E. Mark Mahone, PhD

Childhood ADHD is a major public health problem with prevalence estimates of over 5 million children in the US alone. Of particular concern is the progressive increase in diagnosis. For example, in 2013, the National Center for Health Statistics 

 that 9.5% of children in the US aged 4 to 17 years (13.3% of boys, 5.6% of girls) have been diagnosed with ADHD.

 Moreover, nearly 2% of children aged 3 to 4 years had been 

-an almost 4-fold increase from 0.5% in 1997.

 warned that the movement toward universal pre-kindergarten might inadvertently lead to an “epidemic” of preschool children wrongly identified as having ADHD. This is largely due to the mismatch between biological readiness and earlier academic demands.



Increased prevalence of ADHD is of great concern because the disorder is associated with extraordinary societal costs. In 2011, for example, it was estimated that the annual incremental cost of illness for ADHD in the US was $143 to $266 billion,

 driven largely by high rates of psychiatric and learning disorders, injury, and 

An especially alarming trend is the identification of adverse outcomes among preschool children with ADHD.

 Even when children with ADHD are identified and treated in the preschool years, symptoms and functional difficulties continue throughout the elementary school years.

 A recent prospective study from the UK found that adults who were rated as hyperactive at aged 3 years incurred 17.6 times higher annual health care costs than concomitantly studied cohort of adults who had not been identified as hyperactive at aged 3 years.

The costly toll that ADHD takes on individual adjustment, family life, schools, health care, and social services underscores the importance of earlier identification and treatment. Biomarkers of ADHD, including neuroanatomic and functional anomalies, are associated with chronic cognitive and behavioral dysfunction.

 These brain-based changes develop early in life (even before formal diagnosis) and include delayed brain maturation (delay from to 2 to 5 years) by the time children with ADHD reach middle school age.

Researchers are now seeking to identify biomarkers of ADHD as early as possible in order to facilitate improved outcomes. In one of the first neuroimaging studies of preschoolers with ADHD (aged 4 to 5 years), 

 identified significant reductions in the caudate nucleus among children with ADHD-with greater reductions associated with more severe symptoms of hyperactivity.


The emerging research literature now suggests that with careful and thorough assessment, ADHD can be accurately diagnosed in the preschool years.

 Given these considerations, the following signs are offered as examples of behavioral risk factors for ADHD in children aged 3 to 4 years that may help clinicians and parents differentiate early signs of ADHD from “typical” behavior.

1. Dislikes or avoids activities that require paying attention for more than a minute or two
2. Loses interest and starts doing something else after engaging in an activity for only a few moments
3. Talks a lot more and makes much more noise than other children the same age
4. Climbs on things when not supposed to
5. Can’t hop on one foot (one time) by age 4 years
6. Nearly always restless-wants to constantly kick or jiggle feet, or twisting around in seat; “must” get up after being seated for only a few minutes
7. Has gotten into dangerous situations because of fearlessness
8. Warms up too quickly with strangers
9. Consistently aggressive with playmates; has been expelled from preschool or daycare for aggression
10. Has been injured (eg, stitches) because of moving too fast or running when not supposed to

If 2 or more of these symptoms are observed in young children, a referral should be made to a clinician with expertise in diagnosis and treatment of ADHD in the preschool years.

Dr Mahone is Director of Neuropsychology at the Kennedy Krieger Institute and Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine, Baltimore, MD. He reports that he has received support by NIH/CTSA grants (UL10RR25005; U54 HD079123; R01 HD068425) and Johns Hopkins Brain Sciences Institute.

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ADHD in Preschool Children: Assessment and Treatment.

 New York: Oxford University Press; 2014: 42-65.

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Do you know these 10 signs that may help you differentiate early signs of ADHD from the “typical” behavior of a 3- to 4-year-old?

Assessing ADHD in Preschool Children

Before DSM-IV, investigators identified a subset of symptoms termed “sluggish cognitive tempo” (SCT) that were thought to be distinct from the core features of ADHD.

 Features of SCT include daydreaming, difficulty in sustaining attention, decreased orientation, confusion, lethargy, drowsiness, and physical underactivity.

 Functionally, SCT manifests in reduced speed and efficiency of responses (ie, slow processing speed).

At the time of publication of DSM-IV, there was insufficient evidence to warrant a separate ADHD subtype to characterize SCT. More recent factor analytic investigations, however, have honed the definition of SCT to include 3 core symptoms-lethargy, underactivity, and slowness-that appear distinct from the inattention associated with ADHD and are hypothesized to be a function of earlier selective attention processes.

