Attention-deficit hyperactivity disorder pathophysiology: Difference between revisions

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[[Image:Adhdbrain.gif|180px|framed|center|PET scans of glucose metabolism in the brains of a normal adult (left) compared to an adult diagnosed with ADHD (right).<ref name="Zametkin">Zametkin AJ, Nordahl TE, Gross M, et al. "Cerebral glucose metabolism in adults with hyperactivity of childhood onset." ''N Engl J Med''. 1990 November 15;323(20):1361–6. PMID 2233902</ref> "This PET scan was taken from Zametkin's landmark 1990 study, which found lower glucose metabolism, in the brains of patients with ADHD who had never taken medication. Scans were taken while patients were engaging in tasks requiring focused attention. The greatest deficits were found in the premotor cortex and superior prefrontal cortex."]]
[[Image:Adhdbrain.gif|180px|framed|center|PET scans of glucose metabolism in the brains of a normal adult (left) compared to an adult diagnosed with ADHD (right).<ref name="Zametkin">Zametkin AJ, Nordahl TE, Gross M, et al. "Cerebral glucose metabolism in adults with hyperactivity of childhood onset." ''N Engl J Med''. 1990 November 15;323(20):1361–6. PMID 2233902</ref> "This PET scan was taken from Zametkin's landmark 1990 study, which found lower glucose metabolism, in the brains of patients with ADHD who had never taken medication. Scans were taken while patients were engaging in tasks requiring focused attention. The greatest deficits were found in the premotor cortex and superior prefrontal cortex."]]


==Other Imaging Studies==
===Other Imaging Studies===
According to an advanced high-precision [[imaging]] study by researchers at the United States [[National Institutes of Health]]'s [[National Institute of Mental Health]], an actual delay in physical development in some brain structures, with a median value of three years, was observed in the brains of 223 ADHD patients beginning in elementary school, during the period when cortical thickening during childhood begins to change to thinning following [[puberty]]. The delay was most prominent in the [[frontal cortex]] and temporal cortex, which are believed responsible for the ability to control and focus thinking, attention and planning, suppress inappropriate actions and thoughts, remember things from moment to moment, and work for reward, all functions whose disturbance is associated with a diagnosis of ADHD; the region with the greatest average delay, the middle of the prefrontal cortex, lagged a full five years in development in the ADHD patients. In contrast, the [[motor cortex]] in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might both be required for the restlessness and fidgetiness that characterise an ADHD diagnosis. Aside from the delay, both groups showed a similar back-to-front development of brain maturation with different areas peaking in thickness at different times. This contrasts with the pattern of development seen in other disorders such as [[autism]], where the peak of cortical thickening occurs much earlier than normal.<ref>[http://www.nimh.nih.gov/science-news/2007/brain-matures-a-few-years-late-in-adhd-but-follows-normal-pattern.shtml Brain Matures a Few Years Late in ADHD, But Follows Normal Pattern] NIMH Press Release, November 12, 2007 </ref>
According to an advanced high-precision [[imaging]] study by researchers at the United States [[National Institutes of Health]]'s [[National Institute of Mental Health]], an actual delay in physical development in some brain structures, with a median value of three years, was observed in the brains of 223 ADHD patients beginning in elementary school, during the period when cortical thickening during childhood begins to change to thinning following [[puberty]]. The delay was most prominent in the [[frontal cortex]] and temporal cortex, which are believed responsible for the ability to control and focus thinking, attention and planning, suppress inappropriate actions and thoughts, remember things from moment to moment, and work for reward, all functions whose disturbance is associated with a diagnosis of ADHD; the region with the greatest average delay, the middle of the prefrontal cortex, lagged a full five years in development in the ADHD patients. In contrast, the [[motor cortex]] in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might both be required for the restlessness and fidgetiness that characterise an ADHD diagnosis. Aside from the delay, both groups showed a similar back-to-front development of brain maturation with different areas peaking in thickness at different times. This contrasts with the pattern of development seen in other disorders such as [[autism]], where the peak of cortical thickening occurs much earlier than normal.<ref>[http://www.nimh.nih.gov/science-news/2007/brain-matures-a-few-years-late-in-adhd-but-follows-normal-pattern.shtml Brain Matures a Few Years Late in ADHD, But Follows Normal Pattern] NIMH Press Release, November 12, 2007 </ref>


