Editing Schizophrenia (section)

==Causes==
{{Main|Causes of schizophrenia}}{{See also|Aberrant salience}}
The causes of schizophrenia are still unknown. Several models have been put forward to explain the link between altered brain function and schizophrenia.<ref name=Lancet2009/> The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the [[Gene-environment interaction|interaction between genes and the environment]].<ref>{{cite journal |vauthors=Hayes D, Kyriakopoulos M |title=Dilemmas in the treatment of early-onset first-episode psychosis |journal=Therapeutic Advances in Psychopharmacology |volume=8 |issue=8 |pages=231–239 |date=August 2018 |pmid=30065814 |doi=10.1177/2045125318765725|pmc=6058451 |doi-access= free }}</ref> Extensive studies support this model.<ref name=George2017/> Maternal infections, malnutrition and [[Complications of pregnancy|complications during pregnancy]] and [[Obstetric labor complication|childbirth]] are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18 and 25, a period that overlaps with certain stages of neurodevelopment.<ref>{{cite journal |vauthors=Cannon TD |title=How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis |journal=Trends Cogn Sci |volume=19 |issue=12 |pages=744–756 |date= December 2015 |pmid=26493362 |pmc=4673025 |doi=10.1016/j.tics.2015.09.009 }}</ref> Gene-environment interactions lead to deficits in the [[neural circuit]]ry that affect sensory and cognitive functions.<ref name=George2017/>

The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia.<ref>{{cite journal |vauthors=Correll CU, Schooler NR |title=Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment |journal= Neuropsychiatric Disease and Treatment |volume=16 |pages=519–534 |date=2020 |pmid=32110026 |doi=10.2147/NDT.S225643 |pmc=7041437 |doi-access=free }}</ref> The most common model put forward was the [[dopamine hypothesis of schizophrenia]], which attributes psychosis to the mind's faulty interpretation of the misfiring of [[Dopaminergic pathways|dopaminergic neurons]].<ref>{{cite journal | vauthors = Howes OD | title = The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia | journal = Biological Psychiatry | date = 1 January 2017 | volume = 81 | issue = 1 | pages = 9–20 | doi = 10.1016/j.biopsych.2016.07.014 | pmid = 27720198| pmc = 5675052 }}</ref> This has been directly related to the symptoms of delusions and hallucinations.<ref>{{cite journal|vauthors=Broyd A, Balzan RP, Woodward TS, Allen P|date=June 2017|title=Dopamine, cognitive biases and assessment of certainty: A neurocognitive model of delusions| url= https://kclpure.kcl.ac.uk/portal/en/publications/dopamine-cognitive-biases-and-assessment-of-certainty-a-neurocognitive-model-of-delusions(138513dd-3a44-4deb-bac1-be45767ef51b).html|journal=Clinical Psychology Review|volume=54|pages=96–106|doi= 10.1016/j.cpr.2017.04.006 |pmid= 28448827|s2cid=3729566 }}</ref><ref name=Lancet2014>{{cite journal | vauthors = Howes OD, Murray RM | title = Schizophrenia: an integrated sociodevelopmental-cognitive model | journal = Lancet | volume = 383 | issue = 9929 | pages = 1677–1687 | date = May 2014 | pmid = 24315522 | pmc = 4127444 | doi = 10.1016/S0140-6736(13)62036-X }}</ref><ref>{{cite journal | vauthors = Grace AA | title = Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression | journal = Nature Reviews. Neuroscience | volume = 17 | issue = 8 | pages = 524–532 | date = August 2016 | pmid = 27256556 | pmc = 5166560 | doi = 10.1038/nrn.2016.57 }}</ref> Abnormal dopamine signaling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis.<ref>{{cite journal | vauthors = Fusar-Poli P, Meyer-Lindenberg A | title = Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies | journal = Schizophrenia Bulletin | volume = 39 | issue = 1 | pages = 33–42 | date = January 2013 | pmid = 22282454 | pmc = 3523905 | doi = 10.1093/schbul/sbr180 }}</ref><ref>{{cite journal | vauthors = Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S | title = The nature of dopamine dysfunction in schizophrenia and what this means for treatment | journal = Archives of General Psychiatry | volume = 69 | issue = 8 | pages = 776–786 | date = August 2012 | pmid = 22474070 | pmc = 3730746 | doi = 10.1001/archgenpsychiatry.2012.169 }}</ref> A decrease in [[dopamine receptor D1|D<sub>1</sub> receptors]] in the [[dorsolateral prefrontal cortex]] may also be responsible for deficits in [[working memory]].<ref>{{cite journal | vauthors = Arnsten AF, Girgis RR, Gray DL, Mailman RB | title = Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia | journal = Biological Psychiatry | volume = 81 | issue = 1 | pages = 67–77 | date = January 2017 | pmid = 26946382 | pmc = 4949134 | doi = 10.1016/j.biopsych.2015.12.028 }}</ref><ref>{{cite journal | vauthors = Maia TV, Frank MJ | title = An Integrative Perspective on the Role of Dopamine in Schizophrenia | journal = Biological Psychiatry | volume = 81 | issue = 1 | pages = 52–66 | date = January 2017 | pmid = 27452791 | pmc = 5486232 | doi = 10.1016/j.biopsych.2016.05.021 }}</ref>

The [[glutamate hypothesis of schizophrenia]] links alterations between [[glutamatergic neurotransmission]] and the [[neural oscillation]]s that affect [[Thalamocortical radiations|connections between the thalamus and the cortex]].<ref name=Pratt2017/> Studies have shown that a reduced expression of a [[glutamate receptor]] – [[NMDA receptor]], and glutamate blocking drugs such as [[phencyclidine]] and [[ketamine]] can mimic the symptoms and cognitive problems associated with schizophrenia.<ref name=Pratt2017>{{cite journal | vauthors = Pratt J, Dawson N, Morris BJ, Grent-'t-Jong T, Roux F, Uhlhaas PJ | title = Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations: A unique window into the origins of ScZ? | journal = Schizophrenia Research | volume = 180 | pages = 4–12 | date = February 2017 | pmid = 27317361 | doi = 10.1016/j.schres.2016.05.013 | s2cid = 205075178 | url = https://eprints.gla.ac.uk/132874/1/132874.pdf }}</ref><ref>{{cite journal | vauthors = Catts VS, Lai YL, Weickert CS, Weickert TW, Catts SV | title = A quantitative review of the post-mortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits? | journal = Biological Psychology | volume = 116 | pages = 57–67 | date = April 2016 | pmid = 26549579 | doi = 10.1016/j.biopsycho.2015.10.013 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Michie PT, Malmierca MS, Harms L, Todd J | s2cid = 41179430 | title = The neurobiology of MMN and implications for schizophrenia | journal = Biological Psychology | volume = 116 | pages = 90–97 | date = April 2016 | pmid = 26826620 | doi = 10.1016/j.biopsycho.2016.01.011 }}</ref> Post-mortem studies consistently find that a subset of these neurons fail to express [[Glutamate decarboxylase#Schizophrenia and bipolar disorder|GAD67]] ([[GAD1]]),<ref name = Marin2012>{{cite journal | vauthors = Marín O | s2cid = 205507186 | title = Interneuron dysfunction in psychiatric disorders | journal = Nature Reviews. Neuroscience | volume = 13 | issue = 2 | pages = 107–120 | date = January 2012 | pmid = 22251963 | doi = 10.1038/nrn3155 }}</ref> in addition to abnormalities in [[brain morphometry]]. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles needed during working memory tasks. These give the neural oscillations produced as [[gamma wave]]s that have a frequency of between 30 and 80 [[hertz]]. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality.<ref name = Marin2012 /><ref>{{cite journal | vauthors = Lewis DA, Hashimoto T, Volk DW | s2cid = 3335493 | title = Cortical inhibitory neurons and schizophrenia | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 4 | pages = 312–324 | date = April 2005 | pmid = 15803162 | doi = 10.1038/nrn1648 }}</ref><ref>{{cite journal | vauthors = Senkowski D, Gallinat J | s2cid = 206104940 | title = Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia | journal = Biological Psychiatry | volume = 77 | issue = 12 | pages = 1010–1019 | date = June 2015 | pmid = 25847179 | doi = 10.1016/j.biopsych.2015.02.034 |quote=Several studies that investigated perceptual processes found impaired GBR in ScZ patients over sensory areas, such as the auditory and visual cortex. Moreover, studies examining steady-state auditory-evoked potentials showed deficits in the gen- eration of oscillations in the gamma band.}}</ref><ref>{{cite journal | vauthors = Reilly TJ, Nottage JF, Studerus E, Rutigliano G, Micheli AI, Fusar-Poli P, McGuire P | title = Gamma band oscillations in the early phase of psychosis: A systematic review | journal = Neuroscience and Biobehavioral Reviews | volume = 90 | pages = 381–399 | date = July 2018 | pmid = 29656029 | doi = 10.1016/j.neubiorev.2018.04.006 | quote = Decreased gamma power in response to a task was a relatively consistent finding, with 5 out of 6 studies reported reduced evoked or induced power. | s2cid = 4891072 | url = https://kclpure.kcl.ac.uk/portal/en/publications/e2f500b7-f358-433d-9f9c-7f6b9c52bb2f }}</ref> An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of [[astrocyte]]s. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia.<ref name=Sloan2014>{{cite journal |vauthors=Sloan SA, Barres BA |title=Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders |journal=Curr Opin Neurobiol |volume=27 |pages=75–81 |date=August 2014 |pmid=24694749 |pmc=4433289 |doi=10.1016/j.conb.2014.03.005 }}</ref> Evidence suggests that reduced numbers of astrocytes in deeper cortical layers are assocociated with a diminished expression of [[EAAT2]], a [[glutamate transporter]] in astrocytes; supporting the glutamate hypothesis.<ref name=Sloan2014/>

Deficits in [[executive function]]s, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to use this to direct cognition and behavior.<ref>{{cite journal | vauthors = Lesh TA, Niendam TA, Minzenberg MJ, Carter CS | title = Cognitive control deficits in schizophrenia: mechanisms and meaning |journal=Neuropsychopharmacology | volume = 36 | issue = 1 | pages = 316–338 | date = January 2011 | pmid = 20844478 |pmc = 3052853 |doi =10.1038/npp.2010.156 }}</ref><ref>{{cite journal | vauthors = Barch DM, Ceaser A | title = Cognition in schizophrenia: core psychological and neural mechanisms | journal = Trends in Cognitive Sciences | volume = 16 | issue = 1 | pages = 27–34 | date = January 2012 | pmid = 22169777 | pmc = 3860986 | doi = 10.1016/j.tics.2011.11.015 }}</ref> These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced [[neuropil]], evidenced by increased [[pyramidal cell]] density and reduced [[dendritic spine]] density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced [[grey matter]] volume in association with deficits in working memory tasks.<ref>{{cite journal | vauthors = Eisenberg DP, Berman KF | title = Executive function, neural circuitry, and genetic mechanisms in schizophrenia | journal = Neuropsychopharmacology | volume = 35 |issue = 1 | pages = 258–277 | date = January 2010 | pmid = 19693005 | pmc = 2794926 | doi = 10.1038/npp.2009.111}}</ref>

