Review Article

Received: 19 April 2013, Accepted: 27 April 2013

ISSN: 2321-2969

Int. J. Pharm. Biosci. Technol.

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International Journal of Pharma Bioscience and Technology; Volume 1, Issue 1, May 2013, Pg 10-15

Journal home page: www.ijpbst.com

NEUROSCIENCE OF ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) - A REVIEW

Salahuddin Mohammed1*, Demissew Berihun Haile2
1* Associate Professor of Pharmacology, College of Health Sciences, Department of Pharmacy, Mizan Tepi university, Mizan Teferi, Ethiopia 2 Lecturer of Clinical Pharmacy, College of Health Sciences, Department of Pharmacy, Mizan Tepi University, Mizan Teferi, Ethiopia. Corresponding Author* E-mail address- salahuddin_pharma48@yahoo.com

ABSTRACT: Attention Deficit Hyperactivity disorder (ADHD) does not have a single underlying pathophysiology which seems it has a multifaceted etiology. There are various contributing factors for ADHD, environmental and genetic being few of them. This neurobiological disorder has been a result of continuous actions of the risk factors. Neuroimaging study has indicated that children suffering from ADHD had immature brains compared to other children. This has pointed towards the fact that the Cerebellum, Basal Ganglia and the Prefrontal cortex parts of the brain are predominantly affected. The pharmacological & neuroimaging studies implicated that the dysregulation of the neuronal pathways of the Neurotransmitters (Dopamine and Norepinephrine) being primarily responsible for ADHD. The principal treatment procedure involves Pharmacotherapy (Medication) and other effective Psychotherapy (Psychopharmacological methods) for ADHD. Presently immediate release Methylphenidate (Ritalin, Coencerta) has been clinically approved for the diagnosis of ADHD. The psychotherapy evolves self-consciousness of sensory and cognitive thinking strengths and blind spots deliver some respite and enhanced enactment. The pharmacotherapy should strategize complete treatment plan including behavioural and educational aspects. Key words: Attention Deficit Hyperactivity disorder (ADHD), Neuroscience, Methylphenidate (Ritalin), Neuroimaging, Striatum, White matter. INTRODUCTION ADHD is the most common neuropsychiatric disorder mostly affecting the children. The boys are 2-3 times more susceptible to girls. The symptoms begin as early as 3 years of age and would continue in teens and also often continue into adulthood. Most of them respond well to the Stimulants, Methylphenidate (Ritalin, Coencerta). ADHD is characterised by Inattention, Impulsivity and Hyperactivity behaviour. The affected lot shows quite bizarre behaviour. They behave in a fidgeting manner, less attentive towards studies, cant wait patiently, interrupt others, switch tasks rapidly and never complete their tasks. The diagnosis involves Pharmacotherapy and Practical neuroscience methods. Mohammed et al Clinical diagnosis and comorbidities The clinical management of ADHD may be different from person to person. This might be due to the difference in the symptoms associated with various types of ADHD. The age and the stage of development are the factors that may responsible for different clinical presentation for each ADHD patient [1]. The clinical manifestation requires transparent information regarding the type of ADHD with a proven track with respect to the social, occupational and academic functioning [2]. Thus ADHD has been classified into 3 types: 1. Inattentive type: Predominantly common in females. 2. Hyperactive-Impulsive ADHD: Most prominently affecting children and 3. Combined Pg. 10

