum, suggesting that higher DAT density in the striatum is associated with a decrease in regional cerebral blood flow in the cortical and subcortical attention network (70). A systematic review of 9 task-based fMRI studies showed that the middle and inferior frontal gyri were most often affected by a single dose of methylphenidate during inhibitory control tasks, but that the basal ganglia and cerebellum were also affected (66). Another review suggested that methylphenidate may normalize brain activation patterns as well as functional connectivity during cognitive control, attention, and rest (259).
Functional connectivity. Despite the inability to use functional neuroimaging for diagnostic purposes, converging data from neuroimaging, neuropsychology, genetics, and neurochemical studies have implicated dysfunction in frontostriatal structures (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) as being involved in the pathophysiology of ADHD (42). Although the evidence is compelling that frontostriatal dysfunction underlies ADHD, neuroimaging findings point to distributed neural substrates rather than a single one (53; 159) and suggest that abnormalities in brain circuitry in ADHD may go beyond the fronto-striatal model.
It has been argued that ADHD is characterized not only by deficits in the structure and function of isolated frontal, parietal, and cerebellar brain regions but also in the functional interregional connectivity between these regions that form neural networks. In a review, Cubillo and Rubia reported that similar areas of dysfunction (inferior prefrontal cortex, cingulate, striatal parietal and cerebellar regions) were noted in children and adults and concluded that there was a disturbance in fronto-striato-parieto-cerebellar neural networks during executive functions (65). Diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach were used to characterize white matter connectivity in 71 children and adolescents with ADHD and defined a significant network comprising 25 distinct fiber bundles that linked 23 different brain regions spanning frontal, striatal, and cerebellar regions that showed altered white matter structure in ADHD (134).
A study of a drug-naive sample of right-handed young adults with ADHD using resting state fMRI found that 2 main symptom dimensions of ADHD are related to altered intrinsic connectivity in orbitofrontal-temporal-occipital and fronto-amygdala-occipital networks, and led the authors to conclude that ADHD extended beyond frontostriatal alterations (58). A metaanalysis of 55 studies not only found dysfunction in higher-level cognitive functions but also sensorimotor processing including visual system and the default network. Hypoactivation was seen in systems involved in executive function (frontoparietal network) and attention (ventral attention network) but hyperactivation was noted in the default, visual, and somatomotor networks (61). Another metaanalysis that focused on imaging studies of inhibition and attention concluded that there are 2 distinct domain-dissociated right hemispheric frontobasal ganglia networks including the inferior frontal cortex, supplementary motor area, and anterior cingulate cortex for inhibition and dorsolateral prefrontal cortex, parietal, and cerebellar areas for attention (123).
Neuroimaging has been used to investigate the effects of stimulant medication. Using positron emission tomography, Del Campo and colleagues found that decreased dopamine activity in the left caudate nucleus, but treatment with methylphenidate, increased dopamine activity in all nigrostriatal regions and normalized the activity in the left caudate (72). Wang and colleagues reported that chronic use of methylphenidate upregulates the dopamine transporter availability and may decrease treatment efficacy and exacerbate symptoms when not taking medication (302). Functional connectivity studies analysis showed that methylphenidate altered intrinsic connectivity between brain areas involved in sustained attention and also induced significant changes in the cortical-cortical and cortico-subcortical connectivity of many other cognitive and sensory-motor resting state networks (210).
EEGs provide a possible way of defining ADHD based on brain function and not behavior. However, a metaanalysis has failed to support the use of theta/beta ratios as a reliable diagnostic measure in children with ADHD (12). Increased theta/beta ratios may have prognostic use in children who deviate on this measure. Another study showed that children with ADHD showed increased theta/beta ratio over the control group; however, this finding was not seen in adults with ADHD (188).
A complex range of event-related potential deficits have been associated with ADHD. Barry and colleagues have reviewed the subject (23). They have noted that differences between subjects with ADHD and controls have been reported in the preparatory responses, auditory modality, and visual attention systems. In the auditory modality, ADHD-related differences are apparent in all components from the auditory brainstem response to the late slow wave. Results suggesting an inhibitory processing deficit have been reported. Studies of the frontal inhibitory system indicate difficulties in inhibitory regulation. In a follow-up review, the authors note robust differences from controls in early orienting, inhibitory control, and error-processing components (143).
Comparing event-related potentials of children with ADHD to typical children in a series of auditory and visual selective attention tasks suggested a deficit in the activation of the P3b process, although this might be caused by other disturbances of the attention processes that precede P3b (144). Methylphenidate ameliorates some, but not all, deficits and improves processing where no differences with normal children are present (145). Ozdag and colleagues found indirect evidence that ADHD is associated with deficits in signal detection (inattention) and discrimination and information processing (217). Methylphenidate normalized event related potential indices except FN2A and PN2A, and they concluded that methylphenidate may be effective on impaired information processing in ADHD but not on receiving information.
