Array ( [0] => {{Short description|Area of study within psychosomatic medicine}} [1] => {{more citations needed|date=May 2015}} [2] => '''Psychoneuroimmunology''' ('''PNI'''), also referred to as '''psychoendoneuroimmunology''' ('''PENI''') or '''psychoneuroendocrinoimmunology''' ('''PNEI'''), is the study of the interaction between psychological processes and the nervous and immune systems of the human body.{{cite book | last = Michael Irwin| first = Kavita Vedhara | title = Human Psychoneuroimmunology| publisher = Oxford University Press|year=2005| isbn = 978-0-19-856884-1}}{{Cite book |title=The Oxford handbook of psychoneuroimmunology |date=2012 |publisher=Oxford University Press |editor=Segerstrom, Suzanne C. |isbn=9780195394399 |location=New York |oclc=775894214}} It is a subfield of [[psychosomatic medicine]]. PNI takes an interdisciplinary approach, incorporating [[psychology]], [[neuroscience]], [[immunology]], [[physiology]], [[genetics]], [[pharmacology]], [[molecular biology]], [[psychiatry]], [[behavioral medicine]], [[infectious diseases]], [[endocrinology]], and [[rheumatology]]. [3] => [4] => The main interests of PNI are the interactions between the [[central nervous system|nervous]] and [[Immune system|immune systems]] and the relationships between mental processes and [[health]].{{cite book|last1=Betts|first1=J Gordon|last2=Desaix|first2=Peter|last3=Johnson|first3=Eddie|last4=Johnson|first4=Jody E|last5=Korol|first5=Oksana|last6=Kruse|first6=Dean|last7=Poe|first7=Brandon|last8=Wise|first8=James|last9=Womble|first9=Mark D|last10=Young|first10=Kelly A|url=https://openstax.org/books/anatomy-and-physiology/pages/21-7-transplantation-and-cancer-immunology|title=Anatomy & Physiology|location=Houston|publisher=OpenStax CNX|isbn=978-1-947172-04-3|date=June 8, 2023|at=21.7 Transplantation and cancer immunology}} PNI studies, among other things, the physiological functioning of the neuroimmune system in health and disease; disorders of the neuroimmune system ([[autoimmune diseases]]; [[hypersensitivity|hypersensitivities]]; [[immune deficiency]]); and the physical, chemical and physiological characteristics of the components of the neuroimmune system [[in vitro]], [[in situ]], and [[in vivo]]. [5] => [6] => ==History== [7] => Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine. [8] => [[File:Claude Bernard and his pupils. Oil painting after Léon-Augus Wellcome V0017769.jpg|thumbnail|Claude Bernard, the father of modern physiology, with his pupils]] [9] => [[Claude Bernard]], a French physiologist of the [[Muséum national d'Histoire naturelle]] (National Museum of Natural History in [[English language|English]]), formulated the concept of the ''[[milieu interieur]]'' in the mid-1800s. In 1865, Bernard described the perturbation of this internal state: "... there are protective functions of organic elements holding living materials in reserve and maintaining without interruption humidity, heat and other conditions indispensable to vital activity. Sickness and death are only a dislocation or perturbation of that mechanism" (Bernard, 1865). [[Walter Cannon]], a professor of physiology at [[Harvard University]] coined the commonly used term, [[homeostasis]], in his book ''The Wisdom of the Body'', 1932, from the [[Ancient Greek|Greek]] word ''homoios'', meaning similar, and ''stasis'', meaning position. In his work with animals, Cannon observed that any change of emotional state in the beast, such as [[anxiety]], [[Distress (medicine)|distress]], or [[rage (emotion)|rage]], was accompanied by total cessation of movements of the stomach (''Bodily Changes in Pain, Hunger, Fear and Rage'', 1915). These studies looked into the relationship between the effects of emotions and perceptions on the [[autonomic nervous system]], namely the [[Sympathetic nervous system|sympathetic]] and [[Parasympathetic nervous system|parasympathetic]] responses that initiated the recognition of the [[fight or flight response|freeze, fight or flight response]]. His findings were published from time to time in professional journals, then summed up in book form in ''The Mechanical Factors of Digestion'', published in 1911. [10] => [[File:Hans