Editing Attention deficit hyperactivity disorder (section)

== Pathophysiology ==
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's [[neurotransmitter systems]], particularly those involving [[dopamine]] and [[norepinephrine]].<ref name="Malenka ADHD neurosci">{{cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE |publisher=McGraw-Hill Medical |year=2009 |isbn=978-0-07-148127-4 |veditors=Sydor A, Brown RY |edition=2nd |location=New York |pages=266, 315, 318–323 |chapter=Chapters 10 and 13 |quote=Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.}}</ref> The dopamine and norepinephrine pathways that originate in the [[ventral tegmental area]] and [[locus coeruleus]] project to diverse regions of the brain and govern a variety of cognitive processes.<ref name="VTA+LC projection systems">{{cite journal |vauthors=Chandler DJ, Waterhouse BD, Gao WJ |title=New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons |journal=[[Frontiers in Neural Circuits]] |volume=8 |page=53 |date=May 2014 |pmid=24904299 |pmc=4033238 |doi=10.3389/fncir.2014.00053 |doi-access=free}}</ref><ref name="Malenka pathways" /> The [[dopamine pathway]]s and [[LC-NA system|norepinephrine pathway]]s which project to the [[prefrontal cortex]] and [[striatum]] are directly responsible for modulating [[executive function]] (cognitive control of behaviour), motivation, reward perception, and motor function;<ref name="Malenka ADHD neurosci" /><ref name="Malenka pathways" /> these pathways are known to play a central role in the [[wikt:pathophysiology|pathophysiology]] of ADHD.<ref name="VTA+LC projection systems" /><ref name="Malenka pathways" /><ref name="pmid22169776" /><ref name="pmid22983386" /> Larger models of ADHD with additional pathways have been proposed.<ref name="pmid22169776">{{cite journal |vauthors=Castellanos FX, Proal E |title=Large-scale brain systems in ADHD: beyond the prefrontal-striatal model |journal=Trends in Cognitive Sciences |volume=16 |issue=1 |pages=17–26 |date=January 2012 |pmid=22169776 |pmc=3272832 |doi=10.1016/j.tics.2011.11.007 |quote=Recent conceptualizations of ADHD have taken seriously the distributed nature of neuronal processing. Most of the candidate networks have focused on prefrontal-striatal-cerebellar circuits, although other posterior regions are also being proposed.}}</ref><ref name="pmid22983386">{{cite journal |vauthors=Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, Castellanos FX |title=Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies |journal=[[The American Journal of Psychiatry]] |volume=169 |issue=10 |pages=1038–1055 |date=October 2012 |pmid=22983386 |pmc=3879048 |doi=10.1176/appi.ajp.2012.11101521 |lccn=22024537 |oclc=1480183 |eissn=1535-7228}}</ref>

=== Brain structure ===
[[File:Attention deficit hyperactivity disorder - Attention deficit hyperactivity disorder - Reduced brain volume on the left side from ADHD.jpg|thumb|upright=1.3|The left prefrontal cortex, shown here in blue, is often affected in ADHD]]
In children with ADHD, there is a general reduction of volume in certain brain structures, with a proportionally greater decrease in the volume in the left-sided prefrontal cortex.<ref name="Malenka ADHD neurosci" /><ref name="Krain2006">{{cite journal |vauthors=Krain AL, Castellanos FX |title=Brain development and ADHD |journal=[[Clinical Psychology Review]] |volume=26 |issue=4 |pages=433–444 |date=August 2006 |pmid=16480802 |doi=10.1016/j.cpr.2006.01.005}}</ref> The [[posterior parietal cortex]] also shows thinning in individuals with ADHD compared to controls. Other brain structures in the prefrontal-striatal-cerebellar and prefrontal-striatal-thalamic circuits have also been found to differ between people with and without ADHD.<ref name="Malenka ADHD neurosci" /><ref name="pmid22169776" /><ref name="pmid22983386" />