In a subsequent event-related potential study, Jonkman and colleagues found that children without ADHD showed enhancement of the parietal P3 to task-relevant stimuli in harder visual tasks, whereas children with the disorder did not. Methylphenidate improved the number of correct responses and the task P3 amplitudes in both easy and hard tasks but did not influence the probe P3 amplitudes. The authors concluded that children with the disorder do not suffer from a shortage in attentional capacity, but from a problem with capacity allocation (146). These findings were extended in an investigation of the effect of intelligence on event-related potentials (39), which evaluated P3 amplitudes in 45 subjects who were divided into 3 groups, Learning Disability (IQ 70-84), ADHD, and ADHD + LD, and compared to 42 control children. The authors concluded that the behavioral inhibition effect was essentially moderated by the primary intelligence rather than the attention deficit.
A study of brainstem auditory-evoked responses reported that, compared to controls, subjects with ADHD had (1) prolonged latencies of wave III and wave V, (2) longer brainstem transmission of wave I to wave III and wave I to wave V, and (3) significant asymmetry of wave III latencies between ears (165).
The major components of neural systems relevant to ADHD have been reviewed (41). Reviews of work in norepinephrine, epinephrine, and dopamine neurotransmitter systems as they relate to ADHD conclude that the findings in this syndrome cannot be explained by abnormality in a single transmitter system, that a role exists for each of the systems, that the dysfunction seen in ADHD is likely to occur at multiple levels, and that drugs that work at a variety of receptor sites are the most effective therapeutic agents for ADHD (199; 231; 110; 104). A review that draws on the findings of genome-wide studies implicates genes associated with synaptic adhesion molecules, glutamate receptors, and mediators of intracellular signaling pathways and concludes that further investigation of the role of the glutamate system in the pathogenesis of ADHD is warranted (173). A subsequent study using magnetic resonance spectroscopy evaluated 89 participants. The authors found that GABA+ levels were altered in a subcortical voxel and change with development; that increased glutamine levels were noted in children but normalized in adults; and that glutamate was not different between groups but demonstrated a strong effect across age (36).
A model based on anatomic neuroimaging studies suggests that relevant regulatory circuits include the prefrontal cortex and the basal ganglia, which are modulated by dopaminergic innervation from the midbrain and by stimulants (46). A model of cognitive control has been suggested wherein the basal ganglia are involved in inhibition of competing actions, and the frontal cortex is involved in representing relevant thoughts and guiding appropriate behaviors (45). More recent studies have attempted to link neuroanatomy to brain function: dorsal frontostriatal circuits have been linked to cognitive control, orbitofrontal-striatal loops to reward processing, and frontocerebellar circuits to timing (84).
The parent-reported prevalence of ADHD approximates 11% (300). In a population-based cohort followed from birth through 19 years, the cumulative incidence of ADHD was 16.0% using the most liberal definition, whereas the most restrictive estimate was 7.4% (16). A survey of a nationally representative sample of 8- to 15-year-old children revealed that 8.7% of the children met DSM IV criteria for ADHD but that less than half were diagnosed with ADHD or received regular medication treatment (101). The pooled estimate resulting from a metaanalysis of 175 studies was 7.2% (293). The 2007 National Survey of Children’s Health found significantly increased frequencies of learning disability (46%), speech problems (12%), anxiety (18%), depression (14%), and conduct disorder (27%) in children with ADHD (169).
Injured children with ADHD are more likely to sustain severe injuries than children without it. Review of charts submitted to the National Pediatric Trauma Registry between October 1988 and April 1996 showed that children with ADHD were significantly more likely than controls to be boys, to be injured as pedestrians, or on bicycles, or suffer self-inflicted injury. They were more likely to sustain injuries to multiple body regions, to sustain head injuries, and to be severely injured as measured by the Injury Severity Score and the Glasgow Coma Scale (75). Although ADHD is a significant risk factor for unintentional injuries in children and adolescents, ADHD medications have shown a protective effect, at least in the short term, according to the systematic review with meta-analysis (247).
In a population-based cohort study of children born in Rochester, Minnesota, people with attention deficit exhibited significantly greater use of medical care in multiple care delivery settings (172). Compared to those without the disorder, people with the disorder are more likely to have multiple diagnoses that require medical attention, have higher rates of inpatient, hospital outpatient, or emergency department admissions, and increased median health cost over a 9-year period. The authors note that the burden of ADHD extends beyond the recognized social, behavioral, and academic outcomes to include markedly increased use of medical care. In Seattle, a retrospective matched cohort study found that children with ADHD had over twice the per capita costs than children without ADHD; had more outpatient mental health visits, pharmacy fills, primary care visits, and coexisting mental health disorders; and the presence of coexisting mental health disorders substantially increased the cost of care (116).
The prevention of ADHD is related to the prevention of the associated disorders. No information is available about preventive measures that specifically target ADHD.
The major point of differential diagnosis is to discern primary attention problems from those that are secondary to other disorders. Specific learning disabilities, unrecognized intellectual disability, developmental language disorders, hearing impairment, adjustment disorders, or mental disorders (eg, mood disorder, anxiety disorder, dissociative disorder, or a personality disorder) may masquerade as attention disorders. Often these disorders coexist with ADHD and may not be distinguished. Some children who will develop Tourette syndrome will present with ADHD. The presence of schizophrenia or other psychotic disorders precludes the diagnosis of ADHD.