Revision as of 15:42, 12 August 2012

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

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Overview

Attention deficit hyperactivity disorder appears to be highly heritable, although one-fifth of all cases are estimated to be caused from trauma or toxic exposure. Evidence suggests that hyperactivity has a strong heritable component, and in all probability ADHD is a heterogeneous disorder, meaning that several causes could create very similar symptomology.[1]. Although there is evidence for dopamine abnormalities in ADHD, it is not clear whether abnormalities of the dopamine system are the molecular abnormality of ADHD or a secondary consequence of a problem elsewhere.

Pathophysiology

It is believed that there are several different causes of ADHD. Roughly 80 percent of ADHD is considered genetic in nature and the estimated contribution of non genetic factors to the contribution of all cases of ADHD is believed to be 20 percent.[2]. Environmental agents also cause ADHD. These agents, such as alcohol, tobacco, and lead, are believed to stress babies prenatally and cause ADHD. Studies have found that malnutrition is also correlated with attention deficits. Diet seems to cause ADHD symptoms or make them worse. Many studies point to synthetic preservatives and artificial coloring agents aggravating ADD & ADHD symptoms in those affected.[3][4] Older studies were inconclusive quite possibly due to inadequate clinical methods of measuring offending behavior. Parental reports were more accurate indicators of the presence of additives than clinical tests.[5] Several major studies show academic performance increased and disciplinary problems decreased in large non-ADD student populations when artificial ingredients, including artificial colors were eliminated from school food programs.[6][7]. Professor John Warner stated, “significant changes in children’s hyperactive behaviour could be produced by the removal of artificial colourings and sodium benzoate from their diet.” and “you could halve the number of kids suffering the worst behavioural problems by cutting out additives”.

In 1982, the NIH had determined, based on research available at that time, that roughly 5% of children with ADHD could be helped significantly by removing additives from their diet. The vast majority of these children were believed to have food allergies. [8] More recent studies have shown that approximately 60-70% of children with and without allergies improve when additives are removed from their diet,[9] that up to almost 90% of them react when an appropriate amount of additive is used as a challenge in double blind tests,[10] and that food additives may elicit hyperactive behavior and/or irritability in normal children as well.[11]

Genetics

According to a majority of medical research in the United States, as well as other countries, ADHD is today generally regarded as a chronic disorder for which there are some effective treatments, but no true cure.[12] Evidence suggests that hyperactivity has a strong heritable component, and in all probability ADHD is a heterogeneous disorder, meaning that several causes could create very similar symptomology.[13] Candidate genes include dopamine transporter (DAT), dopamine receptor D4 (DRD4), dopamine beta-hydroxylase (DBH), monoamine oxidase A (MAOA), catecholamine-methyl transferase (COMT), serotonin transporter promoter (SLC6A4), 5-hydroxytryptamine 2A receptor (5-HT2A), and 5-hydroxytryptamine 1B receptor (5-HT1B). Researchers believe that a large majority of ADHD arises from a combination of various genes, many of which affect dopamine transporters.[14] Suspect genes include the 10-repeat allele of the DAT1 gene,[15] the 7-repeat allele of the DRD4 gene,[15] and the dopamine beta hydroxylase gene (DBH TaqI).[16]

Genome wide surveys have shown linkage between ADHD and loci on chromosomes 7, 11, 12, 15, 16, and 17.[17] If anything, the broad selection of targets indicates the likelihood that ADHD does not follow the traditional model of a "genetic disease" and is better viewed as a complex interaction among genetic and environmental factors. As the authors of a review of the question have noted, "Although several genome-wide searches have identified chromosomal regions that are predicted to contain genes that contribute to ADHD susceptibility, to date no single gene with a major contribution to ADHD has been identified."[18]

Studies show that there is a familial transmission of the disorder which does not occur through adoptive relationships.[19] Twin studies indicate that the disorder is highly heritable and that genetics contribute about three quarters of the total ADHD population.[19] While the majority of ADHD is believed to be genetic in nature,[19] roughly one-fifth of all ADHD cases are thought to be acquired after conception due to brain injury caused by either toxins or physical trauma prenatally or postnatally.[19]