Selye.JPG|thumbnail|left|Bust of Hans Selye at [[Selye János University]], [[Komárno]], Slovakia]] [11] => [[Hans Selye]], a student of [[Johns Hopkins University]] and [[McGill University]], and a researcher at [[Université de Montréal]], experimented with animals by putting them under different physical and mental adverse conditions and noted that under these difficult conditions the body consistently [[Adaptation|adapted]] to heal and recover. Several years of experimentation that formed the empiric foundation of Selye's concept of the [[General Adaptation Syndrome]]. This syndrome consists of an enlargement of the [[adrenal]] gland, atrophy of the [[thymus]], [[spleen]], and other [[lymphoid]] tissue, and gastric [[Peptic ulcer|ulcerations]]. [12] => [13] => Selye describes three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance, and a terminal stage of exhaustion and death. This foundational work led to a rich line of research on the biological functioning of [[glucocorticoids]].{{cite journal | author = Neylan Thomas C | year = 1998 | title = Hans Selye and the Field of Stress Research | journal = J Neuropsychiatry Clin Neurosci | volume = 10 | issue = 2| page = 230 | doi=10.1176/jnp.10.2.230}} [14] => [15] => Mid-20th century studies of psychiatric patients reported immune alterations in psychotic individuals, including lower numbers of [[lymphocytes]]{{cite journal |vauthors=Freeman H, Elmadjian F | year = 1947 | title = The relationship between blood sugar and lymphocyte levels in normal and psychotic subjects | journal = Psychosom Med | volume = 9 | issue = 4| pages = 226–33 | doi=10.1097/00006842-194707000-00002| pmid = 20260255 | s2cid = 35806157 }}{{cite journal |vauthors=Phillips L, Elmadjian F | year = 1947 | title = A Rorschach tension score and the diurnal lymphocyte curve in psychotic subjects | journal = Psychosom Med | volume = 9 | issue = 6| pages = 364–71 | doi=10.1097/00006842-194711000-00002| pmid = 18913449 | s2cid = 2210570 }} and poorer [[antibody]] response to [[pertussis vaccination]], compared with nonpsychiatric control subjects.{{cite journal |vauthors=Vaughan WT, Sullivan JC, Elmadjian F | year = 1949 | title = Immunity and schizophrenia | journal = Psychosom Med | volume = 11 | issue = 6| pages = 327–33 | pmid = 15406182 | doi=10.1097/00006842-194911000-00001| s2cid = 30835205 }} In 1964, George F. Solomon, from the [[University of California in Los Angeles]], and his research team coined the term "psychoimmunology" and published a landmark paper: "Emotions, immunity, and disease: a speculative theoretical integration."Solomon GF, Moos RH. Emotions, immunity, and disease: a speculative theoretical integration. Arch Gen [16] => Psychiatry 1964; 11: 657–74 [17] => [18] => ===Origins=== [19] => In 1975, [[Robert Ader]] and [[Nicholas Cohen]], at the [[University of Rochester]], advanced PNI with their demonstration of [[Classical conditioning|classic conditioning]] of immune function, and they subsequently coined the term "psychoneuroimmunology".R Ader and N Cohen. [http://www.psychosomaticmedicine.org/cgi/content/abstract/37/4/333 Behaviorally conditioned immunosuppression.] Psychosomatic Medicine, Vol 37, Issue 4 333-340{{cite news|title = Robert Ader, Founder of Psychoneuroimmunology, Dies|url = http://www.urmc.rochester.edu/news/story/index.cfm?id=3370|work = [[University of Rochester Medical Center]]|date = 2011-12-20|access-date = 2011-12-20}} Ader was investigating how long conditioned responses (in the sense of [[Ivan Pavlov|Pavlov]]'s conditioning of dogs to drool when they heard a bell ring) might last in laboratory rats. To condition the rats, he used a combination{{clarify|date=July 2013}} of [[saccharin]]-laced water (the conditioned stimulus) and the drug [[Cytoxan]], which unconditionally induces [[nausea and taste aversion]] and suppression of immune function. Ader was surprised to discover that after conditioning, just feeding the rats saccharin-laced water was associated with the death of some animals and he proposed that they had been immunosuppressed after receiving the conditioned stimulus. Ader (a psychologist) and Cohen (an immunologist) directly tested this hypothesis by