Distinguishing children with developmental language disorders from those with ADHD is difficult. McInnes and colleagues found that children with ADHD and those with developmental language disorders both had impairments in working memory and listening comprehension (195). They noted that children with ADHD but no language impairment comprehended factual information from spoken passages as well as typically developing children but were poorer at comprehending inferences and monitoring comprehension of instructions. Wassenberg and colleagues noted that children with ADHD performed more slowly on tests of language comprehension (305). Children with ADHD demonstrate better performance on measures of utterance formulation whereas children with developmental language disorders perform more poorly on measure of lexical diversity, average sentence length, and morphosyntactic development (239).
The overlap of ADHD and the autism spectrum disorders has been recognized in DSM-5. Forty-one percent of children who met criteria for autism spectrum disorders had suspected ADHD; 22% with suspected ADHD met criteria for an autism spectrum disorder (244). Children with pervasive developmental disorders or high-functioning autism frequently met criteria for ADHD and did not differ from children with ADHD in communication and restricted/repetitive domains on the Autism Spectrum Screening Questionnaire (317; 124).
Children with ADHD tend to confound different emotions, exhibit lower social skills, and have more trouble with facial expression recognition than age, socioeconomic status, class, and school environment matched controls (150). A subgroup of ADHD has been defined that demonstrates poor social perception skills and deficits in complex visual perception and fluid reasoning (253).
Children and adolescents with ADHD are at higher risk for having depression than those without ADHD, and outcomes are poor when both conditions are present. Identification of depression in children with ADHD may be complicated because of an overlap of symptoms. Children with ADHD may underreport their symptoms of depression. When children with ADHD and their parents were interviewed, it was found that children with ADHD reported lower levels of depressive symptoms than their parents, which is the opposite pattern of general population (98).
The diagnosis of ADHD rests on the demonstration of the neurobehavioral characteristics of developmentally inappropriate, functionally impairing inattention and hyperactivity-impulsivity. Four techniques may be employed to diagnose ADHD: (1) interviews (with child, parents, or teachers), (2) questionnaires, (3) direct observation, and (4) measurement. Practice parameters for the diagnosis and treatment of attention deficit have been updated (07; 38; 215; 229).
Rating scales are helpful adjuncts to the diagnostic and management process, but they are not adequate for diagnosis when used alone (273). A study of the Conner’s Teacher Rating Scale-Revised showed that if a T-score of greater than 60 on the Total Score (N scale) was used as a cut point, a child had a 77% chance of having clinical ADHD; a child had a 44% chance of having clinical ADHD if the cut point was not reached (52). One study investigated the validity of the Conner’s Teacher and Parent Rating Scales and found a sensitivity of 83.5% and a specificity of 37.5%, causing the authors to conclude that the Conner’s Teacher and Parent Rating Scales were not sufficient to be used alone to diagnose ADHD (220). Scales are limited by time frame of assessment, general versus specific behavioral targets, psychometric properties, time to administer, cost, and flooding (179). Parent evaluations and teacher evaluations are commonly discordant (202). Despite the shortcomings in diagnosing ADHD, rating scales are useful in research and clinical work, aid treatment planning, and help to ensure accountability in practice (59). Parents are good in perceiving preschool hyperactivity when their child was not hyperactive (89% accuracy), but were not better than chance (50% accuracy) when the child was hyperactive (137). The Conner's Adult ADHD Rating Scale and the Wender Utah Rating Scale (short form) were found to have the most robust psychometric properties and content validity for adults (290). Focusing on the ADHD symptoms (inattention, impulsivity, hyperactivity) alone is insufficient, and assessment should include inquiry about daily life function impairments and adaptive behavior deficits (eg, peer relations, parenting style, academic functioning) (223).
A complete history, physical examination (with emphasis on minor physical anomalies), and assessment of soft neurologic signs are useful to discern associated disorders and define further evaluations. Symptoms of sensory modulation dysfunction (eg, tactile defensiveness, repetitive touching, auditory filtering, taste and smell sensitivity) typically associated with autistic spectrum commonly are noted in children with ADHD (183). Voice problems are also common in children with ADHD (121). They have increased rates of hoarseness, breathiness, and straining in their voices, and they were louder than controls.
The motor examination is of particular interest in children with ADHD. Positive correlations have been established between overflow movements and measures of response inhibition (206). Denckla summarizes the import of the motor examination, “…If a child is seen between the ages of 5 and the onset of puberty, there is a maximum chance that the motor examination will serve as a ‘within-brain’ laboratory for the biological basis of the characteristics of ADHD; conversely, if a child appears to have all of the characteristics of ADHD…but lacks the co-localizing motor signs, it is highly likely that ADHD is not the diagnosis” (73). The presence of motor dysfunction is a marker for more severe ADHD and other neurodevelopmental and behavioral problems, but it does not predict poorer response to treatment (291). In children with ADHD, gross and fine motor performance may be due to different behavioral processes (294).
Schoemaker and coworkers evaluated the nature of the motor deficit relative to handwriting in children with ADHD. Motor planning (a sequence of abstract spatiotemporal goal trajectories that takes place either before a sequence of strokes begins or concurrent with the completion of a stroke pattern) was distinguished from parameter setting (eg, regulation of the force level, tempo, size of letters). The authors found no evidence for a motor planning deficit but noted that parameter setting seemed to be deficient when a group of children with ADHD was compared to normal controls on a series of copying tasks of increasing complexity (258).
