Editing Delirium (section)

==Pathophysiology==
The pathophysiology of delirium is still not well understood, despite extensive research.

===Animal models===
The lack of animal models that are relevant to delirium has left many key questions in delirium pathophysiology unanswered. Earliest rodent models of delirium used [[atropine]] (a [[muscarinic acetylcholine receptor]] blocker) to induce cognitive and electroencephalography (EEG) changes similar to delirium, and other [[anticholinergic]] drugs, such as [[biperiden]] and [[hyoscine]], have produced similar effects. Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a "cholinergic deficiency hypothesis" of delirium.<ref>{{cite journal | vauthors = Hshieh TT, Fong TG, Marcantonio ER, Inouye SK | title = Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 63 | issue = 7 | pages = 764–772 | date = July 2008 | pmid = 18693233 | pmc = 2917793 | doi = 10.1093/gerona/63.7.764 }}</ref>

Profound systemic inflammation occurring during [[sepsis]] is also known to cause delirium (often termed sepsis-associated encephalopathy).<ref>{{cite journal | vauthors = Zampieri FG, Park M, Machado FS, Azevedo LC | title = Sepsis-associated encephalopathy: not just delirium | journal = Clinics | volume = 66 | issue = 10 | pages = 1825–1831 | date = 2011 | pmid = 22012058 | pmc = 3180153 | doi = 10.1590/S1807-59322011001000024 }}</ref> Animal models used to study the interactions between prior degenerative disease and overlying systemic inflammation have shown that even mild systemic inflammation causes acute and transient deficits in working memory among diseased animals.<ref name="Cunningham 2012">{{cite journal | vauthors = Cunningham C, Maclullich AM | title = At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response | journal = Brain, Behavior, and Immunity | volume = 28 | pages = 1–13 | date = February 2013 | pmid = 22884900 | pmc = 4157329 | doi = 10.1016/j.bbi.2012.07.012 }}</ref> Prior [[dementia]] or age-associated cognitive impairment is the primary predisposing factor for clinical delirium and "prior pathology" as defined by these new animal models may consist of synaptic loss, abnormal network connectivity, and "primed [[microglia]]" brain macrophages stimulated by prior neurodegenerative disease and aging to amplify subsequent inflammatory responses in the [[central nervous system]] (CNS).<ref name="Cunningham 2012" />

===Cerebrospinal fluid===
Studies of [[cerebrospinal fluid]] (CSF) in delirium are difficult to perform. Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging. However, a few studies have managed to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.<ref name="Ormseth"/><ref>{{cite journal | vauthors = Derakhshan P, Imani F, Seyed-Siamdoust SA, Garousi S, Nouri N | title = Cerebrospinal Fluid and Spinal Anesthesia Parameters in Healthy Individuals versus Opium-addict Patients during Lower Limb Surgery | journal = Addiction & Health | volume = 12 | issue = 1 | pages = 11–17 | date = January 2020 | pmid = 32582410 | pmc = 7291896 | doi = 10.22122/ahj.v12i1.257 }}</ref><ref>{{cite journal | vauthors = Tigchelaar C, Atmosoerodjo SD, van Faassen M, Wardenaar KJ, De Deyn PP, Schoevers RA, Kema IP, Absalom AR | title = The Anaesthetic Biobank of Cerebrospinal fluid: a unique repository for neuroscientific biomarker research | journal = Annals of Translational Medicine | volume = 9 | issue = 6 | pages = 455 | date = March 2021 | pmid = 33850852 | pmc = 8039635 | doi = 10.21037/atm-20-4498 | doi-access = free }}</ref>

A 2018 [[systematic review]] showed that, broadly, delirium may be associated with neurotransmitter imbalance (namely [[serotonin]] and dopamine signaling), reversible fall in somatostatin, and increased cortisol.<ref name="Hall_2018">{{cite journal | vauthors = Hall RJ, Watne LO, Cunningham E, Zetterberg H, Shenkin SD, Wyller TB, MacLullich AM | title = CSF biomarkers in delirium: a systematic review | journal = International Journal of Geriatric Psychiatry | volume = 33 | issue = 11 | pages = 1479–1500 | date = November 2018 | pmid = 28585290 | doi = 10.1002/gps.4720 | url = http://discovery.ucl.ac.uk/10060989/ | access-date = 2019-07-01 | url-status = live | hdl-access = free | hdl = 20.500.11820/5933392d-bf79-4b57-940f-8a5c51f3b02e | s2cid = 205842730 | archive-url = https://web.archive.org/web/20210828054455/https://discovery.ucl.ac.uk/id/eprint/10060989/ | archive-date = 2021-08-28 }}</ref> The leading "neuroinflammatory hypothesis" (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described,<ref>{{cite journal | vauthors = Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB | title = The neuroinflammatory hypothesis of delirium | journal = Acta Neuropathologica | volume = 119 | issue = 6 | pages = 737–754 | date = June 2010 | pmid = 20309566 | doi = 10.1007/s00401-010-0674-1 | hdl-access = free | s2cid = 206972133 | hdl = 10400.4/806 }}</ref> but current evidence is still conflicting and fails to concretely support this hypothesis.<ref name="Hall_2018" />