deliberately immunizing conditioned and unconditioned animals, exposing these and other control groups to the conditioned taste stimulus, and then measuring the amount of antibody produced. The highly reproducible results revealed that conditioned rats exposed to the conditioned stimulus were indeed immunosuppressed. In other words, a signal via the nervous system (taste) was affecting immune function. This was one of the first scientific experiments that demonstrated that the nervous system can affect the immune system. [20] => [21] => In the 1970s, [[Hugo Besedovsky]], [[Adriana del Rey]] and [[Ernst Sorkin]], working in Switzerland, reported multi-directional immune-neuro-endocrine interactions, since they show that not only the brain can influence immune processes but also the immune response itself can affect the brain and neuroendocrine mechanisms. They found that the immune responses to innocuous antigens triggers an increase in the activity of hypothalamic neurons{{Cite journal|last1=Besedovsky|first1=H.|last2=Sorkin|first2=E.|last3=Felix|first3=D.|last4=Haas|first4=H.|date=May 1977|title=Hypothalamic changes during the immune response|journal=European Journal of Immunology|volume=7|issue=5|pages=323–325|doi=10.1002/eji.1830070516|issn=0014-2980|pmid=326564|s2cid=224774815 }}{{Cite journal|last1=Besedovsky|first1=H.|last2=del Rey|first2=A.|last3=Sorkin|first3=E.|last4=Da Prada|first4=M.|last5=Burri|first5=R.|last6=Honegger|first6=C.|date=1983-08-05|title=The immune response evokes changes in brain noradrenergic neurons|journal=Science|volume=221|issue=4610|pages=564–566|issn=0036-8075|pmid=6867729|doi=10.1126/science.6867729|bibcode=1983Sci...221..564B}} and hormonal and autonomic nerve responses that are relevant for immunoregulation and are integrated at brain levels (see review{{Cite journal|last1=Besedovsky|first1=Hugo O.|last2=Rey|first2=Adriana Del|date=January 2007|title=Physiology of psychoneuroimmunology: a personal view|journal=Brain, Behavior, and Immunity|volume=21|issue=1|pages=34–44|doi=10.1016/j.bbi.2006.09.008|issn=0889-1591|pmid=17157762|s2cid=24279481}}). On these bases, they proposed that the immune system acts as a sensorial receptor organ that, besides its peripheral effects, can communicate to the brain and associated neuro-endocrine structures its state of activity. These investigators also identified products from immune cells, later characterized as cytokines, that mediate this immune-brain communication{{Cite journal|last1=Besedovsky|first1=H.|last2=del Rey|first2=A.|last3=Sorkin|first3=E.|last4=Dinarello|first4=C. A.|date=1986-08-08|title=Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones|journal=Science|volume=233|issue=4764|pages=652–654|issn=0036-8075|pmid=3014662|doi=10.1126/science.3014662|bibcode=1986Sci...233..652B}} (more references in ). [22] => [23] => In 1981, [[David L. Felten]], then working at the [[Indiana University School of Medicine]], and his colleague JM Williams, discovered a network of nerves leading to blood vessels as well as cells of the immune system. The researchers also found nerves in the [[thymus]] and [[spleen]] terminating near clusters of [[lymphocyte]]s, [[macrophage]]s, and [[mast cell]]s, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs. [24] => [25] => Ader, Cohen, and Felten went on to edit the groundbreaking book ''Psychoneuroimmunology'' in 1981, which laid out the underlying premise that the [[brain]] and immune system represent a single, integrated system of defense. [26] => [27] => In 1985, research by [[neuropharmacology|neuropharmacologist]] [[Candace Pert]], of the [[National Institutes of Health]] at [[Georgetown University]], revealed that [[neuropeptide]]-specific receptors are present on the cell walls of both the brain and the immune system.Pert CB, Ruff MR, Weber RJ, Herkenham M. "Neuropeptides and their receptors: a psychosomatic network" ''J Immunol'' 1985 Aug;135(2 Suppl):820s-826s{{cite journal |vauthors=Ruff M, Schiffmann E, Terranova V, Pert CB |date = Dec 1985|title = Neuropeptides are chemoattractants for human tumor cells and monocytes: a possible mechanism for metastasis|url = https://zenodo.org/record/1258295|journal = Clin