Non-Genetic Factors

The estimated contribution of non genetic factors to the contribution of all cases of ADHD is 20 percent.[20] The environmental factors implicated are common exposures and include alcohol, in utero tobacco smoke and lead exposure. Lead concentration below the Center for Disease Control's action level account for slightly more cases of ADHD than tobacco smoke (290 000 versus 270 000, in the USA, ages 4 to 15).[21] Complications during pregnancy and birth—including premature birth—might also play a role. It has been observed that women who smoke while pregnant are more likely to have children with ADHD.[22] This could be related to the fact that nicotine is known to cause hypoxia (lack of oxygen) in utero, but it could also be that ADHD women have more probabilities to smoke both in general and during pregnancy, being more likely to have children with ADHD due to genetic factors.

Dopamine Levels and Blood Circulation

SPECT scans found people with ADHD to have reduced blood circulation,[23] and a significantly higher concentration of dopamine transporters in the striatum which is in charge of planning ahead.[24][25] A study by the U.S. Department of Energy’s Brookhaven National Laboratory in collaboration with Mount Sinai School of Medicine in New York suggest that it is not the dopamine transporter levels that indicate ADHD, but the brain's ability to produce dopamine itself. The study was done by injecting 20 ADHD subjects and 25 control subjects with a radiotracer that attaches itself to dopamine transporters. The study found that it was not the transporter levels that indicated ADHD, but the dopamine itself. ADHD subjects showed lower levels of dopamine across the board. They speculated that since ADHD subjects had lower levels of dopamine to begin with, the number of transporters in the brain was not the telling factor. In support of this notion, plasma homovanillic acid, an index of dopamine levels, was found to be inversely related not only to childhood ADHD symptoms in adult psychiatric patients, but to "childhood learning problems" in healthy subjects as well.[26]

Although there is evidence for dopamine abnormalities in ADHD, it is not clear whether abnormalities of the dopamine system are the molecular abnormality of ADHD or a secondary consequence of a problem elsewhere. Researchers have described a form of ADHD in which the abnormality appears to be sensory overstimulation resulting from a disorder of ion channels in the peripheral nervous system.

Glucose Metabolism

An early PET scan study found that global cerebral glucose metabolism was 8.1% lower in medication-naive adults who had been diagnosed as ADHD while children. The image on the left illustrates glucose metabolism in the brain of a 'normal' adult while doing an assigned auditory attention task; the image on the right illustrates the areas of activity in the brain of an adult who had been diagnosed with ADHD as a child when given that same task; these are not pictures of individual brains, which would contain substantial overlap, these are images constructed to illustrate group-level differences. Additionally, the regions with the greatest deficit of activity in the ADHD patients (relative to the controls) included the premotor cortex and the superior prefrontal cortex.[27] A second study in adolescents failed to find statistically significant differences in global glucose metabolism between ADHD patients and controls, but did find statistically significant deficits in 6 specific regions of the brains of the ADHD patients (relative to the controls). Most notably, lower metabolic activity in one specific region of the left anterior frontal lobe was significantly inversely correlated with symptom severity.[28] These findings strongly imply that lowered activity in specific regions of the brain, rather than a broad global deficit, is involved in ADHD symptoms. However, these readings are of subjects doing an assigned task. They could be found in ADHD diagnosed patients because they simply were not attending to the task. Hence the parts of the brain used by others doing the task would not show equal activity in the ADHD patients.

PET scans of glucose metabolism in the brains of a normal adult (left) compared to an adult diagnosed with ADHD (right).[27] "This PET scan was taken from Zametkin's landmark 1990 study, which found lower glucose metabolism, in the brains of patients with ADHD who had never taken medication. Scans were taken while patients were engaging in tasks requiring focused attention. The greatest deficits were found in the premotor cortex and superior prefrontal cortex."

