Attention‐deficit/hyperactivity disorder: The past 50 years

Attention‐deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder and one of the main diagnoses seen by general paediatricians today. Despite the impression often portrayed in the media, it is not a new condition; in fact it has been described for over 200 years. The past 50 years has seen a progressive increase in our understanding of the underlying neurocognitive deficits in ADHD, and over the past 20 years behavioural genetics and neuroimaging studies have shed light on the complex causal factors and neurobiological processes operating. The plethora of ADHD research has advanced our knowledge of the condition, but so far has had little impact on improving clinical practice. Stimulant medication has been the mainstay of symptomatic treatment for over 30 years; however, it is still unclear how developmental trajectories can be modified to achieve best outcomes. It is hoped that novel therapies and more individualised management will evolve over the coming decades.     

Attention deficit hyperactivity disorder with reading disabilities: preliminary genetic findings on the involvement of the ADRA2A gene

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) and reading disability (RD) tend to co-occur and quantitative genetic studies have shown this to arise primarily through shared genetic influences. However, molecular genetic studies have shown different genes to be associated with each of these conditions. Neurobiological studies have implicated noradrenergic function in the aetiology of ADHD that is comorbid with RD. This paper examines the neurobiological evidence and presents preliminary testing of the hypothesis that the ADRA2A receptor gene is contributing to ADHD and comorbid RD. METHODS: One hundred and fifty-two children (140 boys, 12 girls) of British Caucasian origin, aged between 6 and 13 years and with a diagnosis of ADHD, were recruited. The children's reading ability was tested. Children were identified as having ADHD or ADHD plus RD (n=82). DNA was available for 110 parent child trios and 42 parent child duos. Genotyping was undertaken for an ADRA2A polymorphism. RESULTS: For those with ADHD plus RD there was evidence of association with the alpha 2A adrenergic receptor (ADRA2A) polymorphism with the G allele being preferentially transmitted. CONCLUSIONS: The preliminary evidence together with other neurobiological research findings suggests that the ADRA2A gene may contribute to comorbid ADHD and RD and needs to be properly examined.     

The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent and commonly studied forms of psychopathology in children and adolescents. Causal models of ADHD have long implicated dysfunction in fronto-striatal and frontal-parietal networks supporting executive function, a hypothesis that can now be examined systematically using functional neuroimaging. The present work provides an objective, unbiased statistically-based meta-analysis of published functional neuroimaging studies of ADHD. METHODS: A recently developed voxel-wise quantitative meta-analytic technique known as activation likelihood estimation (ALE) was applied to 16 neuroimaging studies examining and contrasting patterns of neural activity in patients with ADHD and healthy controls. Voxel-wise results are reported using a statistical threshold of p < .05, corrected. Given the large number of studies examining response inhibition, additional meta-analyses focusing specifically on group differences in the neural correlates of inhibition were included. RESULTS: Across studies, significant patterns of frontal hypoactivity were detected in patients with ADHD, affecting anterior cingulate, dorsolateral prefrontal, and inferior prefrontal cortices, as well as related regions including basal ganglia, thalamus, and portions of parietal cortex. When focusing on studies of response inhibition alone, a more limited set of group differences were observed, including inferior prefrontal cortex, medial wall regions, and the precentral gyrus. In contrast, analyses focusing on studies of constructs other than response inhibition revealed a more extensive pattern of hypofunction in patients with ADHD than those of response inhibition. CONCLUSIONS: To date, the most consistent findings in the neuroimaging literature of ADHD are deficits in neural activity within fronto-striatal and fronto-parietal circuits. The distributed nature of these results fails to support models emphasizing dysfunction in any one frontal sub-region. While our findings are suggestive of the primacy of deficits in frontal-based neural circuitry underlying ADHD, we discuss potential biases in the literature that need to be addressed before such a conclusion can be fully embraced.     

Editorial: Can dysregulated myelination be linked to ADHD pathogenesis and persistence?

Converging evidence from new epidemiologic, genetic, epigenetic, neuroimaging, and experimental model findings are further refining a long-standing concept, regarding the underlying neurobiology of attention-deficit/hyperactivity disorder (ADHD): that ADHD onset and its persistence into adulthood are the result of dysregulated myelination and associated alterations in neuronal plasticity – linked to disrupted brain maturation and the persistence of cognitive and emotional impairments across the life span. If supported by further work, this concept represents a pathophysiologic mechanism amenable to therapeutic intervention.     

