Editing Post-traumatic stress disorder (section)

=== Neuroendocrinology ===
PTSD symptoms may result when a traumatic event causes an over-reactive adrenaline response, which creates deep neurological patterns in the brain. These patterns can persist long after the event that triggered the fear, making an individual hyper-responsive to future fearful situations.<ref name="Rothschild 2000" /><ref name="secret">{{cite AV media |url=https://www.pbs.org/wnet/brain/outreach/episode4.html |publisher=PBS |title=The Secret Life of the Brain (Series), episode 4 |year=2001 |access-date=2014-01-29 |url-status=live |archive-url=https://web.archive.org/web/20140202181815/http://www.pbs.org/wnet/brain/outreach/episode4.html |archive-date=2014-02-02 }}</ref> During traumatic experiences, the high levels of stress hormones secreted suppress [[hypothalamus|hypothalamic]] activity that may be a major factor toward the development of PTSD.<ref name="PTSD fact and fiction">{{cite journal |vauthors=Zohar J, Juven-Wetzler A, Myers V, Fostick L |s2cid=206142172 |title=Post-traumatic stress disorder: facts and fiction |journal=[[Current Opinion in Psychiatry]] |volume=21 |issue=1 |pages=74–7 |date=January 2008 |pmid=18281844 |doi=10.1097/YCO.0b013e3282f269ee}}</ref>

PTSD causes [[biochemistry|biochemical]] changes in the brain and body, that differ from other psychiatric disorders such as [[major depression]]. Individuals diagnosed with PTSD respond more strongly to a [[dexamethasone suppression test]] than individuals diagnosed with [[clinical depression]].<ref>{{cite journal |vauthors=Yehuda R, Halligan SL, Golier JA, Grossman R, Bierer LM |s2cid=21615196 |title=Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder |journal=[[Psychoneuroendocrinology]] |volume=29 |issue=3 |pages=389–404 |date=April 2004 |pmid=14644068 |doi=10.1016/S0306-4530(03)00052-0 }}</ref><ref>{{cite journal |vauthors=Yehuda R, Halligan SL, Grossman R, Golier JA, Wong C |s2cid=21403230 |title=The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder |journal=[[Biological Psychiatry]] |volume=52 |issue=5 |pages=393–403 |date=September 2002 |pmid=12242055 |doi=10.1016/S0006-3223(02)01357-4}}</ref>

Most people with PTSD show a low secretion of [[cortisol]] and high secretion of [[catecholamine]]s in [[urine]],<ref>{{cite journal |vauthors=Heim C, Ehlert U, Hellhammer DH |s2cid=25151441 |title=The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders |journal=[[Psychoneuroendocrinology]] |volume=25 |issue=1 |pages=1–35 |date=January 2000 |pmid=10633533 |doi=10.1016/S0306-4530(99)00035-9}}</ref> with a [[norepinephrine]]/cortisol ratio consequently higher than comparable non-diagnosed individuals.<ref>{{cite journal |vauthors=Mason JW, Giller EL, Kosten TR, Harkness L |s2cid=24585702 |title=Elevation of urinary norepinephrine/cortisol ratio in posttraumatic stress disorder |journal=The Journal of Nervous and Mental Disease |volume=176 |issue=8 |pages=498–502 |date=August 1988 |pmid=3404142 |doi=10.1097/00005053-198808000-00008}}</ref> This is in contrast to the normative [[fight-or-flight response]], in which both catecholamine and cortisol levels are elevated after exposure to a stressor.<ref>{{cite journal |vauthors=Bohnen N, Nicolson N, Sulon J, Jolles J |title=Coping style, trait anxiety and cortisol reactivity during mental stress |journal=[[Journal of Psychosomatic Research]] |volume=35 |issue=2–3 |pages=141–7 |year=1991 |pmid=2046048 |doi=10.1016/0022-3999(91)90068-Y |citeseerx=10.1.1.467.4323}}</ref>