Other Imaging Studies

According to an advanced high-precision imaging study by researchers at the United States National Institutes of Health's National Institute of Mental Health, an actual delay in physical development in some brain structures, with a median value of three years, was observed in the brains of 223 ADHD patients beginning in elementary school, during the period when cortical thickening during childhood begins to change to thinning following puberty. The delay was most prominent in the frontal cortex and temporal cortex, which are believed responsible for the ability to control and focus thinking, attention and planning, suppress inappropriate actions and thoughts, remember things from moment to moment, and work for reward, all functions whose disturbance is associated with a diagnosis of ADHD; the region with the greatest average delay, the middle of the prefrontal cortex, lagged a full five years in development in the ADHD patients. In contrast, the motor cortex in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might both be required for the restlessness and fidgetiness that characterise an ADHD diagnosis. Aside from the delay, both groups showed a similar back-to-front development of brain maturation with different areas peaking in thickness at different times. This contrasts with the pattern of development seen in other disorders such as autism, where the peak of cortical thickening occurs much earlier than normal.[29]

Head Injuries

Head injuries can cause a person to present ADHD-like symptoms,[30] possibly because of damage done to the patient's frontal lobes. Because these types of symptoms can be attributable to brain damage, one earlier designation for ADHD was "Minimal Brain Damage".[31]

Social Causes

There is no compelling evidence that social factors alone can create ADHD.[19] Many researchers believe that attachments and relationships with caregivers and other features of a child's environment have profound effects on attentional and self-regulatory capacities. It is noteworthy that a study of foster children found that an inordinate number of them had symptoms closely resembling ADHD.[32] An editorial in a special edition of Clinical Psychology in 2004 stated that "our impression from spending time with young people, their families and indeed colleagues from other disciplines is that a medical diagnosis and medication is not enough. In our clinical experience, without exception, we are finding that the same conduct typically labelled ADHD is shown by children in the context of violence and abuse, impaired parental attachments and other experiences of emotional trauma."[33] Furthermore, Complex Post Traumatic Stress Disorder can result in attention problems that can look like ADHD, as can Sensory Integration Disorders.

