Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review

Attention deficit/hyperactivity disorder (ADHD) involves clinically heterogeneous problems including attention deficits, behavioural hyperactivity and impulsivity. Several animal models of ADHD have been proposed, ranging from models with neurotoxic lesions to genetically manipulated animals. An ADHD model is supposed to show phenomenological similarities with the disorder, i.e. it should mimic the three core symptoms (face validity). A model should also conform to an established or hypothesized pathophysiological basis of the disorder (construct validity). Finally, an animal model should be able to predict previously unknown aspects of the neurobiology of ADHD or to provide potential new treatments (predictive validity). The currently proposed models are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. This might reflect the heterogeneous nature of ADHD. Since the knowledge about the biology of ADHD from human studies is limited, one cannot at present decide which model best represents ADHD or certain ADHD subtypes. Animal models with good face and predictive validity may be useful for investigations of the underlying biological substrates of ADHD. At present, the models in use should be described as animal models of ADHD-like symptoms rather than models of ADHD.     

A psychophysiological marker of attention deficit/hyperactivity disorder (ADHD)--defining the EEG consistency index

This study continues our research to further validate the idea that ADHD (Attention Deficit/Hyperactivity Disorder) interferes with transition from one task to another and this interference can be quantified by a Consistency Index (CI) derived from a specific mathematical representation of EEG data. We reanalyze 32 previously reported data sets present new data for 35 boys and girls, ages 7-12, ADHD or control. Each data set contains EEG, recorded and digitized while participants perform consecutive 10-min tasks: video, reading, and math. For boys, the CI in ADHD was four times lower than in controls, p < .005, for girls this difference was two times, p < .05. ADHD/control classification based on the CI coincided with the DSM-IV criteria for 88% of the boys and for 67% of the girls. Post hoc analysis indicated that the classification utility of the CI diminished with age. A CI below 40% could be a discriminating, reliable, and reproducible marker of ADHD in young boys.     

Characteristics of attention in children with attention deficit hyperactivity disorder (an analytical review)

The information concerning specific features of different attention components (alertness, sustention and selectivity) in children with attention deficit hyperactivity disorder (ADHD) is analyzed and systematized. According to the data reviewed, behavioral and attention problems described as ADHD are not homogeneous. Literature analysis of attention characteristics in children with ADHD shows that different components can be disrupted if ADHD is diagnosed as inattentive or combined subtype, but the main deficit in this case is that of selective voluntary attention. In case of hyperactivity/impulsivity subtype of ADHD, attention is impaired mainly in its brain activation components.     

Training of attention functions in children with attention deficit hyperactivity disorder

Pharmacological treatment of children with ADHD has been shown to be successful; however, medication may not normalize attention functions. The present study was based on a neuropsychological model of attention and assessed the effect of an attention training program on attentional functioning of children with ADHD. Thirty-two children with ADHD and 16 healthy children participated in the study. Children with ADHD were randomly assigned to one of the two conditions, i.e., an attention training program which trained aspects of vigilance, selective attention and divided attention, or a visual perception training which trained perceptual skills, such as perception of figure and ground, form constancy and position in space. The training programs were applied in individual sessions, twice a week, for a period of four consecutive weeks. Healthy children did not receive any training. Alertness, vigilance, selective attention, divided attention, and flexibility were examined prior to and following the interventions. Children with ADHD were assessed and trained while on ADHD medications. Data analysis revealed that the attention training used in the present study led to significant improvements of various aspects of attention, including vigilance, divided attention, and flexibility, while the visual perception training had no specific effects. The findings indicate that attention training programs have the potential to facilitate attentional functioning in children with ADHD treated with ADHD drugs.     

Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths

Background

Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie?

Results

We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered.

Conclusion

The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.

