Attention-deficit hyperactivity disorder pathophysiology: Difference between revisions

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{{ADHD}}
{{ADHD}}


==Overview==
==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.<ref>{{cite web|url=http://www.continuingedcourses.net/active/courses/course003.php|title=Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity|last=Barkley|first=Russel A.|accessdate=2006-06-26}}</ref>. 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.
ADHD appears to be highly [[heritable]], although one-fifth of all cases are caused by [[trauma]] or exposure to [[toxins]]. Evidence suggests that ADHD is a [[heterogeneous]] disorder, meaning that several causes could create very similar symptomology.<ref>{{cite web|url=http://www.continuingedcourses.net/active/courses/course003.php|title=Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity|last=Barkley|first=Russel A.|accessdate=2006-06-26}}</ref> Although there is evidence for dopamine abnormalities in ADHD, it is not clear whether abnormalities of the [[dopamine]] system are a molecular abnormality of ADHD or a secondary consequence of ADHD.


==Pathophysiology==
==Pathophysiology==
===Pathogenesis===
*The exact pathogenesis of ADHD is not fully understood. It is believed that ADHD is caused by a complex interaction between genetic and environmental factors.<ref name="#15">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.</ref> A [[meta-analysis]] of studies of functional and structural [[magnetic resonance imaging]] has identified several pathologies<ref name="pmid27276220">{{cite journal| author=Norman LJ, Carlisi C, Lukito S, Hart H, Mataix-Cols D, Radua J et al.| title=Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis. | journal=JAMA Psychiatry | year= 2016 | volume= 73 | issue= 8 | pages= 815-825 | pmid=27276220 | doi=10.1001/jamapsychiatry.2016.0700 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27276220  }} </ref>.
===Genetics===
===Genetics===
Genome-wide surveys have shown linkage between ADHD and loci on chromosomes 7, 11, 12, 15, 16, and 17, likely indicating that ADHD does not follow the traditional model of an hereditary disease and is better viewed as the result of a complex interaction between genetic and environmental factors.<ref name="#15">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.</ref>
*Common genetic variation accounts for around 75% of cases of ADHD.<ref name="#6"></ref> [[Loci]] on [[chromosomes]] 7, 11, 12, 15, 16, and 17 are associated with ADHD, likely indicating that ADHD does not follow the traditional model of an [[hereditary disease]].<ref name="#15">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.</ref>


Norepinephrine and dopamine play a critical role in modulating attention in ADHD. Norepinephrine seems to have more of an effect on executive function, whereas dopamine may be more important in maintaining attention. Genomic studies have identified a variety of dopamine and serotonin receptors (e.g., dopamine 4 and 5, serotonin 1B) as having significant association with ADHD.<ref name="#7">Briars, L., & Todd, T. (2016). A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder. The Journal of Pediatric Pharmacology and Therapeutics : JPPT, 21(3), 192–206. http://doi.org/10.5863/1551-6776-21.3.192</ref>
*[[Norepinephrine]] and [[dopamine]] play a critical role in modulating [[attention]] in ADHD patients. Norepinephrine seems to have more of an effect on [[executive function]], whereas dopamine may be more important in maintaining attention. A variety of [[dopamine]] and [[serotonin]] receptors (e.g., dopamine 4 and 5, serotonin 1B) are associated with ADHD.<ref name="#7">Briars, L., & Todd, T. (2016). A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder. The Journal of Pediatric Pharmacology and Therapeutics : JPPT, 21(3), 192–206. http://doi.org/10.5863/1551-6776-21.3.192</ref>


