Rodent models of attention-deficit/hyperactivity disorder.

An ideal animal model should be similar to the disorder it models in terms of etiology, biochemistry, symptomatology, and treatment. Animal models provide several advantages over clinical research: simpler nervous systems, easily interpreted behaviors, genetic homogeneity, easily controlled environment, and a greater variety of interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of childhood onset that is characterized by inattentiveness, hyperactivity, and impulsiveness. Its diagnosis is behaviorally based; therefore, the validation of an ADHD model must be based in behavior. An ADHD model must mimic the fundamental behavioral characteristics of ADHD (face validity), conform to a theoretical rationale for ADHD (construct validity), and predict aspects of ADHD behavior, genetics, and neurobiology previously uncharted in clinical settings (predictive validity). Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD. Poor performers in the five-choice serial reaction time task and Naples high-excitability rats (NHE) are useful models for attention-deficit disorder. Other animal models either focus on the less important symptom of hyperactivity and might be of limited value in ADHD research or are produced in ways that would not lead to a clinical diagnosis of ADHD in humans, even if ADHD-like behavior is displayed.     

Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review.

One of the most prominent neuropsychologic theories of attention-deficit/hyperactivity disorder (ADHD) suggests that its symptoms arise from a primary deficit in executive functions (EF), defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal. To examine the validity of the EF theory, we conducted a meta-analysis of 83 studies that administered EF measures to groups with ADHD (total N = 3734) and without ADHD (N = 2969). Groups with ADHD exhibited significant impairment on all EF tasks. Effect sizes for all measures fell in the medium range (.46-.69), but the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. Weaknesses in EF were significant in both clinic-referred and community samples and were not explained by group differences in intelligence, academic achievement, or symptoms of other disorders. ADHD is associated with significant weaknesses in several key EF domains. However, moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD. Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD.     

A developmental perspective on the measurement of cognitive deficits in attention-deficit/hyperactivity disorder.

Research on the cognitive deficits associated with attention-deficit/hyperactivity disorder has highlighted deficits in executive function in individuals with the disorder. This article suggests deconstructing the umbrella term "executive function" and focuses on one of its component processes: cognitive inhibition. Cognitive developmental psychology research suggests that component processes, such as cognitive inhibition, should be examined from a variety of approaches to fully appreciate patterns of competency and deficit. This article contrasts cognitive inhibition from behavioral inhibition and resistance to interference. Two types of cognitive inhibition, automatic and intentional, are proposed. Finally, suggestions for guiding research design are taken from the cognitive developmental psychology literature. These include studying very limited age ranges and conducting longitudinal research, investigating qualitative and quantitative differences in performance, examining the underlying processing and strategy differences between populations, and investigating multiple aspects of performance between populations.     

Attention-deficit/hyperactivity disorder: a selective overview.

Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial and clinically heterogeneous disorder that is associated with tremendous financial burden, stress to families, and adverse academic and vocational outcomes. Attention-deficit/hyperactivity disorder is highly prevalent in children worldwide, and the prevalence of this disorder in adults is increasingly recognized. Studies of adults with a diagnosis of childhood-onset ADHD indicate that clinical correlates--demographic, psychosocial, psychiatric, and cognitive features--mirror findings among children with ADHD. Predictors of persistence of ADHD include family history of the disorder, psychiatric comorbidity, and psychosocial adversity. Family studies of ADHD have consistently supported its strong familial nature. Psychiatric disorders comorbid with childhood ADHD include oppositional defiant and conduct disorders, whereas mood and anxiety disorders are comorbid with ADHD in both children and adults. Pregnancy and delivery complications, maternal smoking during pregnancy, and adverse family environment variables are considered important risk factors for ADHD. The etiology of ADHD has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging studies suggest that dysfunction in the fronto-subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic systems, contribute to the pathophysiology of ADHD. Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.     

Structural brain imaging of attention-deficit/hyperactivity disorder.

Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study (Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.     

Inhibitory deficits in ocular motor behavior in adults with attention-deficit/hyperactivity disorder.

