Pathology Of Attention Deficit Hyperactivity Disorder Research Articles

Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35

Attention-deficit/hyperactivity disorder (ADHD) may result from delayed establishment of corticolimbic circuitry or perturbed dopamine (DA) neurotransmission. Despite the widespread use of stimulants to treat ADHD, little is known regarding their long-term effects on neurotransmitter levels and metabolism. Cyclin-dependent kinase 5 (Cdk5) regulates DA signaling through control of synthesis, postsynaptic responses, and vesicle release. Mice lacking the Cdk5-activating cofactor p35 are deficient in cortical lamination, suggesting altered motor/reward circuitry. We employed mice lacking p35 to study the effect of altered circuitry in vivo. Positron emission tomography measured glucose metabolism in the cerebral cortex using 2-deoxy-2-[¹⁸F] fluoro-d-glucose as the radiotracer. Retrograde dye tracing and tyrosine hydroxylase immunostains assessed the effect of p35 knockout on the medial prefrontal cortex (PFC), especially in relation to mesolimbic circuit formation. We defined the influence of Cdk5/p35 activity on catecholaminergic neurotransmission and motor activity via examination of locomotor responses to psychostimulants, monoamine neurotransmitter levels, and DA signal transduction. Here, we report that mice deficient in p35 display increased glucose uptake in the cerebral cortex, basal hyperactivity, and paradoxical decreased locomotion in response to chronic injection of cocaine or methylphenidate. Knockout mice also exhibited an increased susceptibility to changes in PFC neurotransmitter content after chronic methylphenidate exposure and altered basal DAergic activity in acute striatal and PFC slices. Our findings suggest that dysregulation of Cdk5/p35 activity during development may contribute to ADHD pathology, as indicated by the behavioral phenotype, improperly established mesolimbic circuitry, and aberrations in striatal and PFC catecholaminergic signaling in p35 knockout mice.

Drug policy and treatment bias due to the dopamine-deficit theory of child attention-deficit hyperactivity disorder

Abnormal dopamine (DA) transporter functioning has long been suspected to be involved in attention-deficit hyperactivity disorder (ADHD). My extensive search on theories concerning ADHD included: CENTRAL, MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Complementary and Alternative Medicine-specific databases, Informit, JST, plus grey literature and trial registries from inception to May 2010. A new understanding of ADHD pathophysiology is required. DA-deficit theory of ADHD is insufficient to cover critical aspects of ADHD pathology and medication. The dominance of this theory discourages the human and financial investments needed to explore alternative theories and has caused an evident bias in health and drug policies. A combined theory of altered DA and serotonin (5HT), deficit DA, and weakened prefrontal cortex (PFC) circuits may serve as a good alternate to DA-theory alone. This combined theory may influence the future of drug polices, pharmaceutical investments, treatment options, and drug developments.

Recent findings on the psychiatric and behavioral effects of video games on children with ADHD