 Initially, proposed revisions for DSM-5 included a separate “restrictive inattentive” ADHD subtype that in many ways mimicked the SCT construct; however, upon publication of DSM-5, the restrictive inattentive subtype was not included, leading clinicians and researchers to continue their efforts to clarify the phenotype of SCT and to determine whether (or how) it overlaps with ADHD.

The answer may lie at the intersection between ADHD and dyslexia.

ADHD and dyslexia represent 2 common childhood disorders that co-occur more often than expected by chance.

 The most parsimonious explanation for the co-occurrence is that they partially share genetic risk factors, with a stronger genetic correlation between dyslexia and inattention than between dyslexia and hyperactivity.

 To this end, researchers have identified a “multiple-deficit” model of the comorbidity between ADHD and dyslexia in which each disorder has multiple predictors-some specific and some shared.

The ADHD model includes one unique predictor (response inhibition) and one shared predictor (processing speed), while the dyslexia model includes 2 unique predictors (phonological awareness and naming speed) and one shared predictor (processing speed). Here, processing speed represents the speed with which a task is completed with reasonable accuracy. Children with ADHD commonly display slow processing speed.

 However, slow processing speed is also observed in children with dyslexia.

 Moreover, becoming a skilled reader involves adequate reading fluency, which is linked to efficient processing speed. Thus, while processing speed is separable from the core phonological deficit in dyslexia, it can influence reading fluency, even among individuals who can read single words accurately (ie, those without “classic” phonological dyslexia), and can affect the development of more complex academic skills such as reading comprehension.

To this end, processing speed, a core feature of the SCT construct, may represent a promising candidate for a behavioral “polyphenotype” (ie, a phenotype constituting core deficits of more than one disorder), whose psychological makeup can account for comorbidity between neurodevelopmental conditions and those with genetic architecture that can account for the genetic correlations between these highly prevalent disorders.

It is hypothesized that examination of the shared phenotypic variance between ADHD and dyslexia via the SCT construct will provide more specificity than examination of attentional factors alone. Researchers and clinicians are encouraged to consider the potential mediating influence of SCT in understanding outcomes in children with ADHD and/or dyslexia, and to consider treatments that attend to the potentially unique influence of SCT.

Dr Mahone is Director of Neuropsychology at the Kennedy Krieger Institute and Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine, Baltimore, Maryland. 

He reports that he has received support by the NIH/CTSA grant (UL10RR25005).

 Lahey BB, Pelham WE, Schaughency EA, et al. Dimensions and types of attention deficit disorder. 

 Hartman CA, Willcutt EG, Rhee SH, Pennington BF. The relationship between sluggish cognitive tempo and DSM-IV ADHD. 

 Penny A, Waschbusch D, Klein R, et al. Developing a measure of sluggish cognitive tempo for children: content validity, factor structure, and reliability. 

 Huang-Pollock CL, Nigg JT, Carr TH. Deficient attention is hard to find: applying the perceptual load model of selective attention to attention deficit hyperactivity disorder subtypes. 

 Couto JM, Gomex L, Wigg K, et al. Association of ADHD with a candidate region for reading disabilities on chromosome 6p. 

 Greven CU, Harlaar N, Dale P, Plomin R. Genetic overlap between attention-deficit hyperactivity disorder and reading is largely driven by inattentiveness rather than by hyperactivity-impulsivity.

 Pennington B, McGrath L, Rosenberg J, et al. Gene x environment interactions in reading disability and ADHD. 

 Jacobson L, Ryan M, Martin R, et al. Working memory influences processing speed and reading fluency in ADHD. 

 Willcutt EG, Pennington BF, Olson RK, et al. Neuropsychological analyses of comorbidity between reading disability and attention deficit hyperactivity disorder: in search of the common deficit. 

 Sesma HW, Mahone EM, Levine T, et al. The contribution of executive skills to reading comprehension. 

 Grigorenko EL. Commentary: Translating quantitative genetics into molecular genetics: decoupling reading disorder and ADHD-reflections on Greven et al. and Rosenberg et al. 

Researchers have identified a “multiple-deficit” model of the comorbidity between ADHD and dyslexia in which each disorder has multiple predictors-some specific and some shared.