The subcortical volumes of the [[accumbens]], [[amygdala]], [[Caudate nucleus|caudate]], [[hippocampus]], and [[putamen]] appears smaller in individuals with ADHD compared with controls.<ref>{{cite journal |vauthors=Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LS, van Hulzen KJ, Medland SE, Shumskaya E, Jahanshad N, Zeeuw P, Szekely E, Sudre G, Wolfers T, Onnink AM, Dammers JT, Mostert JC, Vives-Gilabert Y, Kohls G, Oberwelland E, Seitz J, Schulte-Rüther M, Ambrosino S, Doyle AE, Høvik MF, Dramsdahl M, Tamm L, van Erp TG, Dale A, Schork A, Conzelmann A, Zierhut K, Baur R, McCarthy H, Yoncheva YN, Cubillo A, Chantiluke K, Mehta MA, Paloyelis Y, Hohmann S, Baumeister S, Bramati I, Mattos P, Tovar-Moll F, Douglas P, Banaschewski T, Brandeis D, Kuntsi J, Asherson P, Rubia K, Kelly C, Martino AD, Milham MP, Castellanos FX, Frodl T, Zentis M, Lesch KP, Reif A, Pauli P, Jernigan TL, Haavik J, Plessen KJ, Lundervold AJ, Hugdahl K, Seidman LJ, Biederman J, Rommelse N, Heslenfeld DJ, Hartman CA, Hoekstra PJ, Oosterlaan J, Polier GV, Konrad K, Vilarroya O, Ramos-Quiroga JA, Soliva JC, Durston S, Buitelaar JK, Faraone SV, Shaw P, Thompson PM, Franke B |title=Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis |journal=[[The Lancet Psychiatry]] |volume=4 |issue=4 |pages=310–319 |date=April 2017 |pmid=28219628 |pmc=5933934 |doi=10.1016/S2215-0366(17)30049-4}}</ref> Structural MRI studies have also revealed differences in white matter, with marked differences in inter-hemispheric asymmetry between ADHD and typically developing youths.<ref>{{cite journal |vauthors=Douglas PK, Gutman B, Anderson A, Larios C, Lawrence KE, Narr K, Sengupta B, Cooray G, Douglas DB, Thompson PM, McGough JJ, Bookheimer SY |title=Hemispheric brain asymmetry differences in youths with attention-deficit/hyperactivity disorder |journal=NeuroImage. Clinical |volume=18 |pages=744–752 |date=February 2018 |pmid=29876263 |pmc=5988460 |doi=10.1016/j.nicl.2018.02.020}}</ref>

[[Functional magnetic resonance imaging|Functional MRI]] (fMRI) studies have revealed a number of differences between ADHD and control brains. Mirroring what is known from structural findings, fMRI studies have shown evidence for a higher connectivity between subcortical and cortical regions, such as between the caudate and prefrontal cortex. The degree of hyperconnectivity between these regions correlated with the severity of inattention or hyperactivity<ref name="Damiani_2021">{{cite journal |vauthors=Damiani S, Tarchi L, Scalabrini A, Marini S, Provenzani U, Rocchetti M, Oliva F, Politi P |title=Beneath the surface: hyper-connectivity between caudate and salience regions in ADHD fMRI at rest |journal=[[European Child & Adolescent Psychiatry]] |volume=30 |issue=4 |pages=619–631 |date=April 2021 |pmid=32385695 |doi=10.1007/s00787-020-01545-0 |hdl-access=free |s2cid=218540328 |hdl=2318/1755224}}</ref> Hemispheric lateralisation processes have also been postulated as being implicated in ADHD, but empiric results showed contrasting evidence on the topic.<ref name="Tarchi_2022">{{cite journal |vauthors=Tarchi L, Damiani S, Fantoni T, Pisano T, Castellini G, Politi P, Ricca V |title=Centrality and interhemispheric coordination are related to different clinical/behavioral factors in attention deficit/hyperactivity disorder: a resting-state fMRI study |journal=Brain Imaging and Behavior |volume=16 |issue=6 |pages=2526–2542 |date=December 2022 |pmid=35859076 |pmc=9712307 |doi=10.1007/s11682-022-00708-8}}</ref><ref>{{cite journal |vauthors=Mohamed SM, Börger NA, Geuze RH, van der Meere JJ |title=Brain lateralization and self-reported symptoms of ADHD in a population sample of adults: a dimensional approach |journal=[[Frontiers in Psychology]] |volume=6 |page=1418 |date=2015 |pmid=26441789 |pmc=4585266 |doi=10.3389/fpsyg.2015.01418 |doi-access=free}}</ref>