Introduction The relationship between symptoms of attentiondefi cit/ hyperactivity disorder (ADHD) and the playing of video games is not well understood. The American Medical Association and American Academy of Child and Adolescent Psychiatry have refl ected this ambi valence in recommendations and press releases [1,2]. Because video games are among the most popular pastimes of children and teenagers and ADHD is one of the most common childhood psychiatric diagnoses, pediatricians, family practice physicians, and child psychiatrists commonly encounter children with ADHD who play video games regularly. How are we to advise them and their families? Research historically has focused on the negative consequences of playing video games; however, recent studies are illuminating the possible benefi ts. It was argued in one publication that children with ADHD may be using video games as a form of self-medication [3]. Video games may boost self-esteem in a population of children who derive little of it from their schoolwork or family life [4]. Additional research has shown that for boys with ADHD, interactive games can improve classroom learning and social relationships [5]. Evidence indicates that the presence of a computer in the home of a preschool child can improve school readiness and cognitive development regardless of the frequency of access to or ownership of child electronic games or video games in the household, the socioeconomic status of the family, or the developmental stage of the child [6]. Lastly, some evidence suggests that action video games may briefl y improve certain cognitive functions [7]. The issue of the relationship between aggression and video game play is important but complicated by various studies suggesting that exposure to video game violence can increase, reduce, or have no infl uence on aggressive behavior. This relationship was examined in 13 studies published between 1984 and 1996. These different studies showed that playing video games can result in increased aggression, no aggression, or an increased calming effect [8]. A more recent review of the literature found an association between violent video games and short-term aggressive behavior; however, due to study limitations, the authors found it diffi cult to establish a causal effect between playing video games and long-term aggressive behaviors [9]. Some correlation seems to exist between the neurotransmission characteristics of people who play video games and people with ADHD, but this correlation also remains unclear. The dopamine hypothesis of ADHD implicates variants in dopamine receptor subtypes and dopamine transmission in the pathology of ADHD. Decreased dopamine release in the corticostriatal pathway has been observed in individuals with ADHD [10,11]. Some evidence indicates that video game play is associated with dopamine release and low-function D2-receptor polymorphism [12,13]. I believe that at the current state of research, it is premature to advise families to eliminate video games from the lives of children with ADHD, at least until the negative and potentially benefi cial effects of playing video games (colloquially known as gaming) are better characterized. The following is a summary of recent research fi ndings on the psychiatric and behavioral effects of video games on children with ADHD. I hope that this summary better prepares clinicians when they discuss video games with families. This commentary does not address ergonomic or physical problems associated with video games, a topic that has been reviewed elsewhere [14].

Application of the Dual-Component Model of Working Memory to ADHD

Attention deficit/hyperactivity disorder (ADHD) has been associated with a deficit in working memory across both verbal and spatial domains, but the precise nature of this deficit is poorly understood. The dual-component model postulates that working memory capacity consists of two dissociable components: maintenance in primary memory (PM) and recall from secondary memory (SM). Participants diagnosed with ADHD (n = 32) and age-matched controls (n = 31) performed both verbal and spatial free-recall tasks, and subsets of these two samples were selected for further comparison based on their use of a “recency” order-of-report strategy. The primary results showed that maintenance in PM appears to be largely intact whereas recall from SM appears to be deficient in ADHD relative to age-matched controls. Similar outcomes were observed across both task domains. Implications for understanding both the underlying pathology and treatment of ADHD are discussed.

Exploring the genetic link between RLS and ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 ( χ 2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A–A–A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.

Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention

Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1–9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA.

An Open Trial of Light Therapy in Adult Attention-Deficit/Hyperactivity Disorder

In adults with attention-deficit/ hyperactivity disorder (ADHD), a delayed sleep/ activity rhythm and/or seasonal mood symptoms may contribute significantly to core pathology and disability. This study examined whether a chronobiologically based treatment, i.e., morning bright light therapy (LT), might have utility as an adjunctive treatment for adult ADHD in the fall/ winter period. Twenty-nine adults with DSM-IV ADHD were administered a standard 3-week open trial of LT during the fall or winter months. Primary outcome measures included percentage reduction on the Brown Adult ADD Scale and the Conners' Adult ADHD Scale. Secondary measures were decrease in depression scores according to the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version; improvements on various neuropsychological tests; and shift toward an earlier circadian preference as measured by the Horne-Ostberg Morningness-Eveningness questionnaire. Regression analyses determined which variables at baseline best predicted improvement on a given outcome measure and which variables changed in parallel with one another. The study was conducted from November 2003 through February 2004. Morning bright light therapy was associated with a significant decrease in both subjective and objective measures of core ADHD pathology, improved mood symptoms, and a significant phase advance in circadian preference. Multiple regression showed that the shift toward an earlier circadian preference with LT was the strongest predictor of improvement on both subjective and objective ADHD measures. Neither baseline global seasonality scores nor baseline depression scores strongly predicted LT effects on most measures of ADHD. These findings suggest that during the fall/winter period, LT may be a useful adjunct in many adults with ADHD. Strikingly, the strongest correlate of improvement in core ADHD pathology was a phase advance in circadian preference rather than alleviation of comorbid seasonal affective disorder, suggesting important clinical benefits of LT beyond the treatment of seasonal affective disorder.