Editing Post-traumatic stress disorder (section)

== Pathophysiology ==

=== 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>

=== Neuroimmunology ===
Studies on the peripheral immune have found dysfunction with elevated [[cytokine]] levels and a higher risk of immune-related chronic diseases among individuals with PTSD.<ref name="y574">{{cite journal |last1=Katrinli |first1=Seyma |last2=Oliveira |first2=Nayara C. S. |last3=Felger |first3=Jennifer C. |last4=Michopoulos |first4=Vasiliki |last5=Smith |first5=Alicia K. |date=2022-08-04 |title=The role of the immune system in posttraumatic stress disorder |journal=Translational Psychiatry |volume=12 |issue=1 |page= 313|doi=10.1038/s41398-022-02094-7 |issn=2158-3188 |pmc=9352784 |pmid=35927237}}</ref> [[Neuroimmune system|Neuroimmune]] dysfunction has also been found in PTSD, raising the possibility of a suppressed central immune response due to reduced activity of [[microglia]] in the brain in response to immune challenges. Individuals with PTSD, compared to controls, have lower increase in a marker of microglial activation ([[Translocator protein|18-kDa translocator protein]]) following [[lipopolysaccharide]] administration.<ref name="m591">{{cite journal |last1=Bonomi |first1=Robin |last2=Hillmer |first2=Ansel T. |last3=Woodcock |first3=Eric |last4=Bhatt |first4=Shivani |last5=Rusowicz |first5=Aleksandra |last6=Angarita |first6=Gustavo A. |last7=Carson |first7=Richard E. |last8=Davis |first8=Margaret T. |last9=Esterlis |first9=Irina |last10=Nabulsi |first10=Nabeel |last11=Huang |first11=Yiyun |last12=Krystal |first12=John H. |last13=Pietrzak |first13=Robert H. |last14=Cosgrove |first14=Kelly P. |date=2024-08-27 |title=Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia |journal=Proceedings of the National Academy of Sciences |volume=121 |issue=35 |pages=e2406005121 |doi=10.1073/pnas.2406005121 |pmid=39172786 |pmc=11363315 |bibcode=2024PNAS..12106005B |issn=0027-8424}}</ref> This neuroimmune suppression is also associated with greater severity of anhedonic symptoms. Researchers suggest that treatments aimed at restoring neuroimmune function could be beneficial for alleviating PTSD symptoms.<ref name="m591" />

=== Neuroanatomy ===
[[File:PTSD stress brain.gif|thumb|220px|Regions of the brain associated with stress and post-traumatic stress disorder<ref>{{cite web |url=http://www.nimh.nih.gov/health/publications/post-traumatic-stress-disorder-research-fact-sheet/index.shtml |title=NIMH · Post Traumatic Stress Disorder Research Fact Sheet |work=[[National Institutes of Health]] |access-date=2014-01-29 |url-status=live |archive-url=https://web.archive.org/web/20140123205303/http://www.nimh.nih.gov/health/publications/post-traumatic-stress-disorder-research-fact-sheet/index.shtml |archive-date=2014-01-23}}</ref>]]

A [[meta-analysis]] of structural MRI studies found an association with reduced total brain volume, intracranial volume, and volumes of the [[hippocampus]], [[insula cortex]], and [[anterior cingulate]].<ref>{{cite journal |vauthors=Bromis K, Calem M, Reinders AA, Williams SC, Kempton MJ |title=Meta-Analysis of 89 Structural MRI Studies in Posttraumatic Stress Disorder and Comparison With Major Depressive Disorder |journal=The American Journal of Psychiatry |volume=175 |issue=10 |pages=989–998 |date=July 2018 |pmid=30021460 |pmc=6169727 |doi=10.1176/appi.ajp.2018.17111199}}</ref> Much of this research stems from PTSD in those exposed to the Vietnam War.<ref>{{Cite book |vauthors=Liberzon I, Sripada CS |volume=167 |pages=151–69 |date=2008 |pmid=18037013 |doi=10.1016/S0079-6123(07)67011-3 |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=The functional neuroanatomy of PTSD: A critical review}}</ref><ref>{{cite journal |vauthors=Hughes KC, Shin LM |title=Functional neuroimaging studies of post-traumatic stress disorder |journal=Expert Review of Neurotherapeutics |volume=11 |issue=2 |pages=275–85 |date=February 2011 |pmid=21306214 |pmc=3142267 |doi=10.1586/ern.10.198}}</ref>

People with PTSD have decreased brain activity in the dorsal and rostral [[Anterior cingulate cortex|anterior cingulate]] cortices and the [[ventromedial prefrontal cortex]], areas linked to the experience and regulation of emotion.<ref>{{cite journal |vauthors=Etkin A, Wager TD |title=Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia |journal=The American Journal of Psychiatry |volume=164 |issue=10 |pages=1476–88 |date=October 2007 |pmid=17898336 |pmc=3318959 |doi=10.1176/appi.ajp.2007.07030504}}</ref>