ADHD and Dyslexia: The Possible Link Via Sluggish Cognitive Tempo

Childhood ADHD is a major public health problem, with prevalence estimated to be over 5 million children in the US alone. Of particular concern is the recent increase in diagnosis of the disorder. In 2011, the CDC estimated that nearly 9% of children in the US (1 of 11 children between the ages of 5 and 17) have ADHD; the diagnosis is made in approximately twice as many boys as girls.

 Moreover, ADHD rarely exists alone. In most children with ADHD (75% to 80%), a second (or even third) psychiatric disorder develops at some point in their lives.

While the overall prevalence of ADHD among children and adolescents has increased in the past 10 years, diagnosis among girls appears to have increased more rapidly. In the 1990s, the male to female ratio for ADHD was estimated to be about 9 to 1 in clinical settings and 3 to 1 in the general population.

 More recently, however, a large epidemiological study of 3907 children found that of the 8.7% who met DSM-IV-TR criteria for ADHD, 51% were boys and 49% were girls.

 The prevalence of ADHD is reportedly higher in women than in girls, which suggests that ADHD may be underdiagnosed in girls or, alternatively, that the developmental onset of impairing symptoms occurs later in girls than in boys.

The rise in diagnosis of ADHD among girls contributes to the changing face of the disorder. For example, although there are few reported sex differences in problem behavior in infancy and early childhood, sex differences appear to emerge by age 4 years, with boys showing more aggressive and impulsive behaviors.

Two hypotheses have been posited to explain this apparent “remission” of symptoms in young girls. The first is that girls are more likely to channel their problem behavior into internalizing behaviors. In females, ADHD appears to be associated more with anxiety and depression-two-thirds of women with ADHD have comorbid depression.

The second hypothesis is that the change in behavior among girls is a function of more rapid neurobiological, cognitive, motor, and social development.

On one hand, this more rapid rate of development among girls may be protective against the manifestation of some ADHD symptoms in childhood; on the other hand, the onset of pubertal increases in estrogen and subsequent increases in dopamine receptors lead to an acceleration of symptoms in adolescence.

ADHD is nevertheless associated with significant risks for adverse outcomes. Longitudinal studies suggest that individuals with ADHD are far more likely than those without the disorder to drop out of school, to have few or no friends, to underperform at work, to engage in antisocial activities, and to use tobacco or illicit drugs. Also, youths with ADHD are more likely to experience teen pregnancy and sexually transmitted diseases, to drive too fast and have multiple car accidents, and to experience other psychiatric conditions as adults.

What is already known about ADHD in boys and girls? 
? ADHD is a neurodevelopmental disorder in which symptoms begin (most often) in preschool years and persist into adulthood. ADHD is more commonly diagnosed in boys than in girls; however, the rate of diagnosis among girls is rapidly increasing.

What new information does this article provide? 
? Boys with ADHD can present with different cognitive and behavioral patterns than girls with ADHD. These differences may be because of the types of comorbid conditions, earlier maturation among girls, and failure to identify the more subtle patterns of symptoms in girls. Despite these factors, girls with ADHD remain at significant psychosocial risk into adulthood.

What are the implications for psychiatric practice? 
? Up to 75% of persons with ADHD have at least one other psychiatric disorder, which often makes treatment more challenging. Assessment for and diagnosis of ADHD in girls are more complicated than in boys, because of later onset, more subtle clinical manifestations, and wording in many popular ratings scales that emphasizes behaviors seen more commonly in boys. Children who are young for grade in school tend to be rated as having more symptoms of ADHD than those who are older for grade, leading to greatest rates of ADHD diagnosis among children whose birthday is just before the cutoff for school entry. Given the proposed changes for ADHD diagnostic criteria in DSM-5, it is likely that rates of diagnosis among girls will continue to increase.

The sex paradox posits that the sex in which a given disorder is less prevalent should show greater levels of impairment than the sex in which the disorder is more prevalent.

While initial studies suggest that girls with ADHD have better adolescent and adult outcomes than boys with ADHD, more recent findings indicate that girls with ADHD have considerably more functional impairment, including an increased risk of internalizing disorders (eg, depression, suicide), and eating pathology than girls without ADHD.

These observations occur despite the fact that with age, symptoms of hyperactivity/impulsivity decline more in girls than in boys.

In fact, a recent study found that by adolescence, only 16% of girls with ADHD showed adequate social adjustment compared with 86% of girls without ADHD.

 Another 5-year follow-up of 6- to 17-year-old females with ADHD found that by age 16, ADHD persisted in 71% of the sample.