Int. J. Pharm. Biosci. Technol. type: impairs the global functioning. The adolescents diagnosed with ADHD show poor social behaviour, low self-confidence and inclined to more smoking and drugs abuse in their life [3, 4]. Endophenotypes has been strategic biomarkers developed to find the distinct pathophysiological mechanisms and etiological paths in ADHD patients[5]. These endophenotypes may also be useful in the quantitative analysis with the help of distinct spectrum phenotypes[5]. The important symptoms such as cognitive defects and motor impairment can act as major endophenotypes[6]. Etiology The Etiology of ADHD is unclear, but the pathophysiology has been firmly recognised. Various neuroimaging and neuropharmacological studies have indicated that there have been functional and structural abnormalities in the brain areas involving Brain stem, Cerebellum, Prefrontal cortex and Basal Ganglia all of which are involved in various regulatory activities such as (attention, impulsive behaviour and motor activity). There has been evidence stating the dysregulation of the neuronal pathways of the neurotransmitters, dopamine and norepinephrine. The pharmacotherapy has been evolved on basis of amending the regulation of neuronal pathways of dopamine and norepinephrine by using stimulants (increase the release of dopamine & norepinephrine) and non-stimulants, Atomoxetine (blocks norepinephrine reuptake). The Genetic Basis of ADHD The genetic factor plays an important role. Genetic studies have shown substantial evidence associating the role of numerous genes (DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B) responsible for the etiology of ADHD [7]. There has been evidence regarding the environmental factors also quite responsible for ADHD. The example being premature babies are at a greater risk of developing ADHD than the normal ones. Those babies born between 8th and 9th month have 70% chances of getting ADHD and those babies born before 8th month of development period are more likely to suffer from ADHD than the normal ones. There has been evidence stating that premature new-borns are at higher risk of hypoxia in the mothers womb. The patients suffering from neurogenetic syndromes like Williams syndrome, Neurofibromatous I and Tumer syndrome have conventional ADHD symptoms. Though each disorder may be due to different genetic deformities, but these deformities in the genetic system may produce an effect in the underlying pathways which they connect pronounced ADHD symptoms [8]. The Environmental Basis of ADHD The environmental factors play an important role in the pathophysiology of ADHD. They are divided as prenatal, perinatal and postnatal environmental factors. There has been evidence that the regime followed by the mother during pregnancy would be liable for ADHD symptoms in the child. The example being prenatal exposure to alcohol would lead to brain abnormalities especially the cerebellum [9]. There has been evidence also that the children shows hyperactive, disruptive and impulsive behaviour when exposed prenatally to alcohol. They are at increased risks to get the neurogenetic syndromes [10, 11]. Maternal smoking during pregnancy may also produce hyperactive behaviour in children [12]. Perinatal factors have been concomitant with a higher risk of ADHD symptoms in lower weight children during birth and also impediments during birth and pregnancy for the mother, whose children have been diagnosed with ADHD [13]. The postnatal factors contribute to the deficiency of various essential nutrients required by the body. The deficiency of Iron has been one of the implicating factor for the development of ADHD [14]. There has been also evidence regarding the deficiency of fatty acids such as Omega-3 and Omega-6 primarily responsible for ADHD [15]. Gene-Environment Interactions DAT1 genotype has substantial role in the pathophysiology of ADHD. The men homozygous for DAT1 10-repeat allele had a higher hyperactivity and impulsivity behaviours compared to other males[16]. Also there has been significance of DRD4 & DAT1 gene primarily responsible with other substance exposure prenatally for development of ADHD in genetically vulnerable children [17]. Neuroimaging The neuroimaging studies has implicated the fact the frontal striatal network of the brain is primarily responsible for the pathophysiology of ADHD. The frontal striatal network comprises the Lateral prefrontal cortex region, Dorsal anterior cingulate cortex region, Caudate nucleus and the Putamen. There has been evidence stating decreased volumes in the cerebral cortex, Lateral prefrontal cortex region, Dorsal anterior cingulate cortex region, Corpus collasum and the Cerebellum regions of the brain in ADHD patients [18]. The study thus pointed the fact that the Cortex development is the prime caused for ADHD. In Pg. 11 resulting in

