Biological Aspects and prognosis of ADHD in Children

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a strongly genetically determined (heritability ∼70–75%) neuropsychiatric disorder. In most cases ADHD is accompanied by one or more neuropsychological impairments, such as executive dysfunction and impairments in sensory, motor, and timing processes. Given that, in the vast majority of patients, multiple genes of small effect seem related to the disorder in addition to environmental influences, interest has grown in using neuropsychological measures as measures of ADHD pathology that may have a simpler genetic architecture than ADHD itself. Many recent studies have shown the utility of neuropsychological measures for ADHD genetic research. However, error- and/or task-specific variance underlying neuropsychological data may still seriously hamper genetic studies. It may be expected that combining data across tasks increases the heritability estimate of the underlying construct through a reduction in the error variance underlying the individual measures. This is only feasible when the tasks to be aggregated share considerable common variance both genetic and phenotypic, reflecting at least partially shared etiologies; the shared portion of which may provide a suitable target for molecular genetic analysis. Therefore, it is of interest to examine to what extent tasks tap onto the same underlying construct and if such a construct increases the power for detecting gene effects. A great deal of research has been carried out on the genetic factors that may play a role in attention deficit hyperactivity disorder (ADHD). Over 1,800 studies have been published on the subject to date. These studies, including family studies as well as those centered on specific genes or genome-wide screening, have produced strong evidence that genes play a role in susceptibility to ADHD. It was found that genetics account for 70 to 80 % of the risk; with a mean estimate of 76 %. Specific gene studies have produced good evidence linking certain genes to the disorder, particularly the dopamine D4 (DRD4) and dopamine D5 (DRD5) genes. However, it is difficult to implicate any specific gene in ADHD “beyond reasonable doubt,” due to the diversity and complexity of the condition.Gene studies, whether focusing on specific genes or scanning the whole genome, aim to link DNA variations with these observable symptoms. They also endeavor to locate the relevant chromosome regions. A recent analysis of genome-wide studies found only one confirmed location on one chromosome (chromosome 16) that has been repeatedly linked to ADHD. Study of rats, monkeys, and humans showed that when the effects of dopamine are blocked, motivation and pleasure are also blocked. Dopamine itself does not create the pleasure but establishes the conditions where sensations are recognized as pleasurable. Norepinephrine is the primary neurotransmitter produced in the reticular system and locus coeruleus. When the locus coeruleus fires, it distributes norepinephrine through its broad network of connections, alerting and increasing excitability in its many neural networks. Lack of such firing is associated with inattention, increased drowsiness, and sleep distinguish between the two neurotransmitters in this way: Abnormal dopamine levels play a role in attention and hyperactivity, whereas low levels of norepinephrine may contribute to inattention and the inability to control impulsive behavior. Research suggests that persons with ADHD manufacture dopamine and norepinephrine just like everyone else, but their brains do not release and reload these neurotransmitters. As a result many messages that need to get carried along are not transmitted effectively and efficiently. Serotonin-specific reuptake inhibitors (SSRI) lack efficacy in ADHD and have been linked to increased suicide risk. There is a study investigated drugs with affinity for one or more of the monoamine reuptake transporters using the 5-choice serial reaction time task, it also tested the effects of the alpha2-adreoceptor antagonist, idazoxan and novel antidepressant, agomelatine, which both increase cortical noradrenaline concentrations through non-reuptake mechanisms. Improvements in impulse control were observed with venlafaxine, a serotonin and noradrenaline re-uptake inhibitor (SNRI) but not bupropion (dopamine and noradrenaline re-uptake inhibitor). Sibutramine (SNRI) reduced premature responses by ~50% at the highest dose tested but this was not significant. All three of the SSRIs tested reduced premature responding in a dose-dependent manner, although also slowed response and collection latencies. None of the drugs tested improved attention in this task but sibutramine (SNRI), fluoxetine (SSRI) and paroxetine (SSRI) all increased omissions at the highest dose tested. These data suggest that the SNRIs and SSRIs reduce premature responding but tend to be less specific than noradrenaline specific reuptake inhibitors in this model. SSRIs did not induce any specific impairment in impulse control in this mode. Neuroimaging studies have provided evidence for a relation between variations in brain structures and neuropsychiatric disorders in children. In children with Attention Deficit/Hyperactivity Disorder (ADHD), various morphological changes have been reported in brain structures such as the thalamus, striatum, ventricular volumes, right prefrontal cortex, and the corpus callosum. Recently, longitudinal magnetic resonance imaging (MRI) studies showed that growth trajectories of anterior corpus callosum were different in adolescents with ADHD, indicating anomalies in developmental brain trajectories in these children. Few studies investigated the morphological variations in brain structures related to ADHD symptoms in normally developing children. The last two decades of structural and functional imaging studies have shown that ADHD is associated with deficits in the structure, functioning, and connectivity of frontostriatal, parietotemporal, and front cerebellar networks A recent meta-analysis of all structural voxel-based morphometry studies in ADHD, however, showed that the most consistent deficit is low gray matter volume in the basal ganglia. The close clinical relationships, shared genetic risk factors, coupled with other shared features, notably an early age of onset and male excess, provide a strong argument for considering ADHD as one of a group of neurodevelopmental disorders. However, ADHD also shows a high level of comorbidity with other psychiatric and behavioral disorders, notably conduct problems/antisocial behavior, alcohol and substance misuse and mood disorders, that is explained by shared heritability. Presentation of ADHD and associated impairments evolve across development, as do outcome predictors. In early development, in addition to genetics, some forms of prenatal adversity increase the risk for ADHD. In preschool years, symptom severity, cognitive function, and family factors become significant predictors of school age outcomes. These continue to predict long-term outcomes in school aged children, and comorbidity emerges as another significant long-term outcome predictor at this stage. Presentation of ADHD and risk factors for later adversity evolve across development, which calls for developmentally-informed clinical practices.