Research Review: The neurobiology and genetics of maltreatment and adversity

The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individual’s genetic make‐up influence neurobiological development across infancy and childhood, which in turn sets the stage for a child’s psychological and emotional development. This review provides a concise synopsis of those studies investigating the neurobiological and genetic factors associated with childhood maltreatment and adversity. We first provide an overview of the neuroendocrine findings, drawing from animal and human studies. These studies indicate an association between early adversity and atypical development of the hypothalamic‐pituitary‐adrenal (HPA) axis stress response, which can predispose to psychiatric vulnerability in adulthood. We then review the neuroimaging findings of structural and functional brain differences in children and adults who have experienced childhood maltreatment. These studies offer evidence of several structural differences associated with early stress, most notably in the corpus callosum in children and the hippocampus in adults; functional studies have reported atypical activation of several brain regions, including decreased activity of the prefrontal cortex. Next we consider studies that suggest that the effect of environmental adversity may be conditional on an individual’s genotype. We also briefly consider the possible role that epigenetic mechanisms might play in mediating the impact of early adversity. Finally we consider several ways in which the neurobiological and genetic research may be relevant to clinical practice and intervention.     

Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?

BACKGROUND: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. METHOD: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. RESULTS: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. CONCLUSIONS: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.     

Environmental risk factors for attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is the most common cognitive and behavioural disorder diagnosed among school children. It is characterized by deficient attention and problem solving, along with hyperactivity and difficulty withholding incorrect responses. This highly prevalent disorder is estimated to affect 5-10% of children and in many cases, persists into adulthood, leading to 4% prevalence among adults. Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder. The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder. Family studies have identified a 2- to 8-fold increase in the risk for ADHD in parents and siblings of children with ADHD. Various twin and adoption studies have also highlighted the highly genetic nature of ADHD. In fact the mean heritability of ADHD was shown to be 0.77, which is comparable to other neuropsychiatric disorders such as schizophrenia or bipolar disorder. However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight. Many recent studies have specifically examined the relationships between ADHD and these extraneous factors. This review describes some of these possible risk factors. CONCLUSION: Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene-environment interactions also increase the risk for the disorder.     

ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD

BACKGROUND: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological abnormalities and response to stimulant medication. METHOD: A group of concordantly diagnosed ADHD parent-child dyads was compared to a matched sample of normal parent-child dyads. In addition, ADHD dyads were administered double-blind methylphenidate and placebo in a counterbalanced fashion over two consecutive days of testing. Frontostriatal function was measured using functional magnetic resonance imaging (fMRI) during performance of a go/no-go task. RESULTS: Youths and adults with ADHD showed attenuated activity in fronto-striatal regions. In addition, adults with ADHD appeared to activate non-fronto-striatal regions more than normals. A stimulant medication trial showed that among youths, stimulant medication increased activation in fronto-striatal and cerebellar regions. In adults with ADHD, increases in activation were observed in the striatum and cerebellum, but not in prefrontal regions. CONCLUSIONS: This study extends findings of fronto-striatal dysfunction to adults with ADHD and highlights the importance of frontostriatal and frontocerebellar circuitry in this disorder, providing evidence of an endophenotype for examining the genetics of ADHD.     

The conceptual and diagnostic importance of ADHD-related impairment: a Commentary on Arildskov et al. (2021)

Arildskov et al. (2021) provide compelling evidence regarding the importance and nature of functional impairment in advancing diagnostic assessment and treatment of attention-deficit/hyperactivity disorder (ADHD). Their findings indicate that (a) ADHD is dimensional for both symptom severity and impairment, (b) symptoms and impairment are related but separate constructs, (c) diagnostic assessment should focus equally on symptoms and impairment, and (d) the symptom threshold for ADHD diagnosis is arbitrarily defined with respect to presence of impairment. Results from this study can be extended to raise the profile of functional impairment in research and clinical practice in terms of diagnostic assessment, treatment outcome measurement, improvements to diagnostic systems, and advancements in our understanding of ADHD as a disorder.     

