Neurobiological models of attention-deficit/hyperactivity disorder: a brief review of the empirical evidence

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, impulsivity, and overactivity that begins in childhood. While considerable research has focused on the neurobiological substrates of this disorder, the specific nature of the brain dysfunction in ADHD has remained elusive. However, early data from pharmacological treatment studies, as well as from basic research in animals and humans, initially led several investigators to develop neurobiological models of ADHD. These models of ADHD and more recent evidence from neuropsychological, neuroimaging, neurochemical, and genetic research are briefly reviewed. While not completely consistent, the empirical data suggest that dysfunction in prefrontal-striatal neural circuits, as well as in brain stem catecholamine systems that innervate these circuits, may underlie the executive function deficits in ADHD.     

Nature, Nurture, and Attention Deficit Hyperactivity Disorder

This commentary shows that Joseph's (this issue) review of the genetics of attention deficit hyperactivity disorder (ADHD) contains errors of scientific logic and ignores much relevant research. Thus, we reject his conclusions. We also reject Joseph's approach of pitting nature against nurture as if these two facets of human life are at odds with one another. Instead, most scientists who study the genetics of psychiatric disorders embrace the idea that these disorders are influenced by both genes and environmental factors. In fact, the twin studies criticized by Joseph provide the strongest evidence that environmental risk factors play a substantial role in the etiology of ADHD. They do so by showing that when one identical twin has ADHD the risk to the co-twin is much less than 100%, a fact which can only be explained by environmental risk factors. We also reject the idea that genetic studies have hindered psychosocial research, stigmatized patients, or promoted psychopharmacologic treatments. Genetic studies have aimed at solving one part of the puzzle of ADHD. By testing a parsimonious theory, they have set the stage for gene discovery and the delineation of how genes and environment combine to cause this impairing disorder.     

The epidemiology of attention-deficit/hyperactivity disorder (ADHD): a public health view

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood. However, basic information about how the prevalence of ADHD varies by race/ethnicity, sex, age, and socio-economic status remains poorly described. One reason is that difficulties in the diagnosis of ADHD have translated into difficulties developing an adequate case definition for epidemiologic studies. Diagnosis depends heavily on parent and teacher reports; no laboratory tests reliably predict ADHD. Prevalence estimates of ADHD are sensitive to who is asked what, and how information is combined. Consequently, recent systematic reviews report ADHD prevalence estimates as wide as 2%-18%. The diagnosis of ADHD is complicated by the frequent occurrence of comorbid conditions such as learning disability, conduct disorder, and anxiety disorder. Symptoms of these conditions may also mimic ADHD. Nevertheless, we suggest that developing an adequate epidemiologic case definition based on current diagnostic criteria is possible and is a prerequisite for further developing the epidemiology of ADHD. The etiology of ADHD is not known but recent studies suggest both a strong genetic link as well as environmental factors such as history of preterm delivery and perhaps, maternal smoking during pregnancy. Children and teenagers with ADHD use health and mental health services more often than their peers and engage in more health threatening behaviors such as smoking, and alcohol and substance abuse. Better methods are needed for monitoring the prevalence and understanding the public health implications of ADHD. Stimulant medication is the treatment of choice for treating ADHD but psychosocial interventions may also be warranted if comordid disorders are present. The treatment of ADHD is controversial because of the high prevalence of medication treatment. Epidemiologic studies could clarify whether the patterns of ADHD diagnosis and treatment in community settings is appropriate. Population-based epidemiologic studies may shed important new light on how we understand ADHD, its natural history, its treatment and its consequences.     

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis

Multiple theories of Attention-Deficit/Hyper- activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.     

Attention Deficit Hyperactivity Disorder in Adults: Implications for Theories of Diagnosis

The diagnosis of attention deficit hyperactivity disorder (ADHD) in adults has been a source of controversy, with some prominent researchers questioning its very existence and others suggesting it is an urgent clinical problem. This article reviews five domains of data addressing the validity of adult ADHD: clinical correlates, family history, treatment response, laboratory studies, and long-term outcome. It then shows how the debate over adult ADHD reflects a clash of theoretical paradigms and concludes by suggesting ways in which psychological science can collect the data needed to clarify the validity of adult ADHD.     