Mutations in the PTCHD1 gene, which is active in the thalamus, are associated with attention deficit, hyperactivity, and learning disability. Recent studies in mice have shown that selectively knocking out the gene in its primary region of activity, the thalamic reticular nucleus (TRN), resulted in attention deficit, hyperactivity, and disrupted sleep. Notably, the attention deficit was not a general failure in attention, but an inability to filter out distraction; the mice had difficulty with tests that challenged their ability to carry out a task (responding to a light flash to get a reward) while being distracted.<ref name="#5">M. F. Wells, R. D. Wimmer, L. I. Schmitt, G. Feng, M. M. Halassa. (2016). "Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice." Nature 532: 58-63.</ref>
*Mutations in the PTCHD1 gene, which is active in the [[thalamus]], are associated with [[attention deficit]], [[hyperactivity]], and [[learning disability]]. Lack of a functional copy of the gene in the [[thalamic reticular nucleus]] (TRN) results in [[attention deficit]], [[hyperactivity]], and disrupted sleep.<ref name="#5">M. F. Wells, R. D. Wimmer, L. I. Schmitt, G. Feng, M. M. Halassa. (2016). "Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice." Nature 532: 58-63.</ref>


To determine precisely how the gene loss altered TRN function, investigators looked at the patterns of electrical activity in these neurons. They were able to pinpoint a change in activity of channels that shuttle potassium (SK channels) across the cell membrane; the exchange of ions across the membrane determines the conditions that make it more or less likely that a neuron will fire. They then confirmed the connection between the SK channels and TRN activity using an approach they developed to monitor real-time changes in the inhibitory activity of TRN neurons. The system uses a fluorescent protein to track movements of chloride ions, an indicator of electrical signaling activity in the neuron. Binding of chloride to the protein produces optical signals and thus a means of tracking the electrical activity of TRN neurons with great precision. In mice with the deleted gene (but not mice with the unaltered gene) the TRN inhibitory activity in response to light pulses was reduced. Pinpointing the SK channels as the gene-related origin of the change in TRN activity suggested a target for restoring function. The team treated mice missing PTCHD1 with a compound that boosts SK channels and found that the treatment corrected the attention deficits and hyperactivity.<ref name="#5">M. F. Wells, R. D. Wimmer, L. I. Schmitt, G. Feng, M. M. Halassa. (2016). "Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice." Nature 532: 58-63.</ref>
===Dopamine Levels and Blood Circulation===


===Dopamine Levels and Blood Circulation===
*ADHD patients have reduced [[blood circulation]]<ref>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</ref> and a significantly higher concentration of [[dopamine]] transporters in the [[striatum]], a part of the brain that plays a role in [[executive function]].<ref>{{cite journal |author=Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ |title=Dopamine transporter density in patients with attention deficit hyperactivity disorder |journal=Lancet |volume=354 |issue=9196 |pages=2132–-33 |year=1999 |pmid=10609822}}</ref><ref>{{cite journal |author=Dresel SH, Kung MP, Plössl K, Meegalla SK, Kung HF |title=Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats |journal=European journal of nuclear medicine |volume=25 |issue=1 |pages=31–9 |year=1998 |pmid=9396872}}</ref>
[[SPECT]] scans found people with ADHD to have reduced blood circulation,<ref>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</ref> and a significantly higher concentration of dopamine transporters in the [[striatum]] which is in charge of planning ahead.<ref>{{cite journal |author=Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ |title=Dopamine transporter density in patients with attention deficit hyperactivity disorder |journal=Lancet |volume=354 |issue=9196 |pages=2132–-33 |year=1999 |pmid=10609822}}</ref><ref>{{cite journal |author=Dresel SH, Kung MP, Plössl K, Meegalla SK, Kung HF |title=Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats |journal=European journal of nuclear medicine |volume=25 |issue=1 |pages=31–9 |year=1998 |pmid=9396872}}</ref> 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.<ref name="pmid17113158">{{cite journal |author=Coccaro EF, Hirsch SL, Stein MA |title=Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects |journal=Psychiatry research |volume=149 |issue=1–3 |pages=297–302 |year=2007 |pmid=17113158 |doi=10.1016/j.psychres.2006.05.009}}</ref>


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 [[Hypokalemic sensory overstimulation|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]].
*It is likely not the dopamine transporter levels that indicate the presence of ADHD, but the brain's ability to produce dopamine itself. ADHD patients show lower levels of dopamine than healthy subjects across the board. Further, plasma [[homovanillic acid]], an index of [[dopamine]] levels, is inversely related not only to childhood ADHD symptoms in adult psychiatric patients, but to "childhood learning problems" in healthy subjects as well.<ref name="pmid17113158">{{cite journal |author=Coccaro EF, Hirsch SL, Stein MA |title=Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects |journal=Psychiatry research |volume=149 |issue=1–3 |pages=297–302 |year=2007 |pmid=17113158 |doi=10.1016/j.psychres.2006.05.009}}</ref>


===Glucose Metabolism===
===Glucose Metabolism===
An early [[Positron emission tomography|PET scan]] study found that global cerebral [[glucose catabolism|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]].<ref name="Zametkin"/> 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.<ref>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</ref>  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.
*An early [[Positron emission tomography|PET scan]] study found that global cerebral [[glucose catabolism|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, but rather 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]].<ref name="Zametkin"/> ADHD symptoms are likely the result of impaired activity in specific regions of the brain, rather than a broad, global deficit.
[[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===
===Associated Conditions===
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>
*ADHD is associated with many of the same inherited genetic variations as [[clinical depression]].<ref name="#6">Cross-Disorder Group of the Psychiatric Genomics Consortium. "Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs." Nat Genet. (2013). 45(9):984-94. doi: 10.1038/ng.2711. Epub 2013 Aug 11.</ref> Other conditions, such as [[learning disabilities]], [[anxiety disorder]], [[conduct disorder]], [[depression]], and [[substance abuse]], are common in people with ADHD.<ref name="#1">National Institute of Mental Health (NIH). (2016). "Attention Deficit Hyperactivity Disorder."</ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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Overview

ADHD appears to be highly heritable, although one-fifth of all cases are caused by trauma or exposure to toxins. Evidence suggests that 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 a molecular abnormality of ADHD or a secondary consequence of ADHD.

Pathophysiology

Pathogenesis

  • The exact pathogenesis of ADHD is not fully understood. It is believed that ADHD is caused by a complex interaction between genetic and environmental factors.[2] A meta-analysis of studies of functional and structural magnetic resonance imaging has identified several pathologies[3].

Genetics

  • Common genetic variation accounts for around 75% of cases of ADHD.[4] Loci on chromosomes 7, 11, 12, 15, 16, and 17 are associated with ADHD, likely indicating that ADHD does not follow the traditional model of an hereditary disease.[2]

Dopamine Levels and Blood Circulation

  • It is likely not the dopamine transporter levels that indicate the presence of ADHD, but the brain's ability to produce dopamine itself. ADHD patients show lower levels of dopamine than healthy subjects across the board. Further, plasma homovanillic acid, an index of dopamine levels, is inversely related not only to childhood ADHD symptoms in adult psychiatric patients, but to "childhood learning problems" in healthy subjects as well.[10]

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, but rather 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.[11] ADHD symptoms are likely the result of impaired activity in specific regions of the brain, rather than a broad, global deficit.
PET scans of glucose metabolism in the brains of a normal adult (left) compared to an adult diagnosed with ADHD (right).[11] "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."

Associated Conditions

References

  1. ↑ Barkley, Russel A. "Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity". Retrieved 2006-06-26.
  2. ↑ 2.0 2.1 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.
  3. ↑ Norman LJ, Carlisi C, Lukito S, Hart H, Mataix-Cols D, Radua J; et al. (2016). "Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis". JAMA Psychiatry. 73 (8): 815–825. doi:10.1001/jamapsychiatry.2016.0700. PMID 27276220.
  4. ↑ 4.0 4.1 Cross-Disorder Group of the Psychiatric Genomics Consortium. "Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs." Nat Genet. (2013). 45(9):984-94. doi: 10.1038/ng.2711. Epub 2013 Aug 11.
  5. ↑ Briars, L., & Todd, T. (2016). A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder. The Journal of Pediatric Pharmacology and Therapeutics : JPPT, 21(3), 192–206. http://doi.org/10.5863/1551-6776-21.3.192
  6. ↑ M. F. Wells, R. D. Wimmer, L. I. Schmitt, G. Feng, M. M. Halassa. (2016). "Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice." Nature 532: 58-63.
  7. ↑ 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
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 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
  12. ↑ National Institute of Mental Health (NIH). (2016). "Attention Deficit Hyperactivity Disorder."

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