Infrequent, but not frequent, reinforcers produce more variable responding and deficient sustained attention in young children with attention-deficit/hyperactivity disorder (ADHD)

BACKGROUND: The underlying behavioral/psychological processes of attention-deficit/hyperactivity disorder are unclear. Motivational factors, related to dopamine dysfunction, may play an important role in the development of the behavioral symptoms. Particularly, infrequent, but not frequent, reinforcers have been suggested to be associated with altered responding and deviant behavior in children with ADHD. The present study was designed to analyze the influence of reinforcement frequency on operationalized measures of hyperactivity, impulsiveness, sustained attention, and response variability. METHODS: Fifty-six boys, half of whom were diagnosed with ADHD, completed a computerized task presented as a game with two squares on the screen. One square was associated with reinforcement. The task required responses by the computer mouse under contingencies alternating between variable interval schedules of short (mean 2 s) and long (mean 20 s) durations. Reinforcers were cartoon pictures and small trinkets. RESULTS: Overall, there was no difference between children with ADHD and comparison children when reinforcers were given frequently. Statistically significant differences on measures of sustained attention and variability, but not hyperactivity and impulsiveness, were found during infrequent reinforcement only. Age effects interacted with group effects on sustained attention, showing that group differences were found in the young children only. Surprisingly, older comparison children showed increased response variability and no learning. CONCLUSIONS: When reinforcers are infrequent, children with ADHD show deficient sustained attention and increased variability in responding. Computer experience may have interfered with measures of hyperactivity and impulsiveness. The unexpectedly poor performance of the older comparison children may have been due to inefficient reinforcers or to verbally governed behavior overruling reinforcer effects. Reinforcer characteristics and experimental procedures are important factors influencing findings in studies investigating motivational factors. The study provides some support for the dynamic developmental theory of ADHD predicting relationships between neurobiological deficits, altered reinforcement mechanisms, and treatment recommendations.     

Le trouble déficitaire de l’attention avec hyperactivité : données récentes des neurosciences et de l’expérience nord-américaine

Attention-deficit/hyperactivity disorder (ADHD) is considered to be the most common neuropsychiatric disorder of childhood in USA with a prevalence rate of approximately 7–9 %. Psyschostimulants are widely prescribed to ADHD children since three decades in USA. Here, we review neurobiological hypotheses about ADHD aetiology and about the North American experience regarding psychostimulant medication. Recent data show that the classical hypotheses positing that ADHD is caused by an underlying dopamine and/or noradrenaline deficit are weak. Although we have no better theory that might receive a general consensus, the high heritability of ADHD is often put forward to support its biological aetiology. However, “heritable” does not mean “genetic” and numerous environmental factors contribute to ADHD aetiology. Recent studies confirm that psychostimulants are safe, well tolerated and efficient regarding the core symptoms of ADHD as ascertained by proper diagnostic procedures. However, children with ADHD are at risk of later development of antisocial behavior, substance abuse and significant academic underachievement. Recent studies show that psychostimulant medication does not affect these long-term risks. In contrast, psychosocial interventions directed towards ADHD children and their parents significantly decrease these risks as well as other comorbid disorders often associated with ADHD (anxiety, depression, conduct disorder). Thus, psychosocial treatments now represent the first-line intervention for ADHD. Therefore, dogmas regarding ADHD are now questioned and this re-examining should lead to look more favorably on the French clinical experience about pediatric psychiatry and psychopathology.     

Variations in prevalence of attention deficit hyperactivity disorder worldwide

Attention deficit hyperactivity disorder (ADHD) is among the most common, intensely investigated, and yet diagnostically controversial neurobehavioral conditions of childhood. The prevalence of ADHD has been reported with great variations among different studies, ranging from 2.2% to 17.8%. The aim of this review was to investigate the variables that influence the prevalence of ADHD and to derive a best estimate for the prevalence of the disorder. We reviewed all the 39 studies on ADHD prevalence appearing in the Pubmed and published since 1992. These studies indicate that ADHD is more common in boys than girls, in younger than older children and adolescents, in one-setting rather than two-setting screening studies, in studies based on DSM-IV rather than DSM-III-R criteria. Additional factors that may well influence prevalence rates include source of information and assessment of clinical impairment. In conclusion, our findings suggest that population characteristics, methodology features, ethnic and cultural differences and diagnostic criteria involved in studies affect the prevalence of ADHD. Standardized designs may lead to firm conclusions on the true prevalence of ADHD, the estimation of which seems impossible to be achieved by reviewing the already existing literature.     

