ADHD

ADHD

In this blog article I will underline the key pathophysiology surrounding attention deficit hyperactivity disorder: ADHD

Brain pathophysiology

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).

Structural connectivity

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

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.

Conclusion

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

AN, L., CAO, X.-H., CAO, Q.-J., SUN, L., YANG, L., ZOU, Q.-H., KATYA, R., ZANG, Y.-F. & WANG, Y.-F. 2013. Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder. Neuropsychopharmacology, 38, 1287-1295.

ASHTARI, M., KUMRA, S., BHASKAR, S. L., CLARKE, T., THADEN, E., CERVELLIONE, K. L., RHINEWINE, J., KANE, J. M., ADESMAN, A., MILANAIK, R., MAYTAL, J., DIAMOND, A., SZESZKO, P. & ARDEKANI, B. A. 2005. Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study. Biological Psychiatry, 57, 448-455.

BARKLEY, R. A. 2003. Issues in the diagnosis of attention-deficit/hyperactivity disorder in children. Brain and Development, 25, 77-83.

CASEY, B. J., CASTELLANOS, F. X., GIEDD, J. N., MARSH, W. L., HAMBURGER, S. D., SCHUBERT, A. B., VAUSS, Y. C., VAITUZIS, A. C., DICKSTEIN, D. P., SARFATTI, S. E. & RAPOPORT, J. L. 1997. Implication of Right Frontostriatal Circuitry in Response Inhibition and Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 374-383.

KEBIR, O., TABBANE, K., SENGUPTA, S. & JOOBER, R. 2009. Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies. J Psychiatry Neurosci, 34, 88-101.

KONRAD, K. & EICKHOFF, S. B. 2010. Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder. Human Brain Mapping, 31, 904-916.

NEALE, B. M., MEDLAND, S. E., RIPKE, S., ASHERSON, P., FRANKE, B., LESCH, K.-P., FARAONE, S. V., NGUYEN, T. T., SCHÄFER, H., HOLMANS, P., DALY, M., STEINHAUSEN, H.-C., FREITAG, C., REIF, A., RENNER, T. J., ROMANOS, M., ROMANOS, J., WALITZA, S., WARNKE, A., MEYER, J., PALMASON, H., BUITELAAR, J., VASQUEZ, A. A., LAMBREGTS-ROMMELSE, N., GILL, M., ANNEY, R. J. L., LANGELY, K., O’DONOVAN, M., WILLIAMS, N., OWEN, M., THAPAR, A., KENT, L., SERGEANT, J., ROEYERS, H., MICK, E., BIEDERMAN, J., DOYLE, A., SMALLEY, S., LOO, S., HAKONARSON, H., ELIA, J., TODOROV, A., MIRANDA, A., MULAS, F., EBSTEIN, R. P., ROTHENBERGER, A., BANASCHEWSKI, T., OADES, R. D., SONUGA-BARKE, E., MCGOUGH, J., NISENBAUM, L., MIDDLETON, F., HU, X. & NELSON, S. 2010. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 884-897.

YU-FENG, Z., YONG, H., CHAO-ZHE, Z., QING-JIU, C., MAN-QIU, S., MENG, L., LI-XIA, T., TIAN-ZI, J. & YU-FENG, W. 2007. Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain and Development, 29, 83-91.

Advertisements

Autism and Genius.

The Oxford Dictionary defines the term genius as “exceptional intellectual or creative power or other natural ability.” Reports of genius in history denotes people with a natural aptitude for a certain discipline, whether this is science, maths, arts or others. It suggests that this genius ability cannot be taught to others and is completely individual. It can therefore be considered to be at least partially down to the genetic makeup of the person.

There are many examples in history of extraordinary individuals reported to have outstanding creativity and intelligence displaying characteristics that we now associate with disorders such as autism. These include Einstein, Newton, Churchill, Socrates and Andy Warhol, all well known for their achievements. These figures were often deemed geniuses, and were credited with altering the field with which they worked in. However, in modern society, people with these traits are deemed as having a lower than average IQ and cognitive disabilities. This article is going to explore the presentation of high functioning autism and how it may play in role in this reported extraordinary natural talent.