BACKGROUNDS: Many of the symptoms of attention-deficit/hyperactivity disorder (ADHD) have been attributed to deficits in behavioral inhibition mediated by the frontostriatal system. The ability to suppress unwanted saccadic eye movements is mediated by prefrontal cortex-basal ganglia circuitry and thus constitutes a useful measure of inhibitory ability. METHODS: To evaluate the functional integrity of this circuitry in ADHD, adult ADHD subjects unmedicated for at least 48 hours and normal comparison adults were studied by means of a comprehensive battery of ocular motor paradigms. RESULTS: On a prosaccade task, in which subjects were required to generate saccades toward a peripheral visual target after a short stimulus-free interval, ADHD subjects generated significantly more of anticipatory (premature) saccades (reaction time <90 msec) and of saccades toward the target on catch trials, in which they were supposed to inhibit eye movements. On the antisaccade task, in which they were required to inhibit gazing toward the target while moving their eyes in the opposite direction, ADHD subjects made significantly more directional errors than normal adults. The performance of ADHD adults was consistent with deficits in saccadic inhibition. CONCLUSIONS: Given the recent evidence for the interdependence between the brain systems mediating visual attention and ocular motor behavior, these findings support the notion that deficits in inhibitory mechanisms might underlie the inattention characteristic of ADHD. These results also implicate abnormalities in prefrontal cortex-basal ganglia circuitry in ADHD.     

Focal EEG abnormalities might reflect neuropathological characteristics of pervasive developmental disorder and attention-deficit/hyperactivity disorder

Neurophysiological characteristics in electroencephalograms (EEG) were investigated for patients with pervasive developmental disorder (PDD) and for patients with attention-deficit/hyperactivity disorder (AD/HD). This study examined 64 PDD children and 22 AD/HD children with no history of epilepsy or progressive neurological or psychiatric disorder. We used multivariate analysis to compare EEG abnormalities, clinical symptoms, and intelligence levels between PDD and AD/AD patient groups. Paroxysmal discharges at the frontopolar-frontal (Fp-F) brain regions and background EEG abnormalities tended to be detected preferentially in the PDD group, although paroxysmal discharges at central-temporal (C-T) regions tended to be detected preferentially in the AD/HD group. The paroxysmal discharges observed in patients expressing persistence and impulsivity are apparently localized respectively in the Fp-F and C-T regions. A combination of EEG abnormalities, including background EEG abnormalities and paroxysmal discharges at Fp-F and C-T regions, might be useful diagnostic hallmarks to distinguish PDD with AD/HD from AD/HD alone using a logistic regression model. The dysfunction of specific brain areas associated with EEG abnormalities might explain characteristics of clinical symptoms observed in PDD and AD/HD patients.     

Treating children with attention-deficit/hyperactivity disorder and comorbid epilepsy

Attention-deficit/hyperactivity disorder (ADHD) is one of common neurodevelopmental disorder often comorbid with epilepsy. There are no existing guidelines on how to manage these two conditions when they are comorbid. To identify relationship between epilepsy and ADHD and to know role of antiepileptics and safety of stimulant like methylphenidate in such conditions from existing literature, we searched articles published in clinical journals available online between 1990-2010, with these key words in medline:children, epilepsy, seizure, comorbid, ADHD, treatment. Relevant abstracts were further selected for their focus on current topic. Cross references were extracted. Finally relevant articles that included original research articles, reviews and abstracts of non-english literature were used. Children with epilepsy may manifest with symptoms of ADHD. Children with ADHD may develop epilepsy. Some antiepileptics like phenobarbitone, gabapentin, topiramate may not be helpful in controlling behavioral symptoms of ADHD. Stimulants are the main stay of pharmacotherapy for ADHD but there is risk of decreasing seizure threshold in children with comorbid epilepsy especially when their epilepsy is not well controlled. Existing evidence is not in favor of screening children with ADHD for EEG abnormality before starting stimulant therapy.     

Diagnosis and treatment of attention-deficit/hyperactivity disorder

TOPIC: Diagnosis and treatment of attention deficit/hyperactivity disorder. PURPOSE: To describe a multidimensional approach to treatment of children with attention deficit/hyperactivity and their parents. SOURCES: Review of the literature and of the author's clinical work. CONCLUSIONS: A great deal of controversy surrounds this diagnosis. The nurse psychotherapist helps children and families through the diagnostic process and into the treatment phase. Emphasis is on psychotherapy of the child and family, parent education, and attention to the child's school environment and social adjustment.     