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Int. J. Pharm. Biosci. Technol. children the gray matter was seen after a delay of 3 years when compared to healthy individuals [18]. The delay was seen primarily in the prefrontal cortical region which is responsible for various cognitive functions relatively attentiveness and motor coordination [19, 20]. The other regions of the brain such as Basal Ganglia & Cerebellum also contribute towards lower cognitive output in ADHD patients [21]. Recent neuroimaging study pointed out that condensed volumes of white matter [21] have been implicating factor for the development of ADHD in the midsaggital corpus collasum [22] and cortex sections [21] of the brain. One recent contradictory statement has been evolved regarding the corpus collasum role in ADHD. Neuroimaging studies show that they have been variations in white matter in patients suffering from ADHD. A study was carried out with 15 young males having ADHD and found that there has been variation in the white matter underlying the following areas of the brain namely (Inferior parietal, occipito parietal, inferior frontal and inferior temporal cortex)[23]. The striatum and the cerebellum has been shown to be connected with the prefrontal and parieto-occipital areas of the brain in the Tractography investigational analysis. This points us to the fact that an alteration in the white matter volumes is responsible for ADHD development. The DTI (Diffusion Tensor Imaging) is a MRI scan that is responsible for the direction and integrity of neuronal network track in the brain of humans. There has been evidence showing progressive changes in ADHD patients in the cortical white matter paths in the prefrontal cortex and in paths surrounding Cerebellum and Basal ganglia apparently revealing to the decreased myelination of axons in the neuron. This alludes to the fact that these developmental changes cause decrease in the neuronal communication speed [24]. There has been evidence regarding the functional neuroimaging studies responsible for the developing treatment strategies in patients suffering from ADHD [14]. PET (Positron Emission Tomography) studies presented that Methyphenidate hydrochloride blocks the dopamine transporter thus increasing the concentration of dopamine in the synaptic cleft which would be supportive for treating ADHD symptoms. Treatment The treatment plan for ADHD has been defined in strategic manner. Initially we have to identify the set of outcomes for the treatment plan. Usually a complete treatment plan constitutes psychosocial, behavioural and educational advice and interventions. There has been two important Mohammed et al treatment plans for the treating ADHD patients, Psychotherapy & Pharmacotherapy. The psychotherapy and pharmacotherapy together has been shown to be beneficial for ADHD patients [25]. The study involved closely monitored medication, psychotherapy, combination of medication and psychotherapy and treatment by community care service have shown significant progress in the behaviour of ADHD patients [26]. The striatal network in the brain is rich in catecholamines involved in the mode of action of drugs are used to treat ADHD patients. There have been neuropharmacological evidence stating the dysregulation of dopamine and Norepinephrine being primarily responsible for ADHD [27]. The main aspect of pharmacotherapy is to regulate the levels of dopamine and norepinephrine in the brain for appropriate neuronal communication. Methylphenidate is a CNS stimulant drug used in ADHD patients. It causes increase in the dopamine levels in the brain through multiple ways; blocking dopamine reuptake mechanism, amplifying dopamine response duration, disinhibition of D2 Receptor and amplifying the dopamine tone [28]. Methylphenidate also block norepinephrine reuptake. Atomoxetine is a non-stimulant used in diagnosis of ADHD patients. It acts by inhibiting the synaptic reuptake of Dopamine thus increasing the extracellular concentration of dopamine in the prefrontal cortex region [29]. Dextroamphetamine is another stimulant drug used in ADHD diagnosis. It acts by increasing the concentration of dopamine and norepinephrine in the synaptic cleft by increasing the release of neurotransmitters in the synaptic cleft, decreasing the reuptake of the neurotransmitter back into the presynaptic region and by inhibiting the breakdown of neurotransmitters [30]. Guanfacine has been responsible for strengthening the functional connection of the prefrontal cortical network thus improving the working memory of the patient by the stimulation of the 2adrenoceptor [31]. Thus Guanfacine has been beneficial in refining ADHD symptoms [32, 33]. Strong evidence indicates that CNS stimulant drugs such as Methylphenidate and Dextroamphetamine and non-stimulant drugs like Atomoxetine has improved the symptoms in ADHD patients [34]. The pharmacotherapy for ADHD has pronounced beneficial effects in improving symptoms associated with ADHD. At the same time there has been apprehension regarding the cardiovascular safety of these drugs in chronic use. There are implications stating that Atomoxetine, Methyphenidate and dextroammphetamine have variable effects on the Blood pressure, Heart rate and E.C.G parameters [35]. The pharmacotherapy has been significantly beneficial in controlling the Pg. 12