Immunol Immunopathol|volume = 37|issue = 3|pages = 387–96|doi = 10.1016/0090-1229(85)90108-4|pmid = 2414046}} The discovery that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with [[emotions]] and suggests mechanisms through which emotions, from the [[limbic system]], and immunology are deeply interdependent. Showing that the immune and [[endocrine]] systems are modulated not only by the brain but also by the [[central nervous system]] itself affected the understanding of emotions, as well as disease. [28] => [29] => Contemporary advances in [[psychiatry]], immunology, [[neurology]], and other integrated disciplines of medicine has fostered enormous growth for PNI. The mechanisms underlying behaviorally induced alterations of immune function, and immune alterations inducing behavioral changes, are likely to have clinical and therapeutic implications that will not be fully appreciated until more is known about the extent of these interrelationships in normal and pathophysiological states. [30] => [31] => ==The immune-brain loop== [32] => {{further|Cell signaling networks|Signal transduction}} [33] => [34] => PNI research looks for the exact mechanisms by which specific neuroimmune effects are achieved. Evidence for nervous-immunological interactions exist at multiple biological levels. [35] => [36] => The immune system and the brain communicate through signaling pathways. The brain and the immune system are the two major adaptive systems of the body. Two major pathways are involved in this cross-talk: the [[Hypothalamic-pituitary-adrenal axis]] (HPA axis), and the [[sympathetic nervous system]] (SNS), via the [[sympathoadrenal system|sympathetic-adrenal-medullary axis]] (SAM axis). The activation of SNS during an immune response might be aimed to localize the inflammatory response. [37] => [38] => The body's primary [[stress management]] system is the HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's [[cortisol]] level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases, with evidence from meta-analyses indicating that different types/duration of stressors and unique personal variables can shape the HPA response.{{cite journal|last=Miller|first=Gregory E.|author2=Chen, Edith |author3=Zhou, Eric S. |title=If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans|journal=Psychological Bulletin|date=January 2007|volume=133|issue=1|pages=25–45|pmid=17201569|doi=10.1037/0033-2909.133.1.25}} HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate [[adrenocorticotropic hormone]] (ACTH) and cortisol secretion, while, in turn, [[glucocorticoids]] suppress the synthesis of proinflammatory cytokines. [39] => [40] => Molecules called pro-inflammatory cytokines, which include [[interleukin-1]] (IL-1), [[Interleukin-2]] (IL-2), [[interleukin-6]] (IL-6), [[Interleukin-12]] (IL-12), [[Interferon-gamma]] (IFN-Gamma) and [[tumor necrosis factor alpha]] (TNF-alpha) can affect brain growth as well as neuronal function. Circulating immune cells such as [[macrophages]], as well as [[glial]] cells ([[microglia]] and [[astrocytes]]) secrete these molecules. Cytokine regulation of hypothalamic function is an active area of research for the treatment of anxiety-related disorders.{{cite journal | pmid = 16029148 | volume=12 | issue=15 | title=Drug targets in stress-related disorders | year=2005 |vauthors=Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L | pages=1801–9 | journal=Curr. Med. Chem. | doi=10.2174/0929867054367202}} [41] => [42] => Cytokines mediate and control [[immune]] and [[inflammation|inflammatory]] responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining [[homeostasis]]. Like the stress response, the inflammatory reaction is crucial for survival. Systemic inflammatory reaction results in stimulation of four major programs:{{cite journal | author = Elenkov IJ | year = 2005 | title = Cytokine dysregulation, inflammation and well-being | journal = Neuroimmunomodulation | volume = 12 | issue = 5| pages = 255–69 | doi=10.1159/000087104 | pmid=16166805| s2cid = 39185155 }} [43] => * the acute-phase reaction [44] => * [[sickness behavior]] [45] => * the pain program [46] => * the stress response [47] => [48] => These are mediated by the HPA axis and the SNS. Common human diseases such as [[allergy]], autoimmunity, chronic infections and [[sepsis]] are characterized by a dysregulation of the pro-inflammatory versus anti-inflammatory and [[T helper]] (Th1) versus (Th2) cytokine balance.