Children with ADHD subtypes that included inattentiveness showed significant difficulties with time and force output and greater variability in difficulty with force control on a finger-tapping test that targeted motor processing, preparation, and execution (221). Those with ADHD and developmental coordination disorder showed particular difficulty with force control (228). Children with ADHD performed less well on a task that required them to move a cursor on a horizontal digitizing tablet between 2 points and did particularly poorly without visual feedback, leading Eliasson and colleagues to posit a primary motor deficit that was independent of inattention and hyperactivity (86). Deficits in bimanual coordination also have been documented (154). One study found that spelling and writing problems in children with ADHD are associated with attentional problems, are nonlinguistic in nature, and reflect impairment in kinematic motor production (05).
Psychological, educational, speech, and language evaluation assists in the diagnosis of cognitive dysfunctions but are not needed to make the diagnosis of ADHD. Psychiatric assessment may be warranted depending on the severity of findings. Routine use of neuroimaging, electroencephalography, evoked potential measurements, metabolic studies, or chromosome tests has low yields.
Academic difficulty often accompanies ADHD. The cumulative incidence of reading disability in children with ADHD approximates 48% (318). Children with inattentive ADHD, diagnosed at 4 to 6 years of age, consistently had lower reading, spelling, and math scores than comparison children and children who met criteria for other types of ADHD, even after controlling for intelligence (192). Dysgraphia is common in children with ADHD and adversely affects academic performance (236). In a population-based birth cohort study, the cumulative incidence of written language disorder by the age of 19 was 65% in boys and 57% in girls (319). In another population study of children 7- to 9-years-old from Norway, more than half (58.5%) of children with ADHD had language impairments (129).
Normal performance on neuropsychological tests does not rule out the diagnosis of ADHD, although impairments on multiple neuropsychological tests are predictive of the disorder (76). In a case-controlled study of 35 children with ADHD, Koschack and colleagues found that the children with ADHD did not show consistent patterns of deficit in attention or activity levels (160). Most ADHD subjects performed on attentional measures within the normal range. They reacted faster than controls on all attentional tests and significantly faster on the go/no go test and the divided attention test. They also performed with significantly fewer errors on the divided attention test. On the go/no go test, visual scanning test, and attentional-shift test, ADHD subjects made significantly more errors than controls. The researchers concluded that the data suggest that children with ADHD do less well in self-paced tasks and better in externally paced attentional tasks. They also questioned the contribution of neuropsychological tests of attention to the clinical diagnosis of ADHD. Neuropsychological deficits were not predicted by ADHD subtype (54).
Continuous performance tests do not have a high correlation with behavioral questionnaires in the diagnosis of ADHD (78). A review of 6 commercially available continuous performance tests found mixed findings with regard to their ability to assess and manage medication and contrasting evidence on their ability to support clinical decision making (119). Continuous performance tests have a high rate of false positives; 30% of control children test positive (254). Actigraphy must be interpreted in the context of situational and temporal factors (71).
Children with ADHD and substantial executive function deficits are at increased risk for grade retention and decreased academic achievement relative to (a) ADHD without executive function deficits, (b) controlled socioeconomic status, (c) learning disability, and (d) IQ (31). Children with ADHD have deficits in some aspects of executive function, but the deficits are not consistent within ADHD samples and are not specific to ADHD (261). A metaanalysis of executive function, encompassing 83 studies and 6705 subjects, found that the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. However, the effects were only in the medium range (.46 to .69) and were not present universally, leading the authors to conclude that executive function deficits among individuals with ADHD are neither necessary nor sufficient to cause all cases of ADHD (312).
Executive function measures are related to IQ; for children with average IQ, executive function measures distinguished those with ADHD from those without (181). At high average and superior level IQ, there were no significant group differences on measures of executive function between children with ADHD and controls. In a cohort of 7- to 11-year-old children with ADHD, executive functions were not related to ADHD symptoms but to comorbid syndromes of depression and autistic symptomatology. Language abilities, rather than executive functions, best predicted teacher ratings of inattention (147). Preschool children with ADHD performed less well on neuropsychological measures, but after accounting for nonexecutive abilities, no deficits could be attributed to specific functions targeted by the tasks. Performance on executive measures was not related to objective indices of activity level or ratings of ADHD symptoms. These results cast doubt on the etiologic contribution of executive dysfunction to early behavioral manifestations of ADHD (189).
Children with ADHD have difficulty with time perception. They show poorer ability on time reproduction tasks (198) as well as significant impairment in time discrimination thresholds (272). Children with ADHD evidence a generic motor timing deficit, and the impaired time perception does not seem to be related to motivational factors (299). It was posited that these deficits might impact perceptual language skills and motor timing abilities. Specific tests of memory do not significantly improve the predictive accuracy of a diagnosis of ADHD, reading disability, or both over and above more standard diagnostic academic, intellectual, and behavioral measures (74). Poor visual habituation also has been documented in children with ADHD (138).