A multitrait-multisource confirmatory factor analytic approach to the construct validity of ADHD rating scales

Confirmatory factor analysis was used to model a multitrait-multisource design to evaluate the construct validity of attention-deficit/hyperactivity disorder (ADHD) rating scales. The 2 trait factors were the ADHD inattention and hyperactivity/impulsivity dimensions. The 2 source factors were parents and teachers. In Study 1, parents and teachers rated 1,475 Australian elementary school children on the ADHD symptoms. In Study 2, parents and teachers rated 285 Brazilian elementary school children on the ADHD symptoms. Similar results occurred in both studies with most of the ADHD symptoms containing more source than trait variance, thus providing weak evidence for the convergent and discriminant validity of the symptoms as measured by rating scales. The study outlines the implications of such strong source effects for understanding ADHD.     

Exploring how symptoms of attention-deficit/hyperactivity disorder are related to reading and mathematics performance: general genes, general environments

Children with attention-deficit/hyperactivity disorder (ADHD) tend to perform more poorly on tests of reading and mathematical performance than their typical peers. Quantitative genetic analyses allow for a better understanding of the etiology of ADHD and reading and mathematics outcomes, by examining their common and unique genetic and environmental influences. Analyses were conducted on a sample 271 pairs of 10-year-old monozygotic and dizygotic twins drawn from the Western Reserve Reading and Mathematics Project. In general, the results suggested that the associations among ADHD symptoms, reading outcomes, and math outcomes were influenced by both general genetic and general shared-environment factors. The analyses also suggested significant independent genetic effects for ADHD symptoms. The results imply that differing etiological factors underlie the relationships among ADHD and reading and mathematics performance. It appears that both genetic and common family or school environments link ADHD with academic performance.     

A Preliminary Study of ADHD Symptoms and Correlates: Do Abused Children Differ from Nonabused Children?

In this pilot study, differences in inattention, impulsivity, and hyperactivity as well as demographic factors were investigated in a community sample of 8- through 11-year-olds, approximately half of whom had experienced child abuse or neglect. Parents completed the Attention Deficit Hyperactivity Disorder Test, the SNAP-IV, the Brief Betrayal Trauma Survey – Parent version, and additional questions. Abused children had more severe impulsivity and inattention, but not hyperactivity, symptoms. Abused boys and girls had a similar age of onset of symptoms, whereas nonabused girls had a much later age of onset than nonabused boys. ADHD is a significant problem among maltreated children. These data support large scale studies investigating possible differences in etiology, presentation, and treatment.     

Test of Alternative Hypotheses Explaining the Comorbidity Between Attention-Deficit/Hyperactivity Disorder and Conduct Disorder

There is significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD). The conclusions of studies that examined the causes of comorbidity between ADHD and CD conflict, with some researchers finding support for the three independent disorders model and others finding support for the correlated risk factors model. We tested these models and eleven alternative hypotheses using the same analytical approach. The participants were 110 monozygotic twin pairs and 181 dizygotic twin pairs recruited from the Colorado Learning Disabilities Research Center Twin Study. The three independent disorders model did not fit the data, whereas the correlated risk factors model fit the data well. Several other comorbidity models fit the data as well as or better than the correlated risk factors model. The results suggest that correlated risk factors are a better explanation for the comorbidity between ADHD and CD than a third, independent ADHD+CD subtype.     

Problems in Psychiatric Genetic Research: A Reply to Faraone and Biederman

This article examines evidence cited in favor of the operation of genetic factors in attention-deficit hyperactivity disorder (ADHD). Like other psychiatric conditions, a belief in the genetic basis of ADHD is derived from the results of family, twin, and adoption studies. Because family studies are widely believed to be confounded by environmental factors, primary emphasis is placed on twin and adoption studies. ADHD twin studies depend on the validity of the equal environment assumption (EEA), which holds that the environments of identical (MZ) and fraternal (DZ) twins are the same. Here it is argued that however the EEA is defined, it cannot be accepted. Therefore, the greater similarity or concordance of MZ twins when compared to DZ twins is plausibly explained by environmental factors. Adoption studies constitute a third method for investigating the role of genetic factors in ADHD. It is argued that these studies are greatly flawed by factors including non blinded diagnoses and the failure to study the biological relatives of adoptees. After an examination of the total weight of evidence in favor of a genetic basis or predisposition for ADHD, it is concluded that a role for genetic factors is not supported and that future research should be directed toward psychosocial causes     

Etiology of Inattention and Hyperactivity/Impulsivity in a Community Sample of Twins with Learning Difficulties

A community sample of 373 8 to 18 year-old twin pairs in which at least one twin in each pair exhibited a history of learning difficulties was utilized to examine the etiology of inattention and hyperactivity/impulsivity (hyp/imp). Symptoms of attention-deficit/hyperactivity disorder (ADHD) were assessed by the DSM-III Diagnostic Interview for Children and Adolescents. Inattention and hyp/imp composite scores were created based on results of a factor analysis. Results indicated that extreme ADHD scores were almost entirely attributable to genetic influences across several increasingly extreme diagnostic cutoff scores. Extreme inattention scores were also highly heritable whether or not the proband exhibited extreme hyp/imp. In contrast, the heritability of extreme hyp/imp increased as a linear function of the number of inattention symptoms exhibited by the proband. This finding suggests that extreme hyp/imp may be attributable to different etiological influences in individuals with and without extreme inattention. If this result can be replicated in other samples, it would provide evidence that the hyp/imp symptoms exhibited by individuals with Combined Type ADHD and Predominantly Hyp/Imp Type ADHD may be attributable to different etiological influences.     

