In this blog article I will underline the key pathophysiology surrounding attention deficit hyperactivity disorder: ADHD
Many of the brain pathophysiological defects of ADHD are linked with that of the prefrontal lobe, an area which plays a large role in cognition. Therefore, it is uncoincidental that the symptoms linked with the disorder include poor concentration, impulsivity and hyperactivity (R.A. Barkley 2003). With the use of functional neuroimaging techniques such as FMRI and PET scans, we are able to understand differences in the brain function and structure of ADHD patients, the most prominent of which is seen when using structural MRI. Scans have revealed specific areas in subjects with ADHD are smaller than an individual that does not had ADHD. These areas include the prefrontal lobe, caudate, cerebellum and cerebellar vermis (Zang Yu-Feng 2006). Using a regional homogeneity method to characterise the local synchronisation of spontaneous brain activity in individuals with methylphenidate and those with placebo. It was seen that in those with the placebo the regional homogeneity of activity was decreased in the bilateral dorsolateral prefrontal cortices. Contrastingly regional homogeneity increased in the bilateral sensorimotor and parieto-visual cortices. Furthermore in those with who taken the methylphenidate, the major effect was down regulation in the right parietal cortex. This down regulation was correlated with decreased symptom scores after 8 weeks of acute methylphenidate doses (Li An et al 2012).
Diffusion tensor imaging allows for the imaging of axonal connections between brain areas. The technique relies on the free movement of water molecules where there are no means of restriction. DTI allows for analysis of the white matter tracts of the brain, where it can map the orientation of the axon and the location. From this, we can image and see the specific connection between brain areas (Konrad and Eickhoff 2010). Decreased fractional anisotropy (FA) in the right supplementary motor area, right anterior limb of internal capsule, right cerebral peduncle, left middle-cerebellar peduncle, and left cerebellum can be seen in children with ADHD. These results were consistent with those seen with MRI. Fractional anisotropy is most simply the degree of which the water molecule is directionally dependent as a result of cell membranes and myelin sheath, to that which is free moving with Brownian motion. Finding of lower FA in children with ADHD specifically in these areas is intriguing, as the supplementary motor area has a role in planning, initiation, and execution of motor acts. Additionally, the right frontostriatal circuitry is thought to be important in the development of organisation and planning (Ashtari et al 2004), which could be linked to poor organisational skills displayed. Consequently, they were able to piece to together links between brain regions and behaviour.
In a study exploring the relationship of frontostriatal structure in ADHD children and behaviour, Casey et al (1997) adopted MRI and behavioural tests. A correlation was found between impulse control and volumetric measure of globus pallidus and basal ganglia. Maps of cortical thickness showed ADHD patients to have a thinner cortex in bilateral frontal regions and the right cingulate cortex, in contrast to those without the disorder. There is now substantial evidence amounting to the role of the cerebellar region in ADHD, as the fractional anisotropy of the area is significant in inattention subscale scores (Durston et al 2003).
Genetics accounts for 75% of ADHD cases, as shown by data gathered across four genome-wide association scans investigating the disorder’s heritability. Furthermore, this research placed emphasis on the rarer variants of genes associated with ADHD, such as those coding for DRD4 and DRD5 dopamine receptors (Neale et al 2010). Further genome-wide association scans show limited overlap apart with the CDH13. Typically, many of the genes involved are involved in dopaminergic signalling. These include DAT, DRD4, DRD5, TAAR1, MAOA, COMT, and DBH. A mutation in the DRD4–7 receptor results in a wide range of behavioural phenotypes, including ADHD symptoms such as split attention (Kebir et al 2009). Furthermore, polymorphisms of this gene show significance in attention sustained performance tasks (Kieling et al 2006) Given the evidence obtained as a result of the study and meta-analysis, is it clear that DRD4 mutations are influential in displaying ”ADHD-like” phenotypes. Other genes associated with ADHD include SERT, HTR1B, SNAP25, GRIN2A, ADRA2A, TPH2, and BDNF.
In conclusion, ADHD presents as difficulties in maintaining attention and concentration, but also can affect social aspects. Studies to find clear brain pathologies through imaging techniques have highlighted defects the prefrontal lobe and cerebellum and thus these regional defects are said to contribute to the symptomatic phenotype of the disorder. There is a clear involvement of biogenic amines, specifically dopamine, with current models showing emphasis on the mesocorticolimbic dopamine pathway and the locus coeruleus-noradrenergic systems. Furthermore, abnormalities may exist in other pathways such as glutamatergic, serotonergic or cholinergic neurotransmission. Genetic studies have shown the significance of specific gene variants in contributing to the disorder, specifically those linked to the G-protein coupled receptors DRD4 and DRD5. Genetic and phenotypic heterogeneity amongst individuals could explain differences between genetic studies. However, these differences may exist in different pathways but present the same phenotypic behavioural traits. Meta-analyses have produced a more reliable result than gene-wide association scanning alone, however, the association found only accounts for a small proportion of the genetics of ADHD. Approaches in neuroimaging genetics and epigenetic studies are being investigated to aid a clearer picture of the genetic component of this disorder.
Author: Liam Read
Editor: Molly Campbell
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