The assessment of adults is the same as children; however, they are less likely to show hyperactivity or impulsivity and more often complain of difficulties with organization and planning. Behaviors and difficulties may be underreported or overemphasized; thus, validation from another person is helpful. Neuropsychological deficits in adults with ADHD cross multiple domains of function, most notably in attention, behavioral inhibition, and memory, but show normal function in simple reaction time (131). In a review of 24 studies of 50 standard instruments, only moderate effect sizes were noted, and the authors concluded that executive functions were not generally reduced in adults with ADHD (257). Finally, the requirement to document the onset of symptoms before 12 years of age necessitates the practical archeology of reviewing old report cards, school notes, and other behavior data (307). Unfortunately, when most adults come to attention, such school files have usually been destroyed.
Protocols have been developed for the treatment of the disorder (08; 132; 114), and algorithms that guide use of medications for the disorder have been published (230; 304). They do not, however, provide clear guidelines for instituting and ceasing the use of stimulants. Consequently, concern remains that stimulants may be overprescribed (140; 249).
Stimulants remain the mainstay of therapy for ADHD (310; 37). Motor activity, aggressiveness, and impulsivity are decreased, whereas classroom behavior and relationships with peers and family members are improved. Irritability, anorexia, insomnia, and behavioral rebound are the most common short-term side effects. Stimulants also seem to improve executive function performance in children with the disorder (152) and affect event-related potentials (288). Stimulants are associated with improvement in academic performance in elementary school (255) and may protect against later psychiatric disorders in adolescence and young adulthood (32). Methylphenidate may also target other behaviors beyond the core inattention, hyperactivity, and impulsivity. Organization, time management, and planning behaviors may be improved but not normalized (04). Children with ADHD and developmental coordination disorder showed improvement in manual dexterity and quality of handwriting (96). The strokes on a graphomotor task became less fluent but more accurate.
Two primary types of stimulants are used to treat ADHD: amphetamine and methylphenidate. There are many different delivery systems for these agents. Short acting, intermediate acting, and long acting formulations are available. A transdermal system of methylphenidate and an amphetamine pro-drug (a preparation that is only effective when taken orally) are available. Newer delivery systems have been developed for children who cannot swallow pills or capsules. The clinical differences of the various formulations are minor. Amphetamine and methylphenidate have similar effectiveness and side-effect profiles, even though their mechanism of action may differ. Associated deficits in cognitive, emotional, educational, or social domains also need to be addressed to optimize outcomes.
The Multimodal Treatment Study for Children with Attention-Deficit Hyperactivity Disorder, a multisite, randomized, controlled, long-term clinical trial that compared medical management, behavioral therapy, and combined therapy to community-based therapy, found: (1) medical management was superior to behavioral therapy on parent and teacher ratings of inattention and teacher ratings of hyperactivity; (2) combined therapy and medical management did not differ on any dependent measure; (3) combined treatment was better than behavior therapy on parent and teacher ratings of inattention and parent ratings of hyperactivity-impulsivity, parent-rated oppositional behavior, and reading achievement; (4) both medical management and combined treatments were generally superior to community treatments on parent and teacher ADHD symptom ratings; and (5) behavioral therapy was generally equivalent to community treatments (207; 208; 222). Peer ratings failed to find support for the superiority of any of the interventions (135). Children from all groups remained significantly impaired in their peer relationships.
A follow-up study at 24 months showed the continuing superiority of medication therapy over behavioral and community care approaches, although the effect sizes were not as large as at 14 months (209). By 36 months, the earlier advantage of the medication algorithm was no longer apparent, possibly due to age-related declines in ADHD behaviors, starting or stopping medication altogether, or other factors not measured in the original study (139).
A subsequent 8-year follow-up study noted that the originally randomized groups did not differ significantly on repeated measures or newly analyzed variables (eg, grades earned at school, arrests, psychiatric hospitalizations, other clinically relevant outcomes) (205). Medication use declined by 62% after the initial 14-month study, but adjusting for this did not change the results. The MTA participants did worse than the local normative comparison group on 91% of the variables tested. The authors concluded that children with combined type ADHD exhibit significant impairment in adolescence and that the type or intensity of treatment for ADHD in childhood does not predict functioning 6 to 8 years later. Early ADHD symptom trajectory is prognostic.
Socioeconomic status was found to moderate treatment outcomes in the MTA study (241). Children from more educated families showed superior reduction of ADHD symptoms with combined therapy. Oppositional-aggressive symptoms were most improved with combined therapy in blue-collar, lower socioeconomic status households, whereas white-collar, higher socioeconomic status homes showed no differential treatment response.
Another study of 103 children ages 7 to 9 years old with ADHD divided the children into 3 groups: medication alone, medication and intensive behavioral intervention (behavioral therapy, academic assistance, and parent training), and medication and “attention control” (play groups). All 3 groups improved equally on academic tests, behavior ratings, or the children’s own ratings. None of the psychosocial treatments were found to make a difference in the outcomes (02; 03; 126).
No criteria exist that predict stimulant response. Approximately 70% of children respond to any single stimulant. Up to 90% of children will respond to at least 1 stimulant without major adverse events if drug titration is done carefully (109). Methylphenidate works in preschool children in a fashion that is similar to their school-aged counterparts (213). Body mass failed to predict optimal dose or gains achieved at optimal dose and did not predict drug response (237). DAT and DRD 4 polymorphisms may be related to stimulant response (100). Children who lack the DAT 10-repeat allele show greater symptom improvement with increasing stimulant dose when compared to DAT 10-repeat carriers. Children lacking the DRD 4-repeat allele show less improvement across methylphenidate doses than 4-repeat carriers.