Hyperactivity in Children: A Focus on Genetic Research and Psychological Theories

Hyperactivity has attracted a large amount of research interest in recent years. Here we review developments in genetic research and in research testing psychological theories of the condition. Family, adoptee and twin studies indicate a strong role for genetic factors in the etiology of hyperactivity. Evidence is emerging also from molecular genetic studies, implicating specific genes that may be involved. At the level of cognitive functioning, a divided, focused or sustained attention deficit does not seem to be a core deficit in hyperactivity. Although children with hyperactivity often perform poorly on certain executive function tasks, there is disagreement about the interpretation of these findings. The association reported in some studies between a slow inhibitory process and hyperactivity may reflect a generally slow, variable in speed and inaccurate pattern of responding. Hypotheses about psychological mechanisms such as state regulation or delay aversion provide alternative, and particularly encouraging, interpretations of the findings. We discuss the possible integration of the two lines of research—those of genetic research and research on psychological mechanisms.     

The Effects of Childhood ADHD Symptoms on Early-onset Substance Use: A Swedish Twin Study

Research has documented that children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of substance use problems. Few studies, however, have focused on early-onset substance use. This study therefore investigated how the two symptom dimensions of ADHD (hyperactivity/impulsivity and inattention) are associated with early-onset substance use, the role of persistent ADHD for the association, and to what extent the association is influenced by genetic and environmental factors. Twins (1,480 pairs) in the Swedish Twin Study of Child and Adolescent Development were followed from childhood to adolescence. ADHD symptoms were measured at age 8–9 and age 13–14 via parent-report, whereas substance use was assessed at age 13–14 via self-report. Results revealed that hyperactive/impulsive symptoms predicted early-onset “sometimes” tobacco use (adjusted odds ratios, 1.12, for one symptom count), controlling for inattentive symptoms and conduct problem behaviors. There is no independent effect of inattentive symptoms on early-onset substance use. Children with persistent hyperactivity/impulsivity (defined as scoring above the 75th percentile at both time points) had a pronounced risk of both early-onset tobacco and alcohol use (adjusted odds ratios from 1.86 to 3.35, compared to the reference group). The associations between hyperactivity/impulsivity and early-onset substance use were primarily influenced by genetic factors. Our results indicated that hyperactivity/impulsivity, but not inattention, is an important early predictor for early-onset substance use, and a shared genetic susceptibility is suggested to explain this association.     

Factor Structure and Criterion Validity of Secondary School Teacher Ratings of ADHD and ODD

Attention-Deficit Hyperactivity Disorder (ADHD) is currently viewed as a heterogeneous disorder with two factors: inattention and impulsivity–hyperactivity. This conceptualization of ADHD is based primarily on research with children or samples that mix children and adolescents. To examine if the 2-factor ADHD model is appropriate for adolescents and if the ADHD factors are distinct from Oppositional Defiant Disorder (ODD) in adolescents, teacher rating data were collected for 2 samples of adolescents. The results of a confirmatory factor analysis supported the convergent and divergent validity of a model with separate but correlated factors for inattention, impulsivity–hyperactivity, and defiant behavior. Further evidence of construct validity was found when factor scores were examined relative to the criterion variables of academic performance and rule-breaking behavior. The results support the utility of teacher ratings of ADHD and ODD in the assessment of adolescents, and the applicability of the DSM-IV conceptualization of these disorders to adolescents.     