Int. J. Pharm. Biosci. Technol. attentive and executive activities to a larger extent. The alteration in the Dopamine and Norepinephrine levels has been clinically efficient in the management of ADHD [36]. Methylphenidate and Atomoxetine has been beneficial for facilitating the brain for learning, eliciting a compensatory experimental program is also mandate for the development of brain. There has been evidence regarding clinical improvement of children after empirical program inputs and timely behaviour and cognitive management [37]. Less is known regarding the long term use of CNS stimulants but it contradicts to be abused by few patients [38]. Recent study shows the chronic usage of methylphenidate had enriched the Recognition Memory component [39]. Thus patients on pharmacotherapy on these drugs should be closely monitored due to the low therapeutic index of these drugs. CONCLUSION The data collated from the various neuroimaging, neuropsychology, genetics and neurochemical studies have indicated that the frontostriatal network is primarily responsible for the pathophysiology of ADHD. Functional neuroimaging technique have shown defective multiple developmental pathways in a brain model due to the dysfunctioning of the neuronal systems including the prefrontal, striatal and parietal regions[40]. Molecular genetic studies have implicated that dysregulation of Dopamine and Norepinephrine and the genotype impact as the base for genetic susceptibility to a disease [41]. Future advances in the various neurobiological techniques would subsidize ascertaining better targeted pharmacotherapies and help neurobiologists to manage the patients in healthier way. REFERENCES 1. Lo-Castro A, D'Agati E, Curatolo P. ADHD and genetic syndromes. Brain Dev. 2011; 33(6): 456-461. 2. Coffin JM, Baroody S, Schneider K, O'Neill J. Impaired cerebellar learning in children with prenatal alcohol exposure: a comparative study of eye blink conditioning in children with ADHD and dyslexia. Cortex. 2005; 41:389398. 3. D'Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Rathouz PJ, Lahey BB. Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems. Arch Gen Psychiatry. 2007; 64:12961304. 4. Sen B, Swaminathan S. Maternal prenatal substance use and behaviour problems among children in the U.S. J Ment Health Policy Econ. 2007; 10:189-206. 5. Kotimaa AJ, Moilanen I, Taanila A, Ebeling H, Smalley SL, McGough JJ, Hartikainen AL, Jarvelin MR. Maternal smoking and hyperactivity in 8-year-old children. J Am Acad Child Adolesc Psychiatry. 2003; 42:826-833. 6. Taylor E, Rogers JW. Practitioner review: early adversity and developmental disorders. J Child Psychol Psychiatry. 2005; 46:451-467. 7. Faraone, S. V., Perlis, R. H., Doyle, A. E., et al. Molecular genetics of attention deficit/hyperactivity disorder. Biol Psychiatry,2005; 57, 13131323. 8. Juneja M, Jain R, Singh V, Mallika V. Iron Deficiency in Indian Children with Attention Deficit Hyperactivity Disorder. Indian Pediatr. 2010; 47(11):955-958. 9. Raz R, Gabis L. Essential fatty acids and attention-deficit-hyperactivity disorder: a systematic review. Dev Med Child Neurol. 2009; 51:580-592. 10. Becker K, El-Faddagh M, Schmidt MH, Esser G, Laucht M. Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms. J Pediatr. 2008; 152:263-269. 11. Neuman RJ, Lobos E, Reich W, Henderson CA, Sun LW, Todd RD. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biol Psychiatry. 2007; 61:1320-1328. 12. Emond V, Joyal C, Poissant H. Structural and functional neuroanatomy of attention-deficit hyperactivity disorder (ADHD). Encephale. 2009; 35:107-114. 13. Shaw P, Lerch J, Greenstein D, Sharp W, Clasen L, Evans A, Giedd J, Castellanos FX, Rapoport J. Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attentiondeficit/hyperactivity disorder. Arc Gen Psychiatry. 2006; 63:540-549.