The adverse effects of pharmacotherapies for ADHD have been reviewed, and the authors concluded that, “by far the majority of prescriptions for ADHD result in only temporary adverse effects in a minority of cases that are troublesome but that do not pose a significant risk to the child” (113). Irritability, anorexia, insomnia, and behavioral rebound are the most common short-term side effects.
More significant side effects have been the subject of a review and included sudden death, suicidality, lowering seizure threshold, tics, growth suppression, substance abuse, hypertension, QT interval prolongation, and heart rate increases (112). They found that the evidence for sudden death was lacking, that systolic blood pressure increased 1 to 4 mmHg and diastolic increased 1 to 2 mmHg, pulse increased 1 to 2 bpm, and that the average QTc interval is not changed significantly. A study of 1.2 million children and young adults between 2 and 24 years of age and 2.6 million person-years of follow-up, including 373,667 person-years of current ADHD drugs, failed to demonstrate that current use of an ADHD drug was associated with an increased risk of serious cardiovascular events (60). Although a Danish national cohort study suggested doubling of the risk for cardiovascular events in stimulant users, the background rate was very low (68). Stimulant effects on linear growth seem to be minimal if present (122). Priapism has been the subject of a safety announcement by the FDA and has been seen with methylphenidate, amphetamine, and atomoxetine (85).
No successful suicides have been reported in relation to stimulants or atomoxetine. Suicidal ideation is reported in ADHD and in comorbid conditions and, thus, may not be a medication side effect. Whether stimulant use adds to the risk of substance abuse is unclear (136). ADHD medications did not increase the incidence of epilepsy, and there was a low seizure risk for patients with infrequent seizures.
The treatment of children with ADHD and tics has been the subject of a Cochrane Review (234). ADHD symptoms were effectively treated by methylphenidate, clonidine, desipramine, dextroamphetamine, guanfacine, and atomoxetine. Tic symptoms improved in children treated with guanfacine, desipramine, methylphenidate, clonidine, and the combination of methylphenidate and clonidine. They concluded that stimulants were safe and effective treatments for ADHD and do not worsen tics. Alpha agonists and atomoxetine are appropriate alternatives for patients whose tics are increased by stimulants.
Concerns also have been raised about the effects of stimulants on the developing brain, but the links between preclinical studies and clinical use are not adequately established. Stimulants exert unique, short-term effects on the developing brain that may have long-term influences. Preclinical studies suggest that stimulants work by the same mechanism but have differing effects on the neural substrate at different ages (10).
A Cochrane systematic review with metaanalyses and trial sequential analyses of 185 randomized clinical trials has been conducted to assess the effects of methylphenidate on ADHD in children and adolescents (282). The study suggests methylphenidate may improve teacher reported symptoms of ADHD, teacher reported general behavior, and parent reported qualify of life. Additionally, methylphenidate is associated with increased risk of nonserious adverse events, but no evidence to show that it increases the risk of serious adverse events. Banaschewski and colleagues raised concerns about the review in the domains of study inclusion, approaches to quality assessment, and interpretation of data relating to serious adverse events and estimation of the effect size of the primary outcome and determined that the conclusion of the Cochrane review is that the status of the evidence regarding methylphenidate is misplaced (15). In a rebuttal, Storebo and associates conceded that there were people who benefit from methylphenidate but maintained that the overall quality of the studies could be questioned (284). An editorial concluded that the Cochrane review demonstrated the complexities of quantifying the benefits of methylphenidate for ADHD (263).
A systematic review of articles published between January 1, 1999 and January 31, 2016 on ADHD treatment in adolescents (aged 12 years to 18 years) was conducted (50). The study identified 16 randomized clinical trials and 1 metaanalysis. Evidence for pharmacological treatment of ADHD in adolescents was stronger for the stimulant class (extended methylphenidate and amphetamine formulations) and atomoxetine. This review only identified 1 randomized controlled trial of alpha-2 adrenergic agonist, extended-release guanfacine, and therapy in adolescents, which showed efficacy in treating ADHD symptoms. Psychosocial treatments (behavioral, cognitive behavioral, and skills training) were associated with inconsistent effects on ADHD symptoms but robust improvements in academic and organizational skills.
Nonstimulant medications have been shown to be useful for adults with ADHD. Atomoxetine, a selective norepinephrine reuptake inhibitor (162), has been shown to reduce ADHD symptoms and improve social and family functioning symptoms at a dose of 1.2 mg/kg daily (200). Atomoxetine does less well than osmotic release oral system methylphenidate (214) or mixed amphetamine salts extended release (308) in direct comparisons, but about as well as immediate release methylphenidate (303).
Among the second line medications are tricyclic antidepressants, bupropion, MAO inhibitors, and clonidine and guanfacine. Carbamazepine and donepezil have also been used. Clonidine did not improve ADHD symptoms on the Conners’ Teachers Abbreviated Symptom Questionnaire, but they did improve on the Conners’ Abbreviated Symptom Questionnaire for Parents and the Global Assessment Scale (219). Clonidine has been recommended to treat sleep disorders associated with ADHD (309). Cardiac arrhythmias have been reported in otherwise healthy children who were taking clonidine (44). Extended-release clonidine has been useful in reducing ADHD symptomatology in children and adolescents with partial response to stimulants (156) but efficacy has not been demonstrated when used as monotherapy (40). Guanfacine extended release has been shown to decrease ADHD symptoms and may be of particular use in children with ADHD and aggression (250). Combinations of tricyclic antidepressants and stimulants or clonidine and stimulants have been used effectively. Bupropion was shown to be effective in a controlled clinical trial (311).