Autism is a spectrum disorder present from birth and is more common in males. It involves social and communication problems; this can involve issues understanding other people’s emotions, not being able to verbalise and also uncontrolled rage. When highly emotional they can present with rhythmic repetitive motions and also throw tantrums (NHS, 2016). High-Functioning Autism or Asperger’s syndrome also have features that show enhanced ingenuity. Sufferers can have intense levels of focus, energy and persistence (Fitzgerald, 2004). They often are highly inquisitive and try to understand the world around them for themselves, not taking anything they are told for granted. This can be what give a child-like personality with an inability to socially interact.

The causes of autism is currently unknown, however there is increasing evidence that there is a strong genetic component. No specific mutations have yet been identified to be responsible for autism and as it is a spectrum disorder it is likely that the genetic cause will be epigenetic with complex environmental interactions. Genes important in the glutamatergic systems in the brain have been implemented. Functional MRIs, EEG and other imaging techniques have shown extensive evidence that autism has atypical connectivity, neuronal organisation and electrophysiology (Freitag and Kondrad, 2014). There is call in current research to combine functional and 3D imaging with genetic studies to find the causes and pathology for autism to better understand and treat the condition. Treatment currently is limited to physical and speech therapy to help autistic patients cope and also improve communication.

In wider society, people with Autism or Asperger’s syndrome are often seen as having severe learning difficulties with a low IQ. However my experience with children suffering from these disorders couldn’t be further from that. While they may struggle to act in what is deemed a ‘normal social manner’ once you have successfully engaged them, their brilliance shines. Often they have a high level of skill in mathematical calculations with an aptitude for dates, mental arithmetic and also ordering (Fitzgerald, 2004). For example, one child would thrive and come to life if you gave him the task of ordering the day and planning, ensuring everything could be done in the time limit given. Another example: you could ask any mental arithmetic problem and he would have the answer within seconds. Once you have experienced this you cannot question whether this is genius. They can perform tasks like these to a higher level than any “normal” individual.

Einstein, whilst incredibly intelligent, was reported to have struggled at school specifically with language. He also failed to acquire a job out of school reportedly due to a lack of social skills. There were also reports that his marriage was troubled and he wouldn’t allow his children to touch him. These are characteristics indicative of autism, and while it is not proven he suffered it, research suggests that he at least had autistic tendencies. Newton suffered similar traits, with periods of such intense focus that he would forget to eat. He also struggled to keep friends and is thought to be on the autism spectrum. It is now widely acknowledged that Newton suffered from classic autism (New Scientist, 2003). Darwin was well known for not liking face to face interaction, and preferred to communicate through letters than speaking. In childhood he was reported to live in solitude, avoiding social contact with anyone. These are not the only cases of autism that appear in history, with Winston Churchill and Andy Warhol being well known autistic sufferers. It is now also common for it to be said that most people are on the spectrum for autism.

From the cases presented above I believe that studying the causes of autism further not only can have clinical relevance, but also unlock information about how we perform cognitive tasks, and what gives high functioning autistic people the ability to be geniuses. It may be the increased focus that autistic suffers tend to present with which causes this aptitude for certain disciplines, but the cause of such are fascinating. If we could understand which systems are enhanced in high functioning autism, we could unlock the secret to intelligence and how and why we socially interact to a superior level to other species.

Author: Rosemary Porter
Editor: Molly Campbell

 

FITZGERALD, M. (2004) Creativity and Autism: Is there a link between autism in males and exceptional ability? Brunner-Routledge, Sussex.

NHS (2016) Autism Spectrum Disorder. Accessed: 04/04/2016 Retrieved from: http://www.nhs.uk/Conditions/Autistic-spectrum-disorder/Pages/Introduction.aspx

HAZEL MUIR (2003) Einstein and Newton showed signs of Autism. New Scientist. Accessed: 04/04/2016. Retrieved from: https://www.newscientist.com/article/dn3676-einstein-and-newton-showed-signs-of-autism

FREITAG, C.M. KONRAD, K (2014) Autism Spectrum Disorder: underlying neurobiology. Journal of Neural Transmission. 121(9) Pgs 1077-1079