The amygdala is strongly involved in forming emotional memories, especially fear-related memories. During high stress, the [[hippocampus]], which is associated with placing memories in the correct context of space and time and memory recall, is suppressed. According to one theory, this suppression may be the cause of the [[flashbacks (psychology)|flashbacks]] that can affect people with PTSD. When someone with PTSD undergoes [[stimulus (physiology)|stimuli]] similar to the traumatic event, the body perceives the event as occurring again because the memory was never properly recorded in the person's memory.<ref name="Skelton 2012 628–637" /><ref>{{cite journal |vauthors=van der Kolk B |title=Posttraumatic stress disorder and the nature of trauma |journal=[[Dialogues in Clinical Neuroscience]] |volume=2 |issue=1 |pages=7–22 |date=March 2000 |pmid=22034447 |pmc=3181584 |doi=10.31887/DCNS.2000.2.1/bvdkolk}}</ref>

The amygdalocentric model of PTSD proposes that the amygdala is very much aroused and insufficiently controlled by the medial [[prefrontal cortex]] and the hippocampus, in particular during [[Extinction (psychology)|extinction]].<ref name="Milad">{{cite journal |vauthors=Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL |title=Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder |journal=[[Biological Psychiatry]] |volume=66 |issue=12 |pages=1075–82 |date=December 2009 |pmid=19748076 |pmc=2787650 |doi=10.1016/j.biopsych.2009.06.026}}</ref> This is consistent with an interpretation of PTSD as a syndrome of deficient extinction ability.<ref name="Milad" /><ref name="Stein">{{cite journal |vauthors=Stein MB, Paulus MP |title=Imbalance of approach and avoidance: the yin and yang of anxiety disorders |journal=[[Biological Psychiatry]] |volume=66 |issue=12 |pages=1072–4 |date=December 2009 |pmid=19944792 |pmc=2825567 |doi=10.1016/j.biopsych.2009.09.023}}</ref>

The [[basolateral amygdala|basolateral]] nucleus (BLA) of the amygdala is responsible for the comparison and development of associations between unconditioned and conditioned responses to stimuli, which results in the fear conditioning present in PTSD. The BLA activates the [[central nucleus]] (CeA) of the amygdala, which elaborates the fear response, (including behavioral response to threat and elevated startle response). Descending inhibitory inputs from the [[medial prefrontal cortex]] (mPFC) regulate the transmission from the BLA to the CeA, which is hypothesized to play a role in the extinction of conditioned fear responses.<ref name="Skelton 2012 628–637" />

While as a whole, amygdala hyperactivity is reported by meta analysis of functional neuroimaging in PTSD, there is a large degree of heterogeniety, more so than in social anxiety disorder or phobic disorder. Comparing dorsal (roughly the CeA) and ventral (roughly the BLA) clusters, hyperactivity is more robust in the ventral cluster, while hypoactivity is evident in the dorsal cluster. The distinction may explain the blunted emotions in PTSD (via desensitization in the CeA) as well as the fear related component.<ref>{{cite book |vauthors=Goodkind M, Etkin A |veditors=Sklar P, Buxbaum J, Nestler E, Charney D |title=Neurobiology of Mental Illness |publisher=[[Oxford University Press]] |edition=5th |chapter=Functional Neurocircuitry and Neuroimaging Studies of Anxiety Disorders}}</ref>

In a 2007 study, [[Vietnam War]] combat veterans with PTSD showed a 20% reduction in the volume of their hippocampus compared with veterans who did not have such symptoms.<ref>{{cite book | vauthors = Carlson NR |date=2007 |title=Physiology of Behavior |edition=9th |publisher=[[Pearson Education]]}}</ref> This finding was not replicated in chronic PTSD patients traumatized at an [[Ramstein air show disaster|air show plane crash in 1988]] (Ramstein, Germany).<ref name="Jatzko">{{cite journal |vauthors=Jatzko A, Rothenhöfer S, Schmitt A, Gaser C, Demirakca T, Weber-Fahr W, Wessa M, Magnotta V, Braus DF |title=Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods |journal=[[Journal of Affective Disorders]] |volume=94 |issue=1–3 |pages=121–6 |date=August 2006 |pmid=16701903 |doi=10.1016/j.jad.2006.03.010 |url=http://dbm.neuro.uni-jena.de/pdf-files/Jatzko-JAD06.pdf |archive-url=https://web.archive.org/web/20131019153804/http://dbm.neuro.uni-jena.de/pdf-files/Jatzko-JAD06.pdf |url-status=live |archive-date=2013-10-19}}</ref>

Evidence suggests that endogenous cannabinoid levels are reduced in PTSD, particularly [[anandamide]], and that cannabinoid receptors (CB1) are increased in order to compensate.<ref name="ECS_PTSD">{{cite journal |vauthors=Neumeister A, Seidel J, Ragen BJ, Pietrzak RH |title=Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder |journal=[[Psychoneuroendocrinology]] |volume=51 |pages=577–84 |date=January 2015 |pmid=25456347 |pmc=4268027 |doi=10.1016/j.psyneuen.2014.10.012}}</ref> There appears to be a link between increased CB1 receptor availability in the amygdala and abnormal threat processing and hyperarousal, but not dysphoria, in trauma survivors.

A 2020 study found no evidence for conclusions from prior research that suggested low IQ is a risk factor for developing PTSD.<ref>{{Cite journal |vauthors=Shura RD, Epstein EL, Ord AS, Martindale SL, Rowland JA, Brearly TW, Taber KH |date=September 2020 |title=Relationship between intelligence and posttraumatic stress disorder in veterans |journal=Intelligence |language=en |volume=82 |pages=101472 |doi=10.1016/j.intell.2020.101472 |issn=0160-2896 |doi-access=free}}</ref>