A metaanalysis of 133 double-blind randomized controlled trials compared efficacy of different pharmacotherapy for ADHD across age-span (55). Accounting for both efficacy and tolerability, the study supported methylphenidate as the preferred first-choice medication for the short-term treatment of ADHD in children and adolescents. The same study supported evidence for amphetamines as the preferred first-choice in adults.
Preschool children require modification of therapeutic approaches (149). Behavioral interventions are recommended as first-line therapy for preschoolers who present with ADHD (51). This is due in part to the higher rate and intensity of side effects, including insomnia, anorexia, weight loss, anxiety, and emotional outbursts. However, pharmacotherapy is indicated in preschool children whose ADHD severely impacts function (eg, expelled from preschool), interferes with other therapies, creates severe parental stress, who represent a danger to themselves or others, whose ADHD is not managed by behavioral interventions, or who have a strong family history of ADHD. Methylphenidate is not FDA approved for children under 6 years old, but some amphetamine preparations are approved for children over the age of 3 years.
Sonuga-Barke and colleagues found little support for non-pharmacological treatments for the core symptoms of ADHD when they performed 6 metaanalyses–elimination diets, artificial food color exclusions, free fatty-acid supplementation, cognitive training, neurofeedback, and behavioral interventions that target ADHD-related behaviors–of randomized, controlled studies that used blinded assessment to evaluate psychological and dietary treatments (275). Using this approach the authors found small but significant effect for free fatty-acid supplementation and artificial food coloring exclusion. By contrast studies that utilized raters who were close to the therapeutic setting were far more likely to find significant effects.
A systematic review to assess effectiveness of nonpharmacologic treatments (neurofeedback, cognitive training, cognitive behavioral therapy, child or parent training, dietary omega fatty acid supplementation, and herbal or dietary approaches) for ADHD concluded that limited evidence exists to offer guidance to these treatment options (111). Another metaanalysis of 174 studies of nonpharmacologic treatments for ADHD found that effect sizes varied with the type of study, but strong and consistent evidence supported the use of behavioral treatments for ADHD (89). An expansion of this study found support for behavior modification and neurofeedback (133). Neurofeedback techniques (theta/beta training and slow cortical potential training) were more effective than computerized attention skills training in a randomized control study with an effect size of 0.6 (105). A subsequent study of neurofeedback failed to demonstrate an effect of neurofeedback on behavioral measures (177). A review of 14 studies concluded that neurofeedback is "probably efficacious" for pediatric ADHD (176). A randomized control trial of approximately 37 sessions of theta/sensorimotor rhythm training on the vertex (Cz) failed to show any additional improvement in behavioral measures over usual treatment (34). Two different studies from the Netherlands and Korea conducted randomized controlled studies in their respective countries, examining the effects of neurofeedback on the treatment of ADHD, and found similar results. Both studies failed to show superior effects of neurofeedback treatment when compared to medication treatment (103; 170).
Cognitive training, either alone or in combination with stimulants, has been suggested to improve cognitive, academic, and behavioral function, but support is minimal for its utility with children with hyperactivity (01). The addition of a 15-session cognitive behavior therapy program to stimulant therapy was studied in a randomized controlled fashion in a group of adults with ADHD and showed moderate to large effect size that continued to improve at follow-up 3 months later and improvement of comorbidities (87).
Organizational skills interventions are associated with significant improvement in the organization of materials, homework management, time management, and planning (168). A review of 11 studies of 747 participants failed to demonstrate benefits of social skills training for 5- to 18-year-old children with ADHD (283).
Parent training programs may have a positive effect on the behavior of school-aged children with ADHD and may reduce parental stress and enhance parental confidence, but the poor methodological quality of the studies does not provide strong enough evidence for practice guidelines (326). A behavioral training program for single mothers of children with ADHD resulted in increased engagement to treatment, but the behavioral training did not normalize behavior for most children, and the treatment gains were not maintained (49). However, metaanalysis of 11 studies to evaluate the effectiveness of parent-administered behavioral interventions for ADHD concluded that parenting interventions are effective, and the authors advocated for the availability of parenting interventions in community settings (57). White noise had a positive effect on the cognitive performance of children with ADHD whereas it deteriorated performance of controls, leading the authors to invoke stochastic resonance as the explanation for the improvement (274).
Moderately intense aerobic exercise improved neurocognitive function and inhibitory control in a group of children with ADHD (232).