Brain catecholamine levels are high,<ref>{{cite journal |vauthors=Geracioti TD, Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE, Kasckow JW |title=CSF norepinephrine concentrations in posttraumatic stress disorder |journal=The American Journal of Psychiatry |volume=158 |issue=8 |pages=1227–30 |date=August 2001 |pmid=11481155 |doi=10.1176/appi.ajp.158.8.1227}}</ref> and [[corticotropin-releasing factor]] (CRF) concentrations are high.<ref>{{cite journal |vauthors=Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L, Johnson JE, Cerbone A, Malaspina D |s2cid=35766262 |title=Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects |journal=[[Biological Psychiatry]] |volume=54 |issue=12 |pages=1382–8 |date=December 2003 |pmid=14675802 |doi=10.1016/S0006-3223(03)00571-7}}</ref><ref>{{Cite book |vauthors=de Kloet CS, Vermetten E, Geuze E, Lentjes EG, Heijnen CJ, Stalla GK, Westenberg HG |volume=167 |pages=287–91 |year=2008 |pmid=18037027 |doi=10.1016/S0079-6123(07)67025-3 |isbn=978-0-444-53140-7 |series=Progress in Brain Research |title=Stress Hormones and Post Traumatic Stress Disorder Basic Studies and Clinical Perspectives |chapter=Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder}}</ref> Together, these findings suggest abnormality in the [[hypothalamic-pituitary-adrenal axis|hypothalamic-pituitary-adrenal (HPA) axis]].

The maintenance of fear has been shown to include the HPA axis, the [[locus coeruleus]]-[[noradrenergic]] systems, and the connections between the [[limbic system]] and [[frontal cortex]]. The HPA axis that coordinates the hormonal response to stress,<ref name="Radley 2011 481–497">{{cite journal |vauthors=Radley JJ, Kabbaj M, Jacobson L, Heydendael W, Yehuda R, Herman JP|author-link6=James P. Herman |title=Stress risk factors and stress-related pathology: neuroplasticity, epigenetics and endophenotypes |journal=Stress |volume=14 |issue=5 |pages=481–97 |date=September 2011 |pmid=21848436 |pmc=3641164 |doi=10.3109/10253890.2011.604751}}</ref> which activates the LC-noradrenergic system, is implicated in the over-consolidation of memories that occurs in the aftermath of trauma.<ref name="Pitman 1989">{{cite journal |vauthors=Pitman RK |s2cid=39057765 |title=Post-traumatic stress disorder, hormones, and memory |journal=[[Biological Psychiatry]] |volume=26 |issue=3 |pages=221–3 |date=July 1989 |pmid=2545287 |doi=10.1016/0006-3223(89)90033-4}}</ref> This over-consolidation increases the likelihood of one's developing PTSD. The [[amygdala]] is responsible for threat detection and the conditioned and unconditioned fear responses that are carried out as a response to a threat.<ref name="Skelton 2012 628–637" />

The HPA axis is responsible for coordinating the hormonal response to stress.<ref name="Skelton 2012 628–637">{{cite journal |vauthors=Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B |title=PTSD and gene variants: new pathways and new thinking |journal=[[Neuropharmacology]] |volume=62 |issue=2 |pages=628–37 |date=February 2012 |pmid=21356219 |pmc=3136568 |doi=10.1016/j.neuropharm.2011.02.013}}</ref> Given the strong cortisol suppression to [[dexamethasone]] in PTSD, HPA axis abnormalities are likely predicated on strong negative feedback inhibition of cortisol, itself likely due to an increased sensitivity of [[glucocorticoid receptor]]s.<ref>{{cite journal |vauthors=Yehuda R |title=Biology of posttraumatic stress disorder |journal=The Journal of Clinical Psychiatry |volume=62 |issue=Suppl 17 |pages=41–46 |year=2001 |pmid=11495096 |series=62}}</ref>

PTSD has been hypothesized to be a maladaptive learning pathway to fear response through a hypersensitive, hyperreactive, and hyperresponsive HPA axis.<ref>{{cite journal |vauthors=Yehuda R |s2cid=19767960 |title=Clinical relevance of biologic findings in PTSD |journal=The Psychiatric Quarterly |volume=73 |issue=2 |pages=123–33 |year=2002 |pmid=12025720 |doi=10.1023/A:1015055711424}}</ref>