Attention-Deficit Hyperactivity Disorder Symptoms and Entrepreneurial Orientation: A Replication Note

There is a small body of literature linking attention-deficit hyperactivity disorder (ADHD) and its symptoms to entrepreneurial manifestations. Some studies take a subclinical perspective by studying the presence of symptoms, while other studies take a clinical perspective by studying the formal diagnosis of ADHD. The entrepreneurial manifestations examined range from entrepreneurial intention to the choice to become self-employed and from entrepreneurial orientation (EO) to entrepreneurial success. Despite its prominence in the entrepreneurship literature, to date only one study tested for a link with EO. The present study aims to replicate the relationship between ADHD symptoms and EO using a large data set of French small business owners. We do so by discriminating between the two dimensions of ADHD, namely attention-deficit and hyperactivity, as well as the three dimensions of EO, namely innovativeness, proactiveness, and risk-taking. We do not find a link between ADHD and EO, although we do find a positive link between ADHD and the risk-taking subdimension of EO. Hyperactivity symptoms are positively related to EO, which is mainly driven by the subdimensions proactiveness and risk-taking. We do not find a link between attention-deficit symptoms and EO, though there is a negative link between attention-deficit and proactiveness.     

Adults With Attention‐Deficit/Hyperactivity Disorder: Assessment and Treatment Strategies

Attention‐deficit/hyperactivity disorder (ADHD) among adults is characterized by inattentiveness and impulsivity. This article provides counselors with information about the etiology, assessment, and treatment of adult ADHD. The identification of the genetic and neurological features of ADHD has led to improvements in evaluation and treatment. Assessment of ADHD requires knowledge of the defining characteristics, subtypes, comorbid features, and functional aspects of ADHD. Effective treatments include both medical management and counseling to address psychosocial deficits.     

Sources of covariation among attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder: the importance of shared environment.

Research has documented high levels of covariation among childhood externalizing disorders, but the etiology of this covariation is unclear. To unravel the sources of covariation among attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), the authors studied 11-year-old twins (N = 1,506) from the Minnesota Twin Family Study. Symptom counts for each of these disorders were obtained from interviews administered to the twins and their mothers. A model was fit that allowed the parsing of genetic, shared environmental (factors that make family members similar to each other), and nonshared environmental (factors that make family members different from each other) contributions to covariation. The results revealed that although each disorder was influenced by genetic and environmental factors, a single shared environmental factor made the largest contribution to the covariation among ADHD, ODD, and CD.     

The Behavioral Genetics of Alcoholism

Twin and adoption studies consistently implicate the importance of genetic influences on alcoholism risk, especially in men. Heritability estimates suggest that approximately 50% to 60% of the variability in alcoholism liability is associated with genetic factors. Although there has been progress in identifying specific genes that predispose toward alcoholism, we know relatively little about the nature of the genetic influence on alcoholism risk. We also know relatively little about how genetic factors combine with environmental factors to affect alcoholism risk. Genotype-environment interaction models posit that alcoholism occurs when individuals both inherit a vulnerability to develop alcoholism and are reared in a provocative environment. Such models hold great promise for understanding alcoholism's etiology.     

Response inhibition in children with and without ADHD after traumatic brain injury

Children with attention‐deficit hyperactivity disorder (ADHD) and traumatic brain injury (TBI) show deficient response inhibition. ADHD itself is a common consequence of TBI, known as secondary ADHD (S‐ADHD). Similarity in inhibitory control in children with TBI, S‐ADHD, and ADHD would implicate impaired frontal‐striatal systems; however, it is first necessary to delineate similarities and differences in inhibitory control in these conditions. We compared performance of children with ADHD and those with TBI without pre‐injury ADHD on a stop signal, response inhibition task. Participants were 274 children aged 6–14 years. There were 92 children with ADHD, 103 children with TBI, and 79 typically developing children who served as controls. Among the TBI participants, injury severity ranged from mild to severe. Children with ADHD and TBI showed deficient inhibition. The deficit in children with ADHD was as great as or greater than that in children with TBI, regardless of degree of TBI severity or the presence of S‐ADHD. The finding indicates that TBI results in deficient inhibition regardless of the development of S‐ADHD.     

Confirming the Factor Structure of Attention Deficit Hyperactivity Disorder Symptoms in Adult, Nonclinical Samples

Three separate models have been proposed to describe the factor structure of attention deficit hyperactivity disorder (ADHD) in the past 20 years. The Diagnostic and Statistical Manual of Mental Disorders-III (DSM-III, 1980) proposed 3 separate factors of inattention, hyperactivity, and impulsivity. The DSM-III-R (1987) proposed a single factor. The DSM-IV (1994) described the disorder as having 2 factors: hyperactivity/impulsivity and inattention. The following 2 studies employed confirmatory factor analysis to compare each of these models and 3 alternative models. University students completed questionnaires that assessed each of the 18 symptoms listed in the DSM-IV for ADHD. The 3-factor model fit the data significantly better than each of the other models in both studies. These findings suggest that a 3-factor model of inattention, hyperactivity, and impulsivity describes adult ADHD symptoms better than current alternatives.