‘Shine bright like a diamond!’: is research on high‐functioning ADHD at last entering the mainstream?

The paper by Greven and colleagues (this issue) is intensifying discussion how research on attention‐deficit/hyperactivity disorder (ADHD) can be moved away from the deficit‐focused view to a concept, which is oriented towards resources a patient might be able to recruit to function at a high‐level despite impairments. To promote understanding of high‐functioning (HF)‐ADHD, more longitudinal studies are required employing neuropsychologic, neuroimaging and neurobiologic approaches, with focus on compensatory mechanisms during fronto‐striatal‐amygdala maturation and adult plasticity as well as epigenetic modification marker screening strategies to identify homoeostatic processes of resilience in endophenotypic traits related to coping styles of target groups.     

"Maturational lag" hypothesis of attention deficit hyperactivity disorder: an update

This article discusses the relationship of maturation to ADHD and hyperkinetic disorder (HKD), with an emphasis on current research in ADHD and HKD, persistence and remission of ADHD symptoms over time and brain maturational trajectories.

Conclusion: ADHD is a broad, heterogeneous syndrome and only a subgroup of subjects has a diagnosis of HKD, which is a subset of individuals with severe ADHD combined subtype. Children showing symptoms above the threshold for a diagnosis of ADHD are at risk of developing comorbid conditions and increasing stress in both parents and teachers. In some subjects, ADHD symptoms can improve over time during maturation and development. These children with a diagnosis of ADHD could be viewed as showing variants of normal childhood behaviour with maturational trajectories that are lagging behind but will catch up. ADHD could therefore represent a continuum from normality at one extreme to a severe disorder, HKD according to ICD-10, at the other extreme.     

Developing ADHD

Over the past 50 years the concept of attention deficit/hyperactivity disorder (ADHD) has developed from the notion of a specific form of brain dysfunction to that of a heterogeneous set of related behaviours. The great advances in genetics, neuroimaging and neuropsychiatry have made it one of the best understood forms of complex mental disturbance – but much remains to be done to translate understanding into practice. More effective treatment may come from identifying and treating more specific components of disorder and by a focus on identifying the factors determining course in the longer term so that they, as well as the core features of disorder, can become targets for intervention.     

Attention deficit hyperactivity disorder and environmental toxic metal exposure in the United Arab Emirates

No systematic studies have been carried out on the effects of toxic metals on childhood behavior in the Gulf Region including the UAE. The relationship between blood levels of heavy metals and Attention Deficit Hyperactivity disorder (ADHD) were explored in school-aged children of UAE and it was found that increased blood concentrations of lead (Pb), manganese (Mn) and zinc (Zn) were significantly associated with ADHD. The findings suggest that monitoring for exposure to heavy metal levels and education on potential child health hazards related to them are indicated.     

Aetiology for the covariation between combined type ADHD and reading difficulties in a family study: the role of IQ

Background: Twin studies using both clinical and population‐based samples suggest that the frequent co‐occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. Methods: Multivariate familial models were run on data from 1,789 individuals at ages 6–19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC–III/WAIS–III). Results: Significant phenotypic (.2–.4) and familial (.3–.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%–72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. Conclusions: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population‐based study to a clinically ascertained sample with combined type ADHD.     