Low [[cortisol]] levels may predispose individuals to PTSD: Following war trauma, [[Sweden|Swedish]] soldiers serving in [[Bosnia and Herzegovina]] with low pre-service salivary cortisol levels had a higher risk of reacting with PTSD symptoms, following war trauma, than soldiers with normal pre-service levels.<ref>{{cite journal |vauthors=Aardal-Eriksson E, Eriksson TE, Thorell LH |s2cid=9149956 |title=Salivary cortisol, posttraumatic stress symptoms, and general health in the acute phase and during 9-month follow-up |journal=[[Biological Psychiatry]] |volume=50 |issue=12 |pages=986–93 |date=December 2001 |pmid=11750895 |doi=10.1016/S0006-3223(01)01253-7}}</ref> Because cortisol is normally important in restoring [[homeostasis]] after the stress response, it is thought that trauma survivors with low cortisol experience a poorly contained—that is, longer and more distressing—response, setting the stage for PTSD.

It is thought that the locus coeruleus-noradrenergic system mediates the over-consolidation of fear memory. High levels of cortisol reduce noradrenergic activity, and because people with PTSD tend to have reduced levels of cortisol, it has been proposed that individuals with PTSD cannot regulate the increased noradrenergic response to traumatic stress.<ref name="PTSD fact and fiction"/> Intrusive memories and conditioned fear responses are thought to be a result of the response to associated triggers. [[Neuropeptide Y]] (NPY) has been reported to reduce the release of norepinephrine and has been demonstrated to have [[anxiolytic]] properties in animal models. Studies have shown people with PTSD demonstrate reduced levels of NPY, possibly indicating their increased anxiety levels.<ref name="Skelton 2012 628–637" />

Other studies indicate that people with PTSD have chronically low levels of [[serotonin]], which contributes to the commonly associated behavioral symptoms such as anxiety, ruminations, irritability, aggression, suicidality, and impulsivity.<ref name="Olszewski 2005 40">{{cite journal |vauthors=Olszewski TM, Varrasse JF |title=The neurobiology of PTSD: implications for nurses |journal=[[Journal of Psychosocial Nursing and Mental Health Services]] |volume=43 |issue=6 |pages=40–7 |date=June 2005 |pmid=16018133 |doi=10.3928/02793695-20050601-09}}</ref> Serotonin also contributes to the stabilization of glucocorticoid production.

[[Dopamine]] levels in a person with PTSD can contribute to symptoms: low levels can contribute to [[anhedonia]], [[apathy]], [[Attentional control|impaired attention]], and motor deficits; high levels can contribute to [[psychosis]], [[Psychomotor agitation|agitation]], and restlessness.<ref name="Olszewski 2005 40" />

Studies have also described elevated concentrations of the [[thyroid hormone]] [[triiodothyronine]] in PTSD.<ref name="Chatzitomaris_2017">{{cite journal |vauthors=Chatzitomaris A, Hoermann R, Midgley JE, Hering S, Urban A, Dietrich B, Abood A, Klein HH, Dietrich JW |title=Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming |journal=[[Frontiers in Endocrinology]] |volume=8 |pages=163 |date=20 July 2017 |pmid=28775711 |pmc=5517413 |doi=10.3389/fendo.2017.00163 |doi-access=free}}</ref> This kind of type 2 [[Allostatic load|allostatic]] adaptation may contribute to increased sensitivity to catecholamines and other stress mediators.

Hyperresponsiveness in the norepinephrine system can also be caused by continued exposure to high stress. Overactivation of norepinephrine receptors in the prefrontal cortex can be connected to the flashbacks and nightmares frequently experienced by those with PTSD. A decrease in other norepinephrine functions (awareness of the current environment) prevents the memory mechanisms in the brain from processing the experience, and emotions the person is experiencing during a flashback are not associated with the current environment.<ref name="Olszewski 2005 40" />

There is considerable controversy within the medical community regarding the neurobiology of PTSD. A 2012 review showed no clear relationship between cortisol levels and PTSD. The majority of reports indicate people with PTSD have elevated levels of [[corticotropin-releasing hormone]], lower basal [[cortisol]] levels, and enhanced negative feedback suppression of the HPA axis by [[dexamethasone]].<ref name="Skelton 2012 628–637" /><ref>{{cite journal |vauthors=Lindley SE, Carlson EB, Benoit M |s2cid=31580825 |title=Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder |journal=[[Biological Psychiatry]] |volume=55 |issue=9 |pages=940–5 |date=May 2004 |pmid=15110738 |doi=10.1016/j.biopsych.2003.12.021}}</ref>