{{medcn|date=November 2016}} [49] => Recent studies show pro-inflammatory [[cytokine]] processes take place during [[Clinical depression|depression]], [[mania]] and [[Bipolar disorder|bipolar]] disease, in addition to autoimmune hypersensitivity and chronic infections.{{cite book |last1=Hall |first1=Rudolph |title=Narcissistic behavior in the postmodern era : the study of neuropsychology |date=2011-06-11 |isbn=9781462884193 |page=136|publisher=Xlibris Corporation LLC }} [50] => [51] => Chronic secretion of [[Stress (medicine)|stress]] [[hormones]], [[glucocorticoids]] (GCs) and [[catecholamines]] (CAs), as a result of disease, may reduce the effect of [[neurotransmitters]], including [[serotonin]], [[norepinephrine]] and [[dopamine]], or other receptors in the brain, thereby leading to the dysregulation of neurohormones. Under stimulation, norepinephrine is released from the sympathetic nerve terminals in organs, and the target immune cells express [[adrenergic receptors|adrenoreceptors]]. Through stimulation of these receptors, locally released norepinephrine, or circulating catecholamines such as [[epinephrine]], affect [[lymphocyte]] traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different [[lymphoid]] cells. [52] => [53] => Glucocorticoids also inhibit the further secretion of [[corticotropin-releasing hormone]] from the [[hypothalamus]] and ACTH from the [[pituitary]] ([[negative feedback]]). Under certain conditions stress hormones may facilitate inflammation through induction of signaling pathways and through activation of the corticotropin-releasing hormone. [54] => [55] => These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of [[metabolic]] and cardiovascular health, developing into a "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local pro-inflammatory factors which may contribute to the pathogenesis of disease. [56] => [57] => This systemic or neuro-inflammation and neuroimmune activation have been shown to play a role in the [[etiology]] of a variety of neurodegenerative disorders such as [[Parkinson's]] and [[Alzheimer's disease]], [[multiple sclerosis]], pain, and [[AIDS]]-associated dementia. However, cytokines and [[chemokine]]s also modulate central nervous system (CNS) function in the absence of overt immunological, physiological, or psychological challenges.{{Cite web|url=https://grants.nih.gov/grants/guide/pa-files/pa-05-054.html|title=PA-05-054: Functional Links between the Immune System, Brain Function and Behavior|website=grants.nih.gov}} [58] => [59] => ==Psychoneuroimmunological effects== [60] => There are now sufficient data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. Although changes related to [[infectious disease]] and [[wound]] healing have provided the strongest evidence to date, the clinical importance of immunological dysregulation is highlighted by increased risks across diverse conditions and diseases. For example, stressors can produce profound health consequences. In one epidemiological study, all-cause mortality increased in the month following a severe stressor – the death of a spouse.{{cite journal |author1=Kaprio J. |author2=Koskenvuo M. |author3=Rita H. | year = 1987 | title = Mortality after bereavement: a prospective study of 95,647 widowed persons | journal = American Journal of Public Health | volume = 77 | issue = 3| pages = 283–7 | doi=10.2105/ajph.77.3.283|pmid=3812831 |pmc=1646890}} Theorists propose that stressful events trigger cognitive and affective responses which, in turn, induce sympathetic nervous system and endocrine changes, and these ultimately impair immune function.Chrousos, G. P. and Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267(Mar 4), 1244-52.Glaser, R. and Kiecolt-Glaser, J. K. (1994). Handbook of Human Stress and Immunity. San Diego: Academic Press. Potential health consequences are broad, but include rates of infection{{cite journal |author1=Cohen