Mohammed et al

Pg. 13

Int. J. Pharm. Biosci. Technol. 14. Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch JP, Greenstein D, Clasen L, Evans A, Giedd J, Rapoport JL. Attentiondeficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA. 2007; 104:19649-19654 15. Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS, Blumenthal JD, James RS, Ebens CL, Walter JM, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. J Am Med Asccoc. 2002; 288:1740-1748. 16. Krain AL, Castellanos FX. Brain development and ADHD. Clin Psychol Rev. 2006; 26:433-444. 17. Silk TJ, Vance A, Rinehart N, Bradshaw JL, Cunnington R. White-matter abnormalities in attention deficit hyperactivity disorder. A diffusion tensor imaging study. Hum Brain Mapp. 2009; 30(9):2757-2765a. 18. D'Agati E, Casarelli L, Pitzianti MB, Pasini A. Overflow movements and white matter abnormalities in ADHD. Prog Neuropsychopharmacol Biol Psychiatry. 34:441445. 19. Taylor E, Dopfner M, Sergeant J, Asherson P, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Rothenberger A, Sonuga-Barke E, et al. European clinical guidelines for hyperkinetic disorder - first upgrade. Eur Child Adolesc Psychiatry. 2004; 13(Suppl 1): I730. 20. APA: Diagnostic and Statistical Manual of Mental Disorders. Fourth, Text Revision edn. Washington. 2000. 21. Elkins IJ, McGue M, Iacono WG. Prospective effects of attention deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry. 2007; 64:1145-1152. 22. Loe IM, Feldman HM. Academic and educational outcomes of children with ADHD. J Pediatr Psychol. 2007; 32:643-654. 23. Crosbie J, Perusse D, Barr CL, Schachar RJ. Validating psychiatric endophenotypes: inhibitory control and attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2008; 32: 40-55. 24. Goos LM, Crosbie J, Payne S, Schachar R. Validation and extension of the endophenotype model in ADHD patterns of inheritance in a family study of inhibitory control. Am J Psychiatry. 2009; 166:711-717. 25. Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, Clevenger W, Davies M, Elliott GR, Greenhill LL, et al. Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry. 2001; 40:168-179. 26. Molina BS, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, Epstein JN, Hoza B, Hechtman L, Abikoff HB, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009; 48:484-500. 27. Pliszka SR. The neuropsychopharmacology of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57:1385-1390. 28. Wilens TE. Effects of methylphenidate on the catecholaminergic system in attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol. 2008; 28:S46-53. 29. Swanson CJ, Perry KW, Koch-Krueger S, Katner J, Svensson KA, Bymaster FP: Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology. 2006; 50:755-760. 30. Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res. 1998; 94:127-152. 31. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, et al. Alpha2Aadrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007; 129:397-410. 32. Sallee FR, Lyne A, Wigal T, McGough JJ. Longterm safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J

Mohammed et al

Pg. 14

Int. J. Pharm. Biosci. Technol. Child Adolesc Psychopharmacol .2009; 19:215226. 33. Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009; 48:155-165. 34. Biederman J, Spencer TJ. Psychopharmacological interventions. Child Adolesc Psychiatr Clin N Am . 2008; 17:439-458 35. Stiefel G, Besag FM. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attentiondeficit hyperactivity disorder. Drug Saf . 2010; 33:821-842. 36. Stahl SM. Mechanism of action of stimulants in attention-deficit/hyperactivity disorder. J Clin Psychiatry. 71:12-13. 37. Rapoport JL, Gogtay N. Brain neuroplasticity in healthy, hyperactive and psychotic children: insights from neuroimaging. Neuropsychopharmacology. 2008; 33:181-197. 38. Konrad K, Neufang S, Fink GR, HerpertzDahlmann B. Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study. J Am Acad Child Adolesc Psychiatry. 2007; 46:1633-1641. 39. Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007; 62:954-962. 40. Sonuga-Barke EJ. Causal models of attentiondeficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways. Biol Psychiatry. 2005; 57:1231-1238. 41. Gilbert DL, Wang Z, Sallee FR, Ridel KR, Merhar S, Zhang J, Lipps TD, White C, Badreldin N, Wassermann EM. Dopamine transporter genotype influences the physiological response to medication in ADHD. Brain. 2006; 129:2038-2046. ___________________________________________ How to cite this article APA style Mohammed, S., & Haile, D. B. (2013). Neuroscience of attention deficit hyperactivity disorder (ADHD)-a review. International Journal of Pharma Bioscience and Technology, 1(1), 1015. Elsevier Harvard style Mohammed, S., Haile, D.B., 2013. Neuroscience of attention deficit hyperactivity disorder (ADHD)-a review. Int. J. Pharm. Biosci. Technol. 1, 1015. Vancouver Style Mohammed S, Haile DB. Neuroscience of attention deficit hyperactivity disorder (ADHD)- a review. Int. J. Pharm. Biosci. Technol. 2013;1(1):1015. To receive bibliographic information in RIS format (For Reference Manager, ProCite, EndNote): Send request to: ijpbst@yahoo.com ___________________________________________

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