 Girls who have a diagnosis of ADHD in childhood continue to show deficits in executive functions as adults, even if their symptoms have remitted to a nondiagnosable level.

Early studies that compared neuropsychiatric function in boys who had ADHD with that of girls who had ADHD may have been confounded by group differences in proportion of ADHD subtype, since among school-aged children with ADHD, girls routinely present more often with the inattentive subtype, while boys are more likely to present with the combined subtype.

 Not surprisingly, an early meta-analysis that examined sex differences in ADHD found that boys with ADHD had greater levels of hyperactivity symptoms and externalizing behaviors, which were associated with reduced academic skills.

More recent neuropsychological studies suggest that when samples of boys and girls with ADHD are matched on subtype, girls are often just as impaired as boys, and in some functional areas (eg, planning skills), more impaired than boys.

 Other studies found that individuals with the subtype less common for their sex (ie, boys with the inattentive subtype and girls with the combined subtype) are at increased risk for cognitive dysfunction.

The diagnosis of ADHD in girls is more complicated than in boys because of the later age of onset, more subtle clinical manifestations, and limitations associated with the DSM-IV diagnostic schema and nomenclature.

 One concern has been that the wording of DSM-IV diagnostic criteria for ADHD and the majority of rating scales are geared toward the manifestation of ADHD in boys. Some have argued that there is a subset of girls who present with symptoms of ADHD and are rated by parents and teachers as having elevated scores when sex-specific norms are used, yet they do not meet DSM-IV criteria for the disorder.

 Parents tend to rate behaviors in boys (ie, inattention, hyperactivity, aggression) as more problematic than behaviors in girls (ie, relational aggression and other “feminine” behaviors).

A Dutch study found that while mothers reported similar levels of disruptive behavior in boys and girls, teachers reported higher levels of concern with attention and aggression among the boys in the same sample.

 Mental health professionals may also display this bias. In a recent study, therapists were presented with 4 diagnostic vignettes: 3 vignettes illustrated some symptoms of ADHD, but not enough to diagnose the disorder according to DSM-IV criteria. Male and female versions of each vignette were created. In the male version of the vignettes, therapists diagnosed ADHD twice as often as they did with the female vignettes. This suggests that therapists do not adhere strictly to DSM-IV criteria, with consequent overdiagnosis of ADHD in boys and underdiagnosis (and undertreatment) in girls.

Developmental maturity also appears to play a part in the diagnosis of ADHD, and boys may be at increased risk for diagnosis because of their later development of self-control skills. A recent US study found that the rate of diagnosis of ADHD varied according to the month of the child’s birthday, relative to the cutoff date for entrance into kindergarten. For example, in approximately 8.4% of children born in the month before the cutoff, ADHD was diagnosed, compared with 5.1% of children born in the month after the cutoff.

 Similar findings were also reported in a Canadian study that showed higher rates of diagnosis (relative to sex-matched peers) for both boys and girls born in the month before kindergarten cutoff.

There are sex differences in incidence or nature of many CNS-related disorders. Human brains are approximately 8% to 10% larger in males than in females

; however, girls’ brains mature earlier and are on a different trajectory. These differences are observed at birth and may be driven by sex chromosome–specific pathways that underlie sexual dimorphism or even by differences in the presence of fetal testosterone.

 It has been estimated that at birth, girls are 3 weeks ahead of boys in physical maturation and by the time they enter school, girls are approximately 1 year ahead.

These findings are highly salient, since different maturation rates appear to be associated with different patterns of cognitive skills (eg, children identified as “late-maturing” performed better than early-maturing children of the same sex on spatial measures).

A recent meta-analysis identified sex differences in reward sensitivity-women were more sensitive to punishment than men but not more sensitive to reward; men showed higher rates of sensation-seeking than women.

 It has been argued that these patterns of behavior are related and may also have sexually dimorphic phenotypic expression of genes linked to ADHD.

Over the past 15 years, Giedd and colleagues at the NIMH have compiled normative growth curves for the brain. Their work reveals the heterochronous, regionally specific, and sexually dimorphic nature of brain development in which total cerebral volume is reached by age 10.5 in girls and age 14.5 in boys.

Of particular importance for understanding sex differences in ADHD are the patterns of growth in the frontal lobes and basal ganglia (both known to be anomalous in ADHD). Bush

 found that frontal lobe gray matter volume peaks at around 9.5 years in girls and 10.5 years in boys. The caudate nucleus peaks at 10.5 years in girls and at 14.0 years in boys.