     

Comorbidity and continuity of attention deficit hyperactivity disorder (ADHD) from childhood to adolescence in Turkey

The aim of this study was to examine clinical outcomes, psychiatric comorbidity and neuropsychological characteristics in Turkish adolescents with an attention deficit hyperactivity disorder (ADHD) diagnosis in childhood. A total of 45 children with ADHD diagnosis and 28 children with a psychiatric diagnosis other than ADHD in a 1-year cohort of 7–10-year-olds were reevaluated 6 years later using Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version and Wechsler Intelligence Scale for Children-Revised and Stroop Test TBAG version. This study shows that the clinical outcomes and the comorbidity patterns for ADHD from childhood to adolescence in Turkey are similar to reported rates in the Western countries. In the ADHD group, 75.6 % still has impairing ADHD symptoms and 46.6 % has comorbid psychiatric disorders. The main difference is anxiety disorders being the most common comorbid disorders (37.8 %) in Turkish ADHD youth. These findings stress the high comorbidity associated with ADHD and support the importance of assessment and treatment for ADHD and comorbidities during adolescence.     

Asymmetry of basal ganglia in children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatry disorder with several key symptoms, such as inattentiveness, impulsivity and hyperactivity. Neuropsychiatry studies have implicated the frontostriatal circuit in the pathological physiology of the disorder. Using magnetic resonance imaging (MRI), we examined the basal ganglia in 13 ADHD patients and eight unaffected comparison children. The volume of caudate, putamen and globus pallidus was measured. In the ADHD patients, we detected an increased left > right asymmetry of the basal ganglia. This reversal of asymmetry in the globus pallidus and caudate nucleus were statistically significant. These finding provide further evidence of morphological brain abnormalities in ADHD.     

Understanding deficient emotional self-regulation in adults with attention deficit hyperactivity disorder: a controlled study

While symptoms of deficient emotional self-regulation (DESR) such as low frustration tolerance, temper outbursts, emotional impulsivity, and mood lability are commonly associated with attention deficit hyperactivity disorder (ADHD), little is known about their nature. The main aim of this post hoc study was to examine the correlates of DESR in a large sample of adults with and without ADHD. Subjects were 206 adults with ADHD and 123 adults without ADHD from a family study of ADHD. Emotional impulsivity was operationalized using items from the Barkley Current Behavior Scale. Subjects were comprehensively assessed for psychiatric comorbidity using structured diagnostic interview methodology. We used the Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (QLES-Q-SF) and Social Adjustment Scale-Self-report (SAS-SR) to assess quality of life and psychosocial functioning. DESR was more common among ADHD compared with non-ADHD adults, and 55 % of adults with ADHD reported extreme DESR of greater severity than 95 % of control subjects. The association of ADHD and DESR was not entirely accounted for by either current or lifetime comorbid disorders. DESR was also associated with significant functional impairment as evaluated by the QLES-Q-SF and SAS-SR, and with reduced marital status, as well as higher risk for traffic accidents and arrests. DESR adversely impacts quality of life in adults with ADHD. More work is needed to further evaluate DESR in clinical and investigational studies of subjects with ADHD.     

Prepotent response inhibition and reaction times in children with attention deficit/hyperactivity disorder from a Caribbean community

Impairment in inhibitory control has been postulated as an underlying hallmark of attention deficit/hyperactivity disorder (ADHD), which can be utilized as a quantitative trait for genetic studies. Here, we evaluate whether inhibitory control, measured by simple automatized prepotent response (PR) inhibition variables, is a robust discriminant function for the diagnosis of ADHD in children and can be used as an endophenotype for future genetic studies. One hundred fifty-two school children (30.9% female, 67.8% with ADHD) were recruited. The ADHD checklist was used as the screening tool, whilst the DSM-IV Mini International Neuropsychiatry Interview, neurologic interview and neurologic examination, and the WISC III FSIQ test were administered as the gold standard procedure to assert ADHD diagnosis. A Go/No-Go task using a naturalistic and automatized visual signal was administered. A linear multifactor model (MANOVA) was fitted to compare groups including ADHD status, age, and gender as multiple independent factors. Linear discriminant analysis and the receiver operating characteristic curve were used to assess the predictive performance of PR inhibition variables for ADHD diagnosis. We found that four variables of prepotent response reaction time- and prepotent response inhibition established statistically significant differences between children with and without ADHD. Furthermore, these variables generated a strong discriminant function with a total classification capability of 73, 84% specificity, 68% sensitivity, and 90% positive predictive value for ADHD diagnosis, which support reaction times as a candidate endophenotype that could potentially be used in future ADHD genetic research.     