=== Neurotransmitter pathways ===
Previously, it had been suggested that the elevated number of [[dopamine transporters]] in people with ADHD was part of the pathophysiology, but it appears the elevated numbers may be due to adaptation following exposure to stimulant medication.<ref name="pmid22294258">{{cite journal |vauthors=Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U |title=Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis |journal=[[The American Journal of Psychiatry]] |volume=169 |issue=3 |pages=264–272 |date=March 2012 |pmid=22294258 |doi=10.1176/appi.ajp.2011.11060940 |lccn=22024537 |hdl=11577/2482784 |doi-access=free |oclc=1480183 |eissn=1535-7228}}</ref> Current models involve the [[mesocorticolimbic projection|mesocorticolimbic dopamine pathway]] and the [[locus coeruleus-noradrenergic system]].<ref name="VTA+LC projection systems" /><ref name="Malenka ADHD neurosci" /><ref name="Malenka pathways" /> ADHD psychostimulants possess treatment efficacy because they increase neurotransmitter activity in these systems.<ref name="Malenka ADHD neurosci" /><ref name="Malenka pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |pages=148, 154–157 |edition=2nd |chapter=Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin |quote={{abbr|DA|dopamine}} has multiple actions in the prefrontal cortex. It promotes the 'cognitive control' of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information 'on line' in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. Cognitive control is impaired in several disorders, including attention deficit hyperactivity disorder.&nbsp;... Noradrenergic projections from the {{abbr|LC|locus coeruleus}} thus interact with dopaminergic projections from the {{abbr|VTA|ventral tegmental area}} to regulate cognitive control.&nbsp;... it has not been shown that {{abbr|5HT|serotonin}} makes a therapeutic contribution to treatment of ADHD.}}</ref><ref name="cognition enhancers" /> There may additionally be abnormalities in [[Serotonin|serotonergic]], [[glutamate (neurotransmitter)|glutamatergic]], or [[cholinergic]] pathways.<ref name="cognition enhancers" /><ref name="Cortese-2012">{{cite journal |vauthors=Cortese S |title=The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): what every clinician should know |journal=European Journal of Paediatric Neurology |volume=16 |issue=5 |pages=422–433 |date=September 2012 |pmid=22306277 |doi=10.1016/j.ejpn.2012.01.009}}</ref><ref name="pmid22939004">{{cite journal |vauthors=Lesch KP, Merker S, Reif A, Novak M |title=Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD |journal=[[European Neuropsychopharmacology]] |volume=23 |issue=6 |pages=479–491 |date=June 2013 |pmid=22939004 |doi=10.1016/j.euroneuro.2012.07.013 |s2cid=14701654}}</ref>

PET mapping of neocortex receptor distribution indicates that the distribution of μ-opioid receptors is the strongest contributor to cortical abnormalities in ADHD, followed by CB<sub>1</sub> cannabinoid receptors.<ref>{{Cite journal |last1=Hansen |first1=Justine Y. |last2=Shafiei |first2=Golia |last3=Markello |first3=Ross D. |last4=Smart |first4=Kelly |last5=Cox |first5=Sylvia M. L. |last6=Nørgaard |first6=Martin |last7=Beliveau |first7=Vincent |last8=Wu |first8=Yanjun |last9=Gallezot |first9=Jean-Dominique |last10=Aumont |first10=Étienne |last11=Servaes |first11=Stijn |last12=Scala |first12=Stephanie G. |last13=DuBois |first13=Jonathan M. |last14=Wainstein |first14=Gabriel |last15=Bezgin |first15=Gleb |date=2022 |title=Mapping neurotransmitter systems to the structural and functional organization of the human neocortex |journal=[[Nature Neuroscience]] |language=en |volume=25 |issue=11 |pages=1569–1581 |doi=10.1038/s41593-022-01186-3 |pmid=36303070 |pmc=9630096 |issn=1546-1726}}</ref>