By adulthood, a number of regions of the brain are larger in women than in men (after adjusting for total cerebral volume), including the frontal lobes and hippocampus.

 Given these observations, when considering neuropsychiatric development in boys and girls in whom ADHD is suspected, it may be best to make determinations of “impairment” on the basis of sex-specific comparisons and to consider the different developmental course of ADHD in males and females.

Early neuroimaging studies of ADHD have identified widespread cortical and subcortical volumetric reductions, including delayed cortical maturation, among school-aged children with ADHD.

 To date, the generalizability of many published MRI findings in children with ADHD to girls with ADHD has been questioned because most conclusions have been based on samples consisting primarily (or exclusively) of boys, with girls underrepresented in imaging studies of ADHD.

A recent meta-analysis of neuroimaging studies in ADHD found that only 20% of participants were female and only 50% of the ADHD samples included females.

 More recent brain mapping studies of ADHD suggest a more subtle pattern of neuroanatomic differences among girls that appears to parallel the earlier reduction in externalizing symptoms.

In a study that compared functional frontal lobe subdivisions in boys and girls with ADHD (aged 8 to 12 years), both boys and girls showed reductions in supplementary motor cortex. Conversely, boys (but not girls) showed reductions in dorsolateral prefrontal cortex, while girls (but not boys) showed reduced premotor cortex volumes. In both sexes, the differential reductions were associated with different patterns of executive dysfunction, but boys showed more relative problems with inhibitory control.

In a study that assessed basal ganglia volume and shape in boys and girls with ADHD (aged 8 to 13 years) and age-matched controls, compared with controls, boys with ADHD showed compression in several regions, including the left anterior and right ventral putamen, the bilateral mid-body of the caudate, and the left dorsolateral and right ventromedial head of the caudate.

 However, no differences were observed in girls with ADHD compared with controls.

The neuropsychiatric signature of ADHD in girls

The research literature has only begun to identify a signature pattern of brain anomalies and behavioral deficits associated with ADHD in girls, in part because girls “age-out” of many symptoms earlier than boys. For example, motor development follows an earlier-maturing developmental course in girls than in boys. The developmental status of the motor system in 144 typically developing children (72 boys and 72 girls, aged 7 to 14 years) was examined by Larson and colleagues.

 They found significant sex effects for atypical subtle signs (involuntary movements) and motor speed. In all cases, girls showed fewer subtle signs and were faster and more proficient than boys. Moreover, by age 7 years, many of the motor skills assessed reached “adult” level in girls, but not in boys.

A pattern of prolonged motor dysfunction emerges in boys, but not in girls, with ADHD. In a study that examined age-related reduction in motor subtle signs (overflow, dysrhythmia) in 268 children aged 7 to 14 years, boys with ADHD had more overflow and dysrhythmia than controls, while girls with ADHD did not differ from controls. Also, during this age range, girls with ADHD showed significant reduction in overflow (associated) movements, while boys showed little change during this period. This suggests that the frontal-striatal and cerebellar brain systems implicated in motor overflow and dysrhythmia mature earlier in girls.

In a study that examined executive functions in school-aged children with ADHD, O’Brien and colleagues

 found that both boys and girls showed similar patterns of deficit on tasks involving response preparation and working memory; however, they manifested different patterns of executive dysfunction. On tasks related to response inhibition, boys were more impaired; on tasks related to strategic planning, girls were more impaired.

The well-established sexual dimorphism in human neurobiological development extends to the patterns of behavior observed along the developmental course of ADHD. Current research suggests that the prevalence of ADHD among females is approaching that of males. Given the proposed changes in the ADHD diagnostic criteria for DSM-5 (which will raise the required age of onset of symptoms from 7 to 12), it is likely that the rate of diagnosis among girls will continue to increase. Cross-sectional research that compared boys and girls with ADHD has yielded inconsistent findings, because adolescent girls are at a different point in their development than boys of the same age.

More recent longitudinal studies highlight the pattern of adolescent and adult risks associated with ADHD in females and bring to fo-cus the importance of making clinical judgments in assessment and treatment of ADHD on the basis of sex-specific comparisons. Continued work examining the sex differences in expression of ADHD from early childhood (ie, preschoolers) through adulthood is encouraged.

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 Boys with ADHD can present with different cognitive and behavioral patterns than girls with ADHD. Despite these factors, girls with ADHD remain at significant psychosocial risk into adulthood.

Author | E. Mark Mahone, PhD

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