Verbal fluency in adults diagnosed with attention-deficit hyperactivity disorder (ADHD) in childhood

It has been increasingly believed that attention-deficit hyperactivity disorder (ADHD) is a disorder with lifelong course associated with cognitive difficulties including among others, language production, verbal learning, and verbal fluency. However, research is limited to children and adolescents, and very few researchers have examined the impact of ADHD in adulthood on the cognitive domain. The aim of the present study is to examine the performance of adults, diagnosed with ADHD in childhood, on semantic and phonemic verbal fluency tasks. It is hypothesized that adults with ADHD will perform worse on both tasks than matched controls. Sixty university students (30 diagnosed with ADHD in childhood and 30 matched controls) of mean age 20.5 participated in the study. They all completed two verbal fluency tasks. The ADHD group had statistically significant lower scores than the non-ADHD group on the phonemic, but not the semantic task. The study provides some evidence that ADHD in childhood has a negative impact on adults’ phonemic verbal fluency. This finding could be probably explained by the fact that phonemic fluency is considered more cognitively demanding and impacting more on the frontal lobe functions, known to be impaired in ADHD, than semantic fluency.     

Emotion recognition in children and adolescents with attention-deficit/hyperactivity disorder (ADHD)

Children with attention-deficit/hyperactivity disorder (ADHD) are impaired in social adaptation and display deficits in social competence. Deficient emotion recognition has been discussed to underlie these social problems. However, comorbid conduct problems have not been considered in the majority of studies conducted so far, and the influence of medication on emotion recognition has rarely been studied. Here, emotion recognition performance was assessed in children with ADHD without medication compared with children with ADHD under stimulant medication and a matched control group. In order to rule out confounding by externalizing symptoms, children with comorbid conduct problems were excluded. Video clips with neutral faces developing a basic emotion (happiness, sadness, disgust, fear and anger) were presented in order to assess emotion recognition. Results indicated between-group differences neither concerning the number of correctly identified emotions nor concerning reaction times and their standard deviations. Thus, we suggest that ADHD per se is not associated with deficits in emotion recognition.     

Anxiety and methylphenidate in attention deficit hyperactivity disorder: a double-blind placebo-drug trial

To examine the relationship between attention and anxiety and the response to methylphenidate in children with attention deficit hyperactivity disorder (ADHD), a total of 57 boys, between the ages of 7-12?years, were assessed for their attention and level of anxiety. Methylphenidate was administered for a week in a randomized double-blind drug/placebo-drug cross-over design. The levels of anxiety were evenly distributed between the inattentive and hyperactive/impulsive types. Anxiety was significantly correlated with the attention as reported by both teachers and parents. The response to methylphenidate was inversely correlated with the reported anxiety level only in boys with the hyperactive/impulsive and combined types. The higher the level of anxiety, the lower level of response to methylphenidate was observed. In the assessment and treatment of children with ADHD, the level of anxiety should be evaluated and taken into account while planning and monitoring treatment regiment.     