=== Executive function and motivation ===
ADHD arises from a core deficit in executive functions (e.g., [[attentional control]], [[inhibitory control]], and [[working memory]]), which are a set of [[Cognition|cognitive processes]] that are required to successfully select and monitor behaviours that facilitate the attainment of one's chosen goals.<ref name="Malenka pathways" /><ref name="Executive functions" /> The executive function impairments that occur in ADHD individuals result in problems with staying organised, time keeping, [[procrastination]] control, maintaining concentration, paying attention, ignoring distractions, regulating emotions, and remembering details.<ref name="Brown_2008" /><ref name="Malenka ADHD neurosci" /><ref name="Malenka pathways" /> People with ADHD appear to have unimpaired long-term memory, and deficits in long-term recall appear to be attributed to impairments in working memory.<ref name="pmid24232170">{{cite journal |vauthors=Skodzik T, Holling H, Pedersen A |title=Long-Term Memory Performance in Adult ADHD |journal=[[Journal of Attention Disorders]] |volume=21 |issue=4 |pages=267–283 |date=February 2017 |pmid=24232170 |doi=10.1177/1087054713510561 |s2cid=27070077}}</ref> Due to the rates of brain maturation and the increasing demands for executive control as a person gets older, ADHD impairments may not fully manifest themselves until adolescence or even early adulthood.<ref name="Brown_2008" /> Conversely, brain maturation trajectories, potentially exhibiting diverging longitudinal trends in ADHD, may support a later improvement in executive functions after reaching adulthood.<ref name="Tarchi_2022" />

ADHD has also been associated with motivational deficits in children. Children with ADHD often find it difficult to focus on long-term over short-term rewards, and exhibit impulsive behaviour for short-term rewards.<ref name="Motivation">{{cite journal |vauthors=Modesto-Lowe V, Chaplin M, Soovajian V, Meyer A |title=Are motivation deficits underestimated in patients with ADHD? A review of the literature |journal=Postgraduate Medicine |volume=125 |issue=4 |pages=47–52 |date=July 2013 |pmid=23933893 |doi=10.3810/pgm.2013.07.2677 |quote=Behavioral studies show altered processing of reinforcement and incentives in children with ADHD. These children respond more impulsively to rewards and choose small, immediate rewards over larger, delayed incentives. Interestingly, a high intensity of reinforcement is effective in improving task performance in children with ADHD. Pharmacotherapy may also improve task persistence in these children.&nbsp;... Previous studies suggest that a clinical approach using interventions to improve motivational processes in patients with ADHD may improve outcomes as children with ADHD transition into adolescence and adulthood. |s2cid=24817804}}</ref>

=== Paradoxical reaction to neuroactive substances ===
Another sign of the structurally altered signal processing in the central nervous system in this group of people is the conspicuously common [[paradoxical reaction]] ({{circa|10–20%}} of patients). These are unexpected reactions in the opposite direction as with a normal effect, or otherwise significant different reactions. These are reactions to neuroactive substances such as [[local anesthetic]] at the dentist, [[sedative]], [[caffeine]], [[antihistamine]], weak [[neuroleptics]] and central and peripheral [[painkillers]]. Since the causes of ''paradoxical reactions'' are at least partly genetic, it may be useful in critical situations, for example before operations, to ask whether such abnormalities may also exist in family members.<ref name="PMID21886668">{{cite journal |pmc=3163785 |date=2011 |title=Paradoxical Reaction in ADHD |journal=Deutsches Ärzteblatt International |department=Correspondence |volume=108 |issue=31–32 |pages=541; author reply 541–2 |doi=10.3238/arztebl.2011.0541a |pmid=21886668 |vauthors=Langguth B, Bär R, Wodarz N, Wittmann M, Laufkötter R |language=de}}</ref><ref>{{cite journal |vauthors=Laufkötter R, Langguth B, Johann M, Eichhammer P, Hajak G |title=ADHS des Erwachsenenalters und Komorbiditäten |language=de |trans-title= |journal=PsychoNeuro |volume=31 |date=2005 |issue=11 |page=563 |doi=10.1055/s-2005-923370 |doi-access=free}}</ref>