The link between health-related quality of life and clinical symptoms among children with attention-deficit hyperactivity disorder

Clinical research on attention-deficit hyperactivity disorder (ADHD) has begun to integrate measures of health-related quality of life (HRQL) as part of the overall assessment of treatment outcomes. This study examines the association between HRQL and measures of clinical symptoms of ADHD. Data were gathered from 297 children and adolescents in an 8-week, randomized, double-blind, placebo-controlled, clinical trial of atomoxetine treatment for ADHD. HRQL was assessed with the Child Health Questionnaire 50-item Parent Form. ADHD symptoms were assessed with the ADHD Rating Scale-IV; Parent Version and Clinical Global Impressions-ADHD-Severity. Associations between HRQL and clinical symptoms were assessed with correlations, analyses of variance with post hoc comparisons, and t tests. The Child Health Questionnaire 50-item Parent Form scales assessing psychosocial domains of HRQL were significantly negatively correlated with clinical measures. Improvement in clinical symptoms was associated with corresponding improvement in psychosocial aspects of HRQL. The findings suggest that HRQL instruments can add important information to efficacy measures in clinical trials of ADHD treatment.     

Assessment and treatment of attention deficit hyperactivity disorder in children with comorbid psychiatric illness

PURPOSE OF REVIEW: Attention deficit hyperactivity disorder (ADHD) frequently occurs with a wide variety of comorbid psychiatric disorders such as conduct disorder, depression, mania, anxiety, and learning disabilities. Because the vast majority of children with ADHD are treated in primary care settings, it is important that primary medical doctors be proficient in the diagnosis and initial treatment of children with ADHD and its commonly occurring comorbid disorders. ADHD research is beginning to focus on the treatment of these comorbidly ill children. This review will summarize the recent findings from the psychiatric literature in an attempt to provide the clinician with some initial diagnostic and treatment guidelines for ADHD and its comorbidities. RECENT FINDINGS: The NIMH Multimodal Treatment Study of ADHD found that children with other disruptive behavior disorders plus ADHD respond well to stimulant medications, with behavioral interventions reducing academic and social impairment. Children with anxiety and ADHD are very responsive across multiple dimensions to behavioral and pharmacological ADHD treatments. Much less is known about the impact of depression on ADHD, and significant debate exists surrounding the identification and treatment of bipolar disorder in children with ADHD. Children with learning disabilities respond well to stimulants but often require additional educational supports. New findings suggest that treating ADHD may prevent the development of future psychiatric disorders. SUMMARY: The presence of comorbid illness is associated with significant additional morbidity and complicates the diagnosis, treatment, and prognosis of ADHD. Therefore, it is important to identify and treat any comorbid psychiatric conditions in a child with ADHD.     

Association of ADHD and conduct disorder--brain electrical evidence for the existence of a distinct subtype

BACKGROUND: To evaluate the impact of psychopathological comorbidity with oppositional defiant/conduct disorder (ODD/CD) on brain electrical correlates in children with attention deficit hyperactivity disorder (ADHD) and to study the pathophysiological background of comorbidity of ADHD+ODD/CD. METHOD: Event-related potentials (ERPs) were recorded during a cued continuous performance test (CPT-A-X) in children (aged 8 to 14 years) with ICD-10 diagnoses of either hyperkinetic disorder (HD; n = 15), hyperkinetic conduct disorder (HCD; n = 16), or ODD/CD (n = 15) and normal children (n = 18). HD/HCD diagnoses in all children were fully concordant with the DSM-IV diagnosis of ADHD-combined type. ERP-microstates, i.e., time segments with stable brain electrical map topography were identified by adaptive segmentation. Their characteristic parameters and behavioral measures were further analyzed. RESULTS: Children with HD but not comorbid children showed slower and more variable reaction times compared to control children. Children with HD and ODD/CD-only but not comorbid children displayed reduced P3a amplitudes to cues and certain distractors (distractor-X) linked to attentional orienting. Correspondingly, global field power of the cue-CNV microstate related to anticipation and preparation was reduced in HD but not in HCD. Topographical alterations of the HD occurred already in the cue-P2/N2 microstate. In sum, the comorbid group was less deviant than both the HD-group and the ODD/CD-group. CONCLUSIONS: The findings suggest that HD children (ADHD-combined type without ODD/CD) suffer from a more general deficit (e.g., suboptimal energetical state regulation) including deficits of attentional orienting and response preparation than just a responseinhibitory deficit, backing the hypothesis of an involvement of a dysregulation of the central noradrenergic networks. The results contradict the hypothesis that ADHD+ODD/CD represents an additive co-occurrence of ADHD and ODD/CD and strongly suggest that it represents a separate pathological entity as considered in the ICD-10 classification system, which differs from both HD and ODD/CD-only.