Vestibular stimulation using the Comprehensive Motion Apparatus was not found to be effective for a group of children with combined type ADHD without comorbid learning disorder (56). A Cochrane review of homeopathy for ADHD or hyperkinetic disorder concluded that there was little evidence for the efficacy of homeopathy in ADHD (62). Shaywitz and colleagues found no support for an effect of aspartame on the urinary excretion of monoamines and metabolites or on the cognitive or behavioral status of children with ADHD (269). A metaanalysis encompassing 16 studies failed to show an effect of sugar on children's behavior or cognition (316). For food supplements, the evidence is best for zinc; mixed for carnitine, pycnogenol, and essential fatty acids; and insufficient for vitamins, magnesium, iron, SAM-e, tryptophan, and Ginkgo biloba with ginseng (246). A systematic review of essential fatty acids and ADHD did not support the use of essential fatty acid supplements as a primary or supplementary treatment for children with ADHD (238) and was confirmed in a Cochrane review (107). A restricted elimination diet was associated with improvement of ADHD and oppositional behaviors, and 18 of 32 children relapsed when challenged (224). A systematic review of 11 randomized control studies of food supplements noted that some studies showed positive results but that more studies were required before conclusions could be drawn (281).
Schachar and colleagues reviewed the literature to determine the effectiveness of long-term therapies for ADHD (252). Studies that were randomized and for which treatment extended 12 or more months were reviewed. They were too heterogeneous to permit metaanalysis. The authors found that pharmacologic interventions were studied more frequently than nonpharmacologic approaches. Six studies permitted the evaluation of the effects of combined drugs and behavioral intervention. Twenty-five different outcomes were measured with 26 different tests. Stimulant medication appears to reduce ADHD symptoms, dysfunctional social behavior, and internalizing symptoms. Available studies provide little evidence for improved academic performance with stimulants. Medications other than stimulants have not been studied extensively. Only 1 study showed that combination therapy adds to the effects of medication. A systematic review of 351 studies concludes that current treatments may reduce the negative impact that untreated ADHD has on life functioning–driving, obesity, self-esteem, social function, academic, drug/addictive–but does not usually "normalize" the recipients (267).
An approach to refractory cases has been published (301). A minimum of 2 psychostimulant trials should be instituted before a child’s symptoms of ADHD are considered treatment refractory. Diagnostic accuracy, comorbid disorders, psychosocial features, medication compliance, symptoms across settings, and behavioral treatment should be addressed before initiating alternative medication trials.
Hechtman reviewed the long-term treatment of children and adolescents with ADHD. She noted that the longest controlled studies involved approximately 2 years of stimulant treatment and that there were an insufficient number of long-term studies of nonstimulant agents. She found that side effects were minimal and tolerance was not a problem. Treated ADHD patients functioned worse in academic, work, social, and emotional domains than matched controls without ADHD. However, a comparison of ADHD patients who were treated with stimulants with ADHD patients who were not treated with stimulants showed that the treated group appeared to have fewer car accidents, better social skills, and more self-esteem. Psychosocial treatments have lasting effects 10 months after cessation of the intervention but not at 22 months after. She concluded that there is a need to continue psychosocial treatments in order to maintain long-term gains (125).
ADHD is a risk factor for driving offenses. Drivers with ADHD are more likely to receive traffic citations, be involved in traffic accidents, and be cited for driving without a license (141; 20). Stimulants may improve driving performance. Adolescents with ADHD showed improved performance in a driving simulator when they received mph-OROS than when they received immediate release methylphenidate 3 times a day (64). This has been replicated in a real-life driving test (63).
ADHD was associated with significantly higher mortality rates in a Danish population study of 1.92 million people over a 32-year period. This difference persisted after excluding oppositional defiant disorder, conduct disorder, and substance use disorder. The mortality rate ratio was highest in those over 18 years of age. The most common cause of death was accidents (69).
Parental ADHD complicates the treatment of ADHD in children. Two studies conclude that treatment of parental ADHD may be a prerequisite to effective treatment of the child. Exposure to parental ADHD predicted higher levels of family conflict and lesser levels of family cohesion relative to families without parental ADHD, independent of other psychopathological conditions in the parents or ADHD status. Significant interactions were detected in which parental ADHD had a deleterious effect on measures of school performance in offspring without ADHD, but not in those with ADHD. Parental ADHD did not increase the risk for ADHD in children beyond that conveyed by the liability associated with the diagnosis. However, because exposure to parental ADHD was associated with increased disruption in family environment, the identification and treatment of adults with ADHD may be an important component of the treatment plan of the children (29). Another study enrolled 83 preschoolers in an 8-week parent-training program and assessed the progress before the program, at the end of the program, and at follow-up 15 weeks later. Children of the mothers with the highest ADHD scores displayed no progress after parent training, whereas children of mothers with lower ADHD scores showed significant improvement over baseline (276). Mothers with ADHD were found to be poorer at monitoring child behavior and less consistent disciplinarians compared to mothers without ADHD (212). Some evidence suggested that mothers with ADHD were less effective at problem solving about child-rearing issues than control mothers. These differences persisted after controlling for child behavior disorders.
First trimester in utero exposure to methylphenidate does not appear to be associated with a substantially increased risk of major congenital malformations (233). Use of ADHD medications has been associated with increased risk of miscarriage and induced abortion (26).
Fentanyl and midazolam were used for forearm-fracture reduction in the emergency department at a children’s hospital. Drug doses, vital signs, and sedation scores did not significantly differ between children with ADHD and controls. The mean emergency department visit duration and sedation duration were significantly longer for children with ADHD (256).
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
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