S. |author2=Tyrrell D. A. |author3=Smith A. P. | year = 1991 | title = Psychological stress and susceptibility to the common cold | journal = The New England Journal of Medicine | volume = 325 | issue = 9| pages = 606–12 | doi=10.1056/nejm199108293250903 | pmid=1713648| doi-access = free }}{{cite journal |author1=Cohen S. |author2=Williamson G. M. | year = 1991 | title = Stress and infectious disease in humans | journal = Psychological Bulletin | volume = 109 | issue = 1| pages = 5–24 | doi=10.1037/0033-2909.109.1.5 | pmid=2006229}} HIV progression{{cite journal |author1=Leserman J. |author2=Petitto J. M. |author3=Golden R. N. |author4=Gaynes B. N. |author5=Gu H. |author6=Perkins D. O. |author6-link=Diana Perkins |author7=Silva S. G. |author8=Folds J. D. |author9=Evans D. L. | year = 2000 | title = Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS | journal = The American Journal of Psychiatry | volume = 157 | issue = 8| pages = 1221–8 | doi=10.1176/appi.ajp.157.8.1221|pmid=10910783 }}{{cite journal |author1=Leserman J. |author2=Jackson E. D. |author3=Petitto J. M. |author4=Golden R. N. |author5=Silva S. G. |author6=Perkins D. O. |author7=Cai J. |author8=Folds J. D. |author9=Evans D. L. | year = 1999 | title = Progression to AIDS: the effects of stress, depressive symptoms, and social support | journal = Psychosomatic Medicine | volume = 61 | issue = 3| pages = 397–406 | doi=10.1097/00006842-199905000-00021|pmid=10367622 }} cancer incidence and progression,{{cite journal |author1=Andersen B. L. |author2=Kiecolt-Glaser J. K. |author3=Glaser R. | year = 1994 | title = A biobehavioral model of cancer stress and disease course | journal = American Psychologist | volume = 49 | issue = 5| pages = 389–404 | doi=10.1037/0003-066x.49.5.389|pmid=8024167 |pmc=2719972}}{{cite journal |author1=Kiecolt-Glaser J. K. |author2=Glaser R. | year = 1999 | title = Psychoneuroimmunology and cancer: fact or fiction? | journal = European Journal of Cancer | volume = 35 | issue = 11| pages = 1603–7 | doi=10.1016/s0959-8049(99)00197-5|pmid=10673969 }} and high rates of infant mortality.Osel, Joseph, D. (2008). "[http://ssrn.com/abstract=2173553 Being (Born) Black in America: Perceived Discrimination & African American Infant Mortality]", ''The Evergreen State College Symposium on Psychoneuroimmunology''; SSRN.{{cite journal |author1=Collins J. W. |author2=David R. |author3=Handler A. |author4=Wall S. |author5=Andes S. | year = 2004 | title = Very low birthweight in African American infants: The role of maternal exposure to interpersonal racial discrimination | journal = American Journal of Public Health | volume = 94 | issue = 12| pages = 2132–2138 | pmc=1448603 | pmid=15569965 | doi=10.2105/ajph.94.12.2132}} [61] => [62] => ===Understanding stress and immune function=== [63] => [64] => [[Stress (medicine)|Stress]] is thought to affect immune function through emotional and/or behavioral manifestations such as [[anxiety]], [[fear]], [[Stress (biology)|tension]], [[anger]] and [[sadness]] and physiological changes such as [[heart rate]], [[blood pressure]], and [[sweating]]. Researchers have suggested that these changes are beneficial if they are of limited duration, but when stress is chronic, the system is unable to maintain equilibrium or [[homeostasis]]; the body remains in a state of arousal, where digestion is slower to reactivate or does not reactivate properly, often resulting in indigestion. Furthermore, blood pressure stays at higher levels.{{cite journal |last1=Gasperin |first1=Daniela |last2=Netuveli |first2=Gopalakrishnan |last3=Dias-da-Costa |first3=Juvenal Soares |last4=Pattussi |first4=Marcos Pascoal |title=Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies |journal=Cadernos de Saúde Pública |date=April 2009 |volume=25 |issue=4 |pages=715–726 |doi=10.1590/S0102-311X2009000400002|doi-access=free |pmid=19347197 }} [65] => [66] => In one of the earlier PNI studies, which was published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives.{{cite journal |vauthors=McDonald RD, Yagi K | year = 1960 | title = A note on eosinopenia as an index of psychological stress | journal = Psychosom Med | volume = 2 | issue = 22| pages = 149–50 | doi = 10.1097/00006842-196003000-00007 | s2cid = 147391585 }} Since then decades of research resulted in two large meta-analyses, which showed consistent immune dysregulation in healthy people who are experiencing stress. [67] => [68] => In the first meta-analysis by Herbert and Cohen in 1993,{{cite journal |vauthors=Herbert TB, Cohen S | year = 1993 | title = Stress and immunity in humans: a meta-analytic review | journal = Psychosom. Med. | volume = 55 | issue = 4| pages = 364–379 | doi=10.1097/00006842-199307000-00004| pmid = 8416086 | citeseerx = 10.1.1.125.6544 | s2cid = 2025176 }} they examined 38 studies of stressful events and immune function in healthy adults. They included studies of acute laboratory stressors (e.g. a speech task), short-term naturalistic stressors (e.g. medical examinations), and long-term naturalistic stressors (e.g. divorce, bereavement, caregiving, unemployment). They found consistent stress-related increases in numbers of total [[white blood cells]], as well as decreases in the numbers of [[helper T cells]], [[suppressor T cells]], and [[cytotoxic T cells]], [[B cells]], and [[natural killer cell]]s (NK). They also reported stress-related decreases in NK and T cell function, and T cell proliferative responses to [[phytohaemagglutinin]] [PHA] and [[concanavalin A]] [Con A]. These effects were consistent for short-term and long-term naturalistic stressors, but not laboratory stressors. [69] => [70] => In the second meta-analysis by Zorrilla et al. in 2001,{{cite journal |author1=Zorrilla E. P. |author2=Luborsky L. |author3=McKay J. R. |author4=Rosenthal R. |author5=Houldin A. |author6=Tax A. |author7=McCorkle R. |author8=Seligman D. A. |author9=Schmidt K. | year = 2001 | title = The relationship of depression and stressors to immunological assays: a meta-analytic review | journal = Brain, Behavior, and Immunity | volume = 15 | issue = 3| pages = 199–226 | doi=10.1006/brbi.2000.0597|pmid=11566046 |s2cid=21106219 }} they replicated Herbert and Cohen's meta-analysis. Using the same study selection procedures, they analyzed 75 studies of stressors and human immunity. Naturalistic stressors were associated with increases in number of circulating [[neutrophils]], decreases in number and percentages of total [[T cells]] and helper T cells, and decreases in percentages of natural killer cell (NK) cells and cytotoxic T cell lymphocytes. They also replicated Herbert and Cohen's finding of stress-related decreases in NKCC and T cell [[mitogen]] proliferation to phytohaemagglutinin (PHA) and concanavalin A (Con A). [71] => [72] => A study done by the [[American Psychological Association]] did an experiment on rats, where they applied [[electrical shocks]] to a rat, and saw how [[Interleukin-1 family|interleukin-1]] was released directly into the brain. Interleukin-1 is the same [[cytokine]] released when a [[macrophage]] chews on a [[bacterium]], which then travels up the [[vagus nerve]], creating a state of heightened immune activity, and behavioral changes.{{Cite web|title=A new take on psychoneuroimmunology|url=https://www.apa.org/monitor/dec01/anewtake|last=Azar|first=Beth|date=December 2001|series=Monitor on Psychology 32(11)|publisher=American Psychological Association|language=en|access-date=2019-03-19}} [73] => [74] => More recently, there has been increasing interest in the links between interpersonal stressors and immune function. For example, marital conflict, loneliness, caring for a person with a chronic medical condition, and other forms on interpersonal stress dysregulate immune function.{{cite journal |author=Jaremka, L.M. |title=Synergistic relationships among stress, depression, and troubled relationships: Insights from Psychoneuroimmunology |journal=Depression and Anxiety|year=2013 |volume= 30|issue=4 |pages= 288–296|url= |doi=10.1002/da.22078|pmid=23412999 |pmc=3816362 }} [75] => [76] => ===Communication between the brain and immune system=== [77] => * Stimulation of brain sites alters immunity (stressed animals have altered immune systems). [78] => * Damage to brain hemispheres alters immunity (hemispheric lateralization effects).{{cite journal |author1=Sumner R.C. |author2=Parton A. |author3=