Diagnosis of ADHD in girls is more complicated than in boys, in part because of the later age of onset, more subtle clinical manifestation, and limitations associated with the DSM diagnostic schema and nomenclature [Keltner and Taylor, 2002
]. Even so, it is clear that ADHD is associated with considerable functional and psychosocial impairment in girls, including an increased risk of internalizing disorders (eating disorders, depression, suicide), especially in adolescence and young adulthood [Gaub and Carlson, 1997
; Gershon, 2002
; Makris et al., 2008
; Mikami et al., 2008
]. Longitudinal follow-up of a large cohort of girls with ADHD aged 6–18 years at baseline showed that girls with ADHD were at significantly higher risk for elevated prevalence of antisocial, addictive, mood, and anxiety disorders, including Major Depression, Bipolar Disorder, Tourette syndrome, and Nicotine Dependence [Biederman et al., 2006]. Indeed, the gender paradox [Eme, 1992
] posits that the sex in which a given disorder is less prevalent (e.g., ADHD in girls) should show greater levels of impairment than the sex in which the disorder is more prevalent (e.g., ADHD in boys). Hinshaw et al. 
reported longitudinal data on adolescent girls with ADHD, noting continued impairment 5 years after initial childhood ascertainment. In that time frame, however, symptoms of hyperactivity/impulsivity had a steeper decline than inattentive symptoms. In addition, these girls continued to demonstrate poorer performance on neuropsychological measures of working memory, planning, set maintenance, and set shifting into adolescence than matched controls.
Studies of school-aged children with ADHD routinely find that girls present more commonly with the inattentive subtype than do boys [Weiler et al., 1999
; Hinshaw et al., 2006
]. Given the earlier maturation of most cortical brain regions in girls, it may be necessary to study girls with ADHD at a younger age, to clarify the brain mechanisms associated with these behavioral problems. On the other hand, while girls may be somewhat protected from the symptoms of ADHD as a function of their earlier maturation, pubertal increases in estrogen and subsequent increases in dopamine receptors lead to an increase in symptoms in adolescence [Keltner and Taylor, 2002
]. Therefore, it is equally important to continue to study brain and behavioral development of girls with ADHD into early adulthood.
Behaviorally, symptoms of ADHD tend to decrease in severity with age in parallel with cortical maturation [Gaub and Carlson, 1997
; Hinshaw et al., 2007
], such that by late elementary school age, the symptoms are more pronounced in boys (compared to girls) with ADHD. However, recent large-scale studies of preschool children with ADHD reveal that the opposite pattern may be true in the preschool years. In preschool children with moderate to severe ADHD studied as part of the multisite Preschool ADHD Treatment Study (PATS), the behavior of girls with ADHD was more deviant, relative to age- and sex-matched peers, than boys with ADHD on the Conners’ Parent and Teacher Rating Scales [Posner et al., 2007
]. However, the study of girls with ADHD in preschool presents a challenge, as the inattentive symptoms (more commonly observed in girls) are not as evident in the preschool years. In fact, Bryne et al.  reported that only 4% of children diagnosed with ADHD in preschool (boys and girls) met criteria for the inattentive subtype, with the large majority meeting criteria for the hyperactive-impulsive subtype (68%).
There is also emerging evidence that the trajectory of early anomalous brain development within ADHD is sex-specific. By examining EEG activation patterns longitudinally in young boys and girls with ADHD, Baving et al. 
demonstrated different patterns and trajectories of cerebral organization (i.e., opposite directions of asymmetry). Boys with ADHD exhibited a less right-lateralized frontal alpha asymmetry than control boys, whereas girls with ADHD displayed a more right-lateralized asymmetry pattern than control girls. This dissociation was present in both preschool (age 4.5 years) and school age (age 8 years) children. Of note, in the girls with ADHD, at age 4 years, the degree of right-lateralization, and difference from age-matched controls and from boys with ADHD, was markedly higher than at age 8 years, suggesting greater atypicality at age 4 years, but a more rapid trajectory of normalization of frontal function by age 8 years in girls with ADHD [Baving et al., 1999
]. A similar pattern of sex-specific findings in adolescents with ADHD was observed by Hermens et al. 
, using simultaneously recorded EEG and electrodermal activity (EDA). Boys with ADHD showed widespread increased theta activity, while girls with ADHD showed localized frontal enhancement of theta, with reduced rate of EDA decrement. The findings were unrelated to ADHD subtype, and interpreted to support a model of anomalous arousal in girls with ADHD, emphasizing both central and autonomic function [Hermens et al., 2005
Few studies have directly compared regional brain volumes in girls with ADHD to those of healthy female controls. Castellanos et al. 
reported a cross-sectional analysis of brain volumes in 50 girls with ADHD (compared to 50 healthy control girls), ages 5–15 years. The girls with ADHD showed significant reductions in left caudate and posterior–inferior cerebellar vermis (lobules VIII–X), but equivocal findings were reported regarding reductions in frontal lobe volumes [Castellanos et al., 2001
]. Because this study was completed separately from earlier studies of boys with ADHD, the authors remarked, “conclusions about sex differences in ADHD must remain tentative until verified in contemporaneously collected and analyzed longitudinal scans” [Castellanos et al., 2001
, p. 293].
In a recently published paper from our lab, ADHD-related abnormalities in cerebral cortex structure and volume were analyzed. Using an automated surface-based analysis technique to examine ADHD-associated differences in additional morphologic features of cerebral cortical gray matter structure, including surface area, thickness, and cortical folding, children with ADHD had a decrease in total cerebral volume and total cortical volume of over 7 and 8%, respectively, with volume reduction observed throughout the cortex, and with significant reduction in all four lobes bilaterally. The ADHD group also showed a decrease in surface area of over 7% bilaterally, and a significant decrease in cortical folding bilaterally [Wolosin et al., 2007
]. In supplemental analyses of these data examining only girls (19 ADHD, 34 controls), the ADHD group had reduced right hemisphere (P
< 0.05) and bilateral frontal (P
≤ 0.01) cortical surface, but not reduced cortical volume.
Taken together, the available neuroimaging and neurobiological literature yields little consensus on the brain anomalies specific to girls with ADHD; however, these recent findings are consistent with the hypothesis that ADHD-specific anomalies occur early
in neural development, but that by school age, the differences are more pronounced and widespread in boys with ADHD. Thus, in view of the available evidence from neuroimaging studies [Bush, 2008
], when considering neurobiological development in ADHD, it is crucial to consider (simultaneously) all three levels of the CNS (cortex, basal ganglia, cerebellum), and study these regions longitudinally with regard to sex. Given the sex difference in maturation, it may be necessary to study girls with ADHD at younger ages, to fully appreciate the early patterns of anomalous brain development, and their effect on behavior and cognitive development.