===Neuroimaging===
[[Neuroimaging]] provides an important avenue to explore the mechanisms that are responsible for delirium.<ref name="Nitchingham_2018">{{cite journal | vauthors = Nitchingham A, Kumar V, Shenkin S, Ferguson KJ, Caplan GA | title = A systematic review of neuroimaging in delirium: predictors, correlates and consequences | journal = International Journal of Geriatric Psychiatry | volume = 33 | issue = 11 | pages = 1458–1478 | date = November 2018 | pmid = 28574155 | doi = 10.1002/gps.4724 | s2cid = 20723293 }}</ref><ref name="Soiza_2008">{{cite journal | vauthors = Soiza RL, Sharma V, Ferguson K, Shenkin SD, Seymour DG, Maclullich AM | title = Neuroimaging studies of delirium: a systematic review | journal = Journal of Psychosomatic Research | volume = 65 | issue = 3 | pages = 239–248 | date = September 2008 | pmid = 18707946 | doi = 10.1016/j.jpsychores.2008.05.021 }}</ref> Despite progress in the development of [[magnetic resonance imaging]] (MRI), the large variety in imaging-based findings has limited our understanding of the changes in the brain that may be linked to delirium. Some challenges associated with imaging people diagnosed with delirium include participant recruitment and inadequate consideration of important confounding factors such as history of [[dementia]] and/or [[Depression (mood)|depression]], which are known to be associated with overlapping changes in the brain also observed on MRI.<ref name="Nitchingham_2018" />

Evidence for changes in structural and functional markers include: changes in [[White matter|white-matter]] integrity (white matter lesions), decreases in brain volume (likely as a result of tissue [[atrophy]]), abnormal [[Resting state fMRI|functional connectivity]] of brain regions responsible for normal processing of executive function, sensory processing, attention, emotional regulation, memory, and orientation, differences in autoregulation of the vascular vessels in the brain, reduction in cerebral blood flow and possible changes in brain metabolism (including cerebral tissue oxygenation and glucose hypometabolism).<ref name="Nitchingham_2018" /><ref name="Soiza_2008" /> Altogether, these changes in MRI-based measurements invite further investigation of the mechanisms that may underlie delirium, as a potential avenue to improve clinical management of people with this condition.<ref name="Nitchingham_2018" />

===Neurophysiology===
[[Electroencephalography]] (EEG) allows for continuous capture of global brain function and brain connectivity, and is useful in understanding real-time physiologic changes during delirium.<ref name="Shafi_2017">{{cite journal | vauthors = Shafi MM, Santarnecchi E, Fong TG, Jones RN, Marcantonio ER, Pascual-Leone A, Inouye SK | title = Advancing the Neurophysiological Understanding of Delirium | journal = Journal of the American Geriatrics Society | volume = 65 | issue = 6 | pages = 1114–1118 | date = June 2017 | pmid = 28165616 | pmc = 5576199 | doi = 10.1111/jgs.14748 }}</ref> Since the 1950s, delirium has been known to be associated with slowing of resting-state EEG rhythms, with abnormally decreased background alpha power and increased theta and delta frequency activity.<ref name="Shafi_2017" /><ref>{{cite journal | vauthors = Engel GL, Romano J | title = Delirium, a syndrome of cerebral insufficiency. 1959 | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 16 | issue = 4 | pages = 526–538 | date = Fall 2004 | pmid = 15616182 | doi = 10.1176/appi.neuropsych.16.4.526 }}</ref>

From such evidence, a 2018 systematic review proposed a conceptual model that delirium results when insults/stressors trigger a breakdown of brain network dynamics in individuals with low brain resilience (i.e. people who already have underlying problems of low neural connectivity and/or low [[neuroplasticity]] like those with Alzheimer's disease).<ref name="Shafi_2017" />

===Neuropathology===
Only a handful of studies exist where there has been an attempt to correlate delirium with pathological findings at autopsy. One research study has been reported on 7 people who died during ICU admission.<ref>{{cite journal | vauthors = Janz DR, Abel TW, Jackson JC, Gunther ML, Heckers S, Ely EW | title = Brain autopsy findings in intensive care unit patients previously suffering from delirium: a pilot study | journal = Journal of Critical Care | volume = 25 | issue = 3 | pages = 538.e7–538.12 | date = September 2010 | pmid = 20580199 | pmc = 3755870 | doi = 10.1016/j.jcrc.2010.05.004 }}</ref> Each case was admitted with a range of primary pathologies, but all had [[acute respiratory distress syndrome]] and/or [[septic shock]] contributing to the delirium, 6 showed evidence of low brain perfusion and diffuse vascular injury, and 5 showed [[Hippocampus|hippocampal]] involvement. A case-control study showed that 9 delirium cases showed higher expression of [[HLA-DR]] and [[CD68]] (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of [[astrocyte]] activity) than age-matched controls; this supports a neuroinflammatory cause to delirium, but the conclusions are limited by methodological issues.<ref>{{cite journal | vauthors = Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE | title = Neuroinflammation in delirium: a postmortem case-control study | journal = Rejuvenation Research | volume = 14 | issue = 6 | pages = 615–622 | date = December 2011 | pmid = 21978081 | pmc = 4309948 | doi = 10.1089/rej.2011.1185 }}</ref>

A 2017 retrospective study correlating autopsy data with [[mini–mental state examination]] (MMSE) scores from 987 brain donors found that delirium combined with a pathological process of dementia accelerated MMSE score decline more than either individual process.<ref>{{cite journal | vauthors = Davis DH, Muniz-Terrera G, Keage HA, Stephan BC, Fleming J, Ince PG, Matthews FE, Cunningham C, Ely EW, MacLullich AM, Brayne C | title = Association of Delirium With Cognitive Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies | journal = JAMA Psychiatry | volume = 74 | issue = 3 | pages = 244–251 | date = March 2017 | pmid = 28114436 | pmc = 6037291 | doi = 10.1001/jamapsychiatry.2016.3423 }}</ref>