References

  1. ↑ Barkley, Russel A. "Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity". Retrieved 2006-06-26.
  2. ↑ Template:PDFlink SchwabLearning.org.
  3. ↑ Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomized, double-blinded, placebo-controlled trial”, Lancet, Sept 2007
  4. ↑ 1997 Graduate Student Research Project conducted at the University of South Florida. Author- Richard W. Pressinger M.Ed.
  5. ↑ "Food Additives May Affect Kids' Hyperactivity", WebMD Medical News, May 24, 2004
  6. ↑ A different kind of school lunch", PURE FACTS October 2002
  7. ↑ The Impact of a Low Food Additive and Sucrose Diet on Academic Performance in 803 New York City Public Schools, Schoenthaler SJ, Doraz WE, Wakefield JA, Int J Biosocial Res., 1986, 8(2); 185-195
  8. ↑ http://www.nimh.nih.gov/health/publications/adhd/complete-publication.shtml#pub4
  9. ↑ Rowe KS, Rowe KJ (1994). "Synthetic food coloring and behavior: A dose response effect in a double-blind, placebo-controlled, repeated-measures study". Journal of Pediatrics. 125: 691&ndash, 698. 7965420.
  10. ↑ Pollock, I. and Warner, J.O. (1990). "Effect of artificial food colours on childhood behaviour". Arch Dis Child. 65 (1): 74–77. PMID 2301986. Unknown parameter |month= ignored (help)
  11. ↑ McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, Kitchin E, Lok K, Porteous L, Prince E, Sonuga-Barke E, Warner JO, Stevenson J. (2007 Nov). "Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial". Lancet. 3;370(9598): 1560–7. PMID 17825405. Check date values in: |year= (help)
  12. ↑ NINDS Attention Deficit-Hyperactivity Disorder Information Page. National Institute of Neurological Disorders and Stroke (NINDS/NIH) February 9, 2007. Retrieved on 2007-08-13.
  13. ↑ Barkley, Russel A. "Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity". Retrieved 2006-06-26.
  14. ↑ Roman T, Rohde LA, Hutz MH. (2004). "Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder." American Journal of Pharmacogenomics 4(2):83–92 PMID 15059031
  15. ↑ 15.0 15.1 Swanson JM, Flodman P, Kennedy J, et al. "Dopamine Genes and ADHD." Neurosci Biobehav Rev. 2000 Jan;24(1):21–5. PMID 10654656
  16. ↑ Smith KM, Daly M, Fischer M, et al. "Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: genetic analysis of the Milwaukee longitudinal study." Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119(1):77–85. PMID 12707943
  17. ↑ M. T. Acosta, M. Arcos-Burgos, M. Muenke (2004). "Attention deficit/hyperactivity disorder (ADHD): Complex phenotype, simple genotype?". Genetics in Medicine. 6 (1): 1–15.
  18. ↑ M. T. Acosta, M. Arcos-Burgos, M. Muenke (2004). "Attention deficit/hyperactivity disorder (ADHD): Complex phenotype, simple genotype?". Genetics in Medicine. 6 (1): 1–15.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Barkley, Russell A. Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity. ContinuinedEdCourse.Net. Retrieved on 2007-08-12.
  20. ↑ Template:PDFlink SchwabLearning.org.
  21. ↑ Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP (2006). "Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children". Environ. Health Perspect. 114 (12): 1904–9. PMID 17185283.: "Compared with the lowest quintile of blood lead levels, children with blood lead levels > 2.0 µg/dL were at a 4.1-fold increased risk of ADHD. When we limited the analysis to children with blood lead levels ≤ 5 µg/dL, the association between increased blood lead levels and ADHD remained. These results are consistent with previous reports that have found significant associations between blood or dentin lead levels and behavior problems .... Our results further indicate that blood lead levels below the CDC action level of 10 µg/dL are associated with an increased risk for ADHD in children. This result is consistent with previous studies that have found cognitive deficits in children with blood lead levels < 10 µg/dL."
  22. ↑ Kotimaa AJ, Moilanen I, Taanila A, et al. ,"Maternal smoking and hyperactivity in 8-year-old children". 2003, J Am Acad Child Adol Psychiatry Jul;42(7):826–33. PMID 12819442
  23. ↑ Lou HC, Andresen J, Steinberg B, McLaughlin T, Friberg L. "The striatum in a putative cerebral network activated by verbal awareness in normals and in ADHD children." Eur J Neurol. 1998 Jan;5(1):67–74. PMID 10210814
  24. ↑ Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ (1999). "Dopamine transporter density in patients with attention deficit hyperactivity disorder". Lancet. 354 (9196): 2132–-33. PMID 10609822.
  25. ↑ Dresel SH, Kung MP, Plössl K, Meegalla SK, Kung HF (1998). "Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats". European journal of nuclear medicine. 25 (1): 31–9. PMID 9396872.
  26. ↑ Coccaro EF, Hirsch SL, Stein MA (2007). "Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects". Psychiatry research. 149 (1–3): 297–302. doi:10.1016/j.psychres.2006.05.009. PMID 17113158.
  27. ↑ 27.0 27.1 Zametkin AJ, Nordahl TE, Gross M, et al. "Cerebral glucose metabolism in adults with hyperactivity of childhood onset." N Engl J Med. 1990 November 15;323(20):1361–6. PMID 2233902
  28. ↑ Zametkin AJ, Liebenauer LL, Fitzgerald GA,, et al. "Brain metabolism in teenagers with attention-deficit hyperactivity disorder." Arch Gen Psychiatry.. 1993 May 50;333(5). PMID 2233902
  29. ↑ Brain Matures a Few Years Late in ADHD, But Follows Normal Pattern NIMH Press Release, November 12, 2007
  30. ↑ McAvinue L, O'Keeffe F, McMackin D, Robertson IH, et al. "Impaired sustained attention and error awareness in traumatic brain injury: implications for insight" Neuropsychological Rehabilitation. 2005 Dec;15(5):569–87. PMID 16381141
  31. ↑ What Causes ADD. Attention Deficit Disorder Association. Retrieved on 2007-08-13.
  32. ↑ Template:PDFlink
  33. ↑ Adam James (2004) Clinical psychology publishes critique of ADHD diagnosis and use of medication on children published on Psychminded.co.uk Psychminded Ltd
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