A novel unstructured performance-based task of executive function in children with attention-deficit/hyperactivity disorder

Objective: Executive functions (EFs) have been assessed with performance-based measures and rating scales. Research has shown a lack of association between these two methods. One factor that might contribute to this difference is the structure provided on performance-based measures that is not provided on rating scales. This study examined the role of structure on self-directed task completion, an aspect of EF, using a novel unstructured performance-based task (UPT).

Method: Children aged 8–12 years (38 attention-deficit/hyperactivity disorder, ADHD; 42 typically developing) and their caregivers participated. We compared performance on the UPT, performance-based measures of EF (Stroop test and Trail-Making Test), and a rating scale to assess EF (Barkley Deficits in Executive Functioning Scale–Children and Adolescents, BDEFS–CA).

Results: Group differences were found across all measures. Significant associations emerged between the UPT and Stroop test, Trail-Making Test, and BDEFS–CA, but no significant associations were found between the Stroop test or Trail-Making Test and the BDEFS–CA. In regression analyses, performance-based tasks and the rating scale both uniquely predicted UPT performance. The UPT was a significant predictor of group status when entered with performance-based tasks, but the UPT did not enter as a significant predictor when entered with the rating scale.

Conclusion: The UPT is a promising measure to assess self-directed task completion in children with ADHD.     

Neurocognitive functioning in children with developmental dyslexia and attention-deficit/hyperactivity disorder: Multiple deficits and diagnostic accuracy

Introduction: This study aimed to investigate the neurocognitive functioning of children with developmental dyslexia (DD) and attention-deficit/hyperactivity disorder (ADHD). Method: Four groups of children between the ages of 8 and 10 years participated in the study: typically developing children (TDC; N = 34), children with DD-only (N = 32), children with ADHD-only (N = 32), and children with DD+ADHD (N = 18). Results: Children with DD and ADHD exhibited significant weaknesses on almost all neurocognitive measures compared with TDC. Large effect sizes were observed for naming speed and phonological awareness. The comorbid group showed deficits consistent with both DD and ADHD without additional impairments. Results from binary logistic regression and receiver-operating characteristic (ROC) curve analyses suggested that some neurocognitive measures revealed an adequate sensitivity for the clinical diagnosis of both neurodevelopmental disorders. Specifically, naming speed and phonological awareness were the strongest predictors to correctly discriminate both disorders. Conclusions: Taken together, the results lend support to the multiple cognitive deficit hypothesis showing a considerable overlap of neurocognitive deficits between both disorders.     

Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder.

BACKGROUND: The frontal-striatal pathway has been previously implicated in the neuropathology of attention-deficit/hyperactivity disorder (ADHD). Hence, we used proton magnetic resonance spectroscopy (1H-MRS) to examine metabolite levels in the prefrontal cortex of children with ADHD. METHODS: Nine age- and gender-matched case-control pairs were examined, ages 7 to 16 years. A long-echo 1H-MRS scan was acquired from the right prefrontal cortex and left striatum in all subjects. Compounds that can be visualized with 1H-MRS include N-acetyl-aspartate (NAA), glutamate/glutamine/gamma-aminobutyric acid (Glx), creatine/phosphocreatine (Cr), and choline compounds (Cho). RESULTS: Frontal-striatal glutamatergic resonances were elevated in the children with ADHD as compared to healthy control subjects. No differences were noted in NAA, Cho, or Cr metabolite ratios. CONCLUSIONS: These findings suggest that frontal-striatal Glx resonances may be increased in children with ADHD in comparison with healthy control subjects.     

Inhibitory deficits in attention-deficit/hyperactivity disorder are independent of basic processing efficiency and IQ

Summary Background. A substantial proportion of children with attention-deficit/hyperactivity disorder (ADHD) show deficits on inhibitory control tests. However, questions remain about (i) the extent of these deficits across different inhibitory domains, (ii) their relationship to deficits in non-executive processes and (iii) whether they extend into adolescence. Methods. Seventy-seven children and adolescents with ADHD and 50 non-ADHD controls completed three inhibitory tasks, a simple two choice RT task (2CR) and an IQ assessment. Results. ADHD was moderately associated with deficits on all tasks (effect sizes d=0.5–0.9). Deficits were equally marked in childhood and adolescence. Inhibitory deficits were not associated with IQ and, although reduced substantially, remained significant after performance on a simple reaction time task was controlled for statistically. Discussion. In highlighting the significant, but limited, role of inhibitory deficits in ADHD, these results are consistent with recent accounts that emphasize the neuropsychological heterogeneity of this condition. Correspondence: Edmund J. S. Sonuga-Barke, Institute for Disorder on Impulse and Attention, School of Psychology, University of Southampton, Highfield, Southampton SO17 1BJ, UK     

Effects of a working memory training program in preschoolers with symptoms of attention-deficit/hyperactivity disorder

Introduction: Preschoolers with attention-deficit/hyperactivity disorder (ADHD) have been found to exhibit impairments on neuropsychological measures of working memory (WM). As WM is an important predictor of future learning abilities, early intervention could help to prevent severe problems. The purpose of this research was to ascertain the efficacy of an intervention for training WM in 5-year-old children with symptoms of ADHD. Method: Thirty-four children with symptoms of ADHD were randomly divided into two groups: One was assigned to the WM training condition, and the other continued normal class activities. The training was provided at school in small groups that also included typically developing children. Results: The trained group showed a significant improvement in tasks measuring their WM and other controlled processes at conclusion of study, whereas no significant improvement was found in the control group. Conclusions: We concluded that early intervention on WM may be effective in children with symptoms of ADHD.     

Shifting-related brain magnetic activity in attention-deficit/hyperactivity disorder.

BACKGROUND: Current theories suggest a role for frontal-striatal circuits in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). METHODS: We used magnetoencephalography (MEG) to measure event-related brain activity during a simplified version of the Wisconsin Card Sorting Test in children with DSM-IV combined type ADHD (ADHD-C) or predominantly inattentive type ADHD (ADHD-PI) and in age- and intelligence-matched control children. RESULTS: In control children, set-shifting cues evoked a higher degree of activation in the medial temporal lobe (MTL) between 200 and 300 msec than non-shifting cues, with MTL activation predicting later activity in left anterior cingulate cortex (ACC) (at 400-500 msec). This MTL-ACC response pattern was diminished in children with ADHD. By contrast, children with ADHD showed early activity in regions barely activated in control children, such as left inferior parietal lobe and posterior superior temporal gyrus. CONCLUSIONS: These preliminary data support theories of frontal dysfunction in ADHD but also suggest that deficits in higher-level functions might be secondary to disruptions in earlier limbic processes.     

Antecedents of opioid dependence and personality disorder: attention-deficit/hyperactivity disorder and conduct disorder

Both attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) were explored as possible antecedents of opioid dependence and personality disorder. One hundred adult opioid-dependent, treatment-seeking male inpatients were explored; an extended clinical semistructured interview to collect sociodemographic, drug use related, and clinical data and the Structural Clinical Interview for DSM-IV personality disorders SCID-II were carried out. Four groups of patients, namely ADHD alone (4 patients). ADHD + CD (7 patients), CD alone (47 patients) and no ADHD/no CD (42 patients) were identified and compared with each other. The results indicate that ADHD alone does not predispose to the development of opioid dependence in male inpatients. Childhood ADHD may nevertheless be found more frequently in male opioid addicts due to its comorbidity with CD, which was identified in more than half of our sample. Patients with ADHD history seemed to go through the drug abuse career earlier and to develop more frequently histrionic and obsessive-compulsive personality disorder. Over half of the CD patients developed borderline and/or antisocial personality disorder; both ADHD and CD predispose significantly to the PD development. Early substance use preventive measures are necessary in children and adolescents suffering from CD and from ADHD comorbid with CD. Received: 27 September 2000 / Accepted: 30 January 2001     

Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication.

BACKGROUND: Despite growing interest in adult attention-deficit/hyperactivity disorder (ADHD), little is known about predictors of persistence of childhood cases into adulthood. METHODS: A retrospective assessment of childhood ADHD, childhood risk factors, and a screen for adult ADHD were included in a sample of 3197 18-44 year old respondents in the National Comorbidity Survey Replication (NCS-R). Blinded adult ADHD clinical reappraisal interviews were administered to a sub-sample of respondents. Multiple imputation (MI) was used to estimate adult persistence of childhood ADHD. Logistic regression was used to study retrospectively reported childhood predictors of persistence. Potential predictors included socio-demographics, childhood ADHD severity, childhood adversity, traumatic life experiences, and comorbid DSM-IV child-adolescent disorders (anxiety, mood, impulse-control, and substance disorders). RESULTS: Blinded clinical interviews classified 36.3% of respondents with retrospectively assessed childhood ADHD as meeting DSM-IV criteria for current ADHD. Childhood ADHD severity and childhood treatment significantly predicted persistence. Controlling for severity and excluding treatment, none of the other variables significantly predicted persistence even though they were significantly associated with childhood ADHD. CONCLUSIONS: No modifiable risk factors were found for adult persistence of ADHD. Further research, ideally based on prospective general population samples, is needed to search for modifiable determinants of adult persistence of ADHD.     

Neuropsychological assessment of attention in adults with different subtypes of attention-deficit/hyperactivity disorder

Summary There is only little information about varying attention functions of adults with different DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD). In the present study groups of adult patients with ADHD – predominantly inattentive type, ADHD – predominantly hyperactive-impulsive type or ADHD – combined type and three healthy control groups were compared regarding multiple components of attention. Assessment of attention was performed using a computerized neuropsychological test battery for attentional functions. In comparison with healthy subjects, the three patient groups displayed impairments of vigilance, selective attention, divided attention, and flexibility. These impairments of attention of ADHD subgroups were primarily observed with regard to reaction time. With regard to tonic and phasic alertness no differences between patient and control groups could be found. Comparison between ADHD subgroups revealed that DSM-IV subtypes of ADHD differ in measures of divided attention, selective attention and flexibility. Differences between ADHD subgroups were primarily observed with regard to task accuracy. The results suggest that while distinct profiles of attentional functioning were observed between adult patients with ADHD and healthy adults indicating gross disturbances of various attention functions in patients with ADHD, differences between ADHD subgroups were only weak. Correspondence: Oliver Tucha, School of Psychology, University of Plymouth, Drake Circus, Plymouth, Devon PL4 8AA, UK     

The potential role of clock genes in children attention-deficit/hyperactivity disorder

BackgroundAttention deficit/ hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder and is thought to be associated with circadian system.MethodsWe performed a pathway-based study to test individual single nucleotide polymorphisms (SNPs) and the overall evidence of genetic polymorphisms involved in the circadian pathway in association with children ADHD susceptibility among a Chinese population. A community-based case–control study was conducted among Chinese children, and 168 ADHD patients and 233 controls were recruited using a combination diagnosis based on the diagnostic and statistical manual of mental disorders iv (DSM-IV) ADHD rating scale, Swanson, Nolan, and Pelham rating scale (SNAP-IV) rating scale, and semi-structured clinical interview.ResultsThe results of single-loci analyses identified that PER1 rs2518023 and ARNTL2 rs2306074 were nominally association with ADHD susceptibility (P < 0.05). Next, we applied multifactor dimensionality reduction (MDR), and classification and regression tree (CART) analyses to explore high-order gene–gene interactions among the functional SNPs to ADHD risks. The results indicated that interactions among the PER1 rs2518023, ARNTL2 rs2306074 and NR1D1 rs939347 were associated with the risk of ADHD in children. Individuals carrying the combination genotypes of the PER1 rs2518023 GG or GT, ARNTL2 rs2306074 TC or TT and NR1D1 rs939347 GA or AA displayed a significantly higher risk for ADHD than who carry the PER1 rs2518023 TT and CRY2 rs2292910 CA/CC genotypes (adjusted OR = 4.37, 95% CI = 2.16–8.85, P < 0.001).ConclusionsThese findings revealed the importance of genetic variations related to the circadian clock system to the susceptibility of children ADHD.