Cognitive effects of polyunsaturated fatty acids in children with attention deficit hyperactivity disorder symptoms: a randomised controlled trial

This study investigated effects of PUFA and micronutrient supplementation on cognition in children with ADHD symptoms. In a randomised controlled trial, 7-12-year-old children with symptoms 2 S.D. on Conners' ADHD Index were given PUFA, PUFA+multivitamins/minerals (MVM), or placebo for 15 weeks, and then all children were given PUFA+MVM for an additional 15 weeks. After 15 weeks there were improvements in a test of the ability to switch and control attention (Creature Counting) in the PUFA groups compared to placebo (N=129, p=0.002). This improvement was also observed in the placebo group after taking PUFA from weeks 16 to 30 (N=104). There were no significant improvements in other cognitive measures, or with additional micronutrient supplementation. However, improvements in cognitive performance mediated previous parent-reported improvements in inattention, hyperactivity and impulsivity [N. Sinn, J. Bryan, Effect of supplementation with polyunsaturated fatty acids and micronutrients on ADHD-related problems with attention and behaviour, J. Dev. Behav. Pediatr. 28 (2) (2007) 82-91], suggestive of a common neurological mechanism for these symptoms.     

The effect of polyphenolic extract from pine bark, Pycnogenol on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) belongs to the neurodevelopmental disorders characterized by impulsivity, distractibility and hyperactivity. In the pathogenesis of ADHD genetic and non-genetic factors play an important role. It is assumed that one of non-genetic factors should be oxidative stress. Pycnogenol, an extract from the pine bark, consists of bioflavonoids, catechins, procyanidins and phenolic acids. Pycnogenol acts as powerful antioxidant, chelating agent; it stimulates the activities of some enzymes, like SOD, eNOS, and exhibits other biological activities. AIM: The aim of this randomized, double-blind, placebo-controlled trial was to investigate the influence of administered Pycnogenol or placebo on the level of reduced (GSH) and oxidized (GSSG) glutathione in children suffering from ADHD and on total antioxidant status (TAS). This is the first investigation of the redox glutathione state in relation to ADHD. RESULTS: One month of Pycnogenol administration (1 mg/kg body weight/day) caused a significant decrease in GSSG and a highly significant increase in GSH levels as well as improvement of GSH/GSSG ratio in comparison to a group of patients taking a placebo. TAS in children with ADHD was decreased in comparison with reference values. Pycnogenol administration normalizes TAS of ADHD children.     

Early maladaptive schemas in adult patients with attention deficit hyperactivity disorder

The main purpose of this study was to examine whether adult patients with attention deficit hyperactivity disorder (ADHD) demonstrate sets of dysfunctional cognitive beliefs and behavioural tendencies according to Jeffrey Young’s schema-focused therapy model. Sets of dysfunctional beliefs (maladaptive schemas) were assessed with the Young Schema Questionnaire (YSQ-S2) in 78 adult ADHD patients and 80 control subjects. Patients with ADHD scored significantly higher than the control group on almost all maladaptive schemas. The ‘Failure’, ‘Defectiveness/Shame’, ‘Subjugation’ and ‘Emotional Deprivation’ schemas were most pronounced in adult ADHD patients, while only ‘Vulnerability to Harm or Illness’ did not differ between the two groups. The schemas which were most pronounced in adult patients with ADHD correspond well with their learning histories and core symptoms. By demonstrating the existence of early maladaptive schemas in adults suffering from ADHD, this study suggests that schema theory may usefully be applied to adult ADHD therapy.     

Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinary-specific biomarkers

Pervasive developmental disorder (PDD) and attention deficit hyperactivity disorder (ADHD) are likely to be associated with increased oxidative stress, particularly that of lipid peroxidation. We evaluated the oxidative stress status of pediatric PDD and ADHD patients using their urine samples. Urinary acrolein-lysine levels in 11 PDD and 10 ADHD children (205 ± 97 and 234 ± 75 nmol/mg Cr, respectively) appeared higher than those of the control subjects (155 ± 59 nmol/mg Cr). Measurement of urinary specific biomarkers is comfortable, non-invasive, and easy to perform in children. Our findings might provide a scientific guide for use in further clinical and biochemical studies of these disorders.