Positive symptoms have been linked to cortical thinning in the [[superior temporal gyrus]].<ref>{{cite journal | vauthors = Walton E, Hibar DP, van Erp TG, Potkin SG, Roiz-Santiañez R, Crespo-Facorro B, Suarez-Pinilla P, Van Haren NE, de Zwarte SM, Kahn RS, Cahn W, Doan NT, Jørgensen KN, Gurholt TP, Agartz I, Andreassen OA, Westlye LT, Melle I, Berg AO, Mørch-Johnsen L, Faerden A, Flyckt L, Fatouros-Bergman H, Jönsson EG, Hashimoto R, Yamamori H, Fukunaga M, Preda A, De Rossi P, Piras F, Banaj N, Ciullo V, Spalletta G, Gur RE, Gur RC, Wolf DH, Satterthwaite TD, Beard LM, Sommer IE, Koops S, Gruber O, Richter A, Krämer B, Kelly S, Donohoe G, McDonald C, Cannon DM, Corvin A, Gill M, Di Giorgio A, Bertolino A, Lawrie S, Nickson T, Whalley HC, Neilson E, Calhoun VD, Thompson PM, Turner JA, Ehrlich S | title = Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium | journal = Acta Psychiatrica Scandinavica | volume = 135 | issue = 5 | pages = 439–447 | date = May 2017 | pmid = 28369804 | pmc = 5399182 | doi = 10.1111/acps.12718 }}</ref> The severity of negative symptoms has been linked to reduced thickness in the left medial [[orbitofrontal cortex]].<ref>{{cite journal | vauthors = Walton E, Hibar DP, van Erp TG, Potkin SG, Roiz-Santiañez R, Crespo-Facorro B, Suarez-Pinilla P, van Haren NE, de Zwarte SM, Kahn RS, Cahn W, Doan NT, Jørgensen KN, Gurholt TP, Agartz I, Andreassen OA, Westlye LT, Melle I, Berg AO, Morch-Johnsen L, Færden A, Flyckt L, Fatouros-Bergman H, Jönsson EG, Hashimoto R, Yamamori H, Fukunaga M, Jahanshad N, De Rossi P, Piras F, Banaj N, Spalletta G, Gur RE, Gur RC, Wolf DH, Satterthwaite TD, Beard LM, Sommer IE, Koops S, Gruber O, Richter A, Krämer B, Kelly S, Donohoe G, McDonald C, Cannon DM, Corvin A, Gill M, Di Giorgio A, Bertolino A, Lawrie S, Nickson T, Whalley HC, Neilson E, Calhoun VD, Thompson PM, Turner JA, Ehrlich S | title = Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium | journal = Psychological Medicine | volume = 48 | issue = 1 | pages = 82–94 | date = January 2018 | pmid = 28545597 | pmc = 5826665 | doi = 10.1017/S0033291717001283 | collaboration = Karolinska Schizophrenia Project Consortium (KaSP) }}</ref> Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that [[Hedonism|hedonic responses]] are intact in schizophrenia,<ref>{{cite journal | vauthors = Cohen AS, Minor KS | title = Emotional experience in patients with schizophrenia revisited: meta-analysis of laboratory studies | journal = Schizophrenia Bulletin | volume = 36 | issue = 1 | pages = 143–150 | date = January 2010 | pmid = 18562345 | pmc = 2800132 | doi = 10.1093/schbul/sbn061 }}</ref> and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward.<ref>{{cite journal | vauthors = Strauss GP, Gold JM | title = A new perspective on anhedonia in schizophrenia | journal = The American Journal of Psychiatry | volume = 169 | issue = 4 | pages = 364–373 | date = April 2012 | pmid = 22407079 | pmc = 3732829 | doi = 10.1176/appi.ajp.2011.11030447 }}</ref> Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses.<ref>{{cite book | vauthors = Young J, Anticevic A, Barch D | veditors = Charney D, Buxbaum J, Sklar P, Nestler E |title=Charney & Nestler's Neurobiology of Mental Illness |date=2018 |publisher=Oxford University Press. |location=New York |isbn=9780190681425 |pages=215, 217 |edition=5th |chapter=Cognitive and Motivational Neuroscience of Psychotic Disorders |quote=Several recent reviews (e.g., Cohen and Minor, 2010) have found that individuals with schizophrenia show relatively intact self-reported emotional responses to affect-eliciting stimuli as well as other indicators of intact response(215)...Taken together, the literature increasingly suggests that there may be a deficit in putatively DA-mediated reward learning and/ or reward prediction functions in schizophrenia. Such findings suggest that impairment in striatal reward prediction mechanisms may influence "wanting" in schizophrenia in a way that reduces the ability of individuals with schizophrenia to use anticipated rewards to drive motivated behavior.(217)}}</ref>

Another theory links abnormal [[Lateralization of brain function|brain lateralization]] to the development of [[Handedness|being left-handed]] which is significantly more common in those with schizophrenia.<ref name=Wilberg2019>{{cite journal | vauthors = Wiberg A, Ng M, Al Omran Y, Alfaro-Almagro F, McCarthy P, Marchini J, Bennett DL, Smith S, Douaud G, Furniss D | title = Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics | journal = Brain | volume = 142 | issue = 10 | pages = 2938–2947 | date = October 2019 | pmid = 31504236 | pmc = 6763735 | doi = 10.1093/brain/awz257 }}</ref> This abnormal development of hemispheric asymmetry is noted in schizophrenia.<ref>{{cite book |vauthors=Tzourio-Mazoyer N, Kennedy H, Van Essen DC, Christen Y |title=Micro-, Meso- and Macro-Connectomics of the Brain |chapter=Intra- and Inter-hemispheric Connectivity Supporting Hemispheric Specialization |series=Research and Perspectives in Neurosciences |date=2016 |pages=129–146 |doi=10.1007/978-3-319-27777-6_9 |pmid=28590670|isbn=978-3-319-27776-9 |s2cid=147813648 }}</ref> Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralization and schizophrenia.<ref name=Wilberg2019/><ref>{{cite journal | vauthors = Ocklenburg S, Güntürkün O, Hugdahl K, Hirnstein M | title = Laterality and mental disorders in the postgenomic age—A closer look at schizophrenia and language lateralization | journal = Neuroscience and Biobehavioral Reviews | volume = 59 | pages = 100–110 | date = December 2015 | pmid = 26598216 | doi = 10.1016/j.neubiorev.2015.08.019 | s2cid = 15983622 }}</ref>

[[Bayesian approaches to brain function|Bayesian models of brain functioning]] have been used to link abnormalities in cellular functioning to symptoms.<ref>{{cite journal | vauthors = Friston KJ, Stephan KE, Montague R, Dolan RJ | title = Computational psychiatry: the brain as a phantastic organ | journal = The Lancet. Psychiatry | volume = 1 | issue = 2 | pages = 148–158 | date = July 2014 | pmid = 26360579 | doi = 10.1016/S2215-0366(14)70275-5 | s2cid = 15504512 }}</ref><ref>{{cite journal | vauthors = Griffin JD, Fletcher PC | title = Predictive Processing, Source Monitoring, and Psychosis | journal = Annual Review of Clinical Psychology | volume = 13 | pages = 265–289 | date = May 2017 | pmid = 28375719 | pmc = 5424073 | doi = 10.1146/annurev-clinpsy-032816-045145}}</ref> Both hallucinations and delusions have been suggested to reflect improper encoding of [[Prior probability|prior expectations]], thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of [[neural circuits|circuits]] that mediate [[predictive coding]], reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.<ref>{{cite journal | vauthors = Fletcher PC, Frith CD | s2cid = 6219485 | title = Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 1 | pages = 48–58 | date = January 2009 | pmid = 19050712 | doi = 10.1038/nrn2536 | url = https://pure.au.dk/ws/files/48560345/fletcher_frithNRN.pdf }}</ref><ref>{{cite journal | vauthors = Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH | title = Toward a neurobiology of delusions | journal = Progress in Neurobiology | volume = 92 | issue = 3 | pages = 345–369 | date = November 2010 | pmid = 20558235 | pmc = 3676875 | doi = 10.1016/j.pneurobio.2010.06.007 }}</ref><ref>{{cite journal | vauthors = Bastos AM, Usrey WM, Adams RA, Mangun GR, Fries P, Friston KJ | title = Canonical microcircuits for predictive coding | journal = Neuron | volume = 76 | issue = 4 | pages = 695–711 | date = November 2012 | pmid = 23177956 | pmc = 3777738 | doi = 10.1016/j.neuron.2012.10.038 }}</ref>