Attention-deficit hyperactivity disorder pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
===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> | |||
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> | |||
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> | |||
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=== | ||
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===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> | ||
==References== | ==References== | ||
Revision as of 15:06, 4 August 2016
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
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.[2]
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.[3]
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.[4]
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.[4]
Dopamine Levels and Blood Circulation
SPECT scans found people with ADHD to have reduced blood circulation,[5] and a significantly higher concentration of dopamine transporters in the striatum which is in charge of planning ahead.[6][7] 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.[8]
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.[9] 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.[10] 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.
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.[11]
References
- ↑ Barkley, Russel A. "Attention-Deficit/Hyperactivity Disorder: Nature, Course, Outcomes, and Comorbidity". Retrieved 2006-06-26.
- ↑ 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.
- ↑ 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
- ↑ 4.0 4.1 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.
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 9.0 9.1 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
- ↑ 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
- ↑ Brain Matures a Few Years Late in ADHD, But Follows Normal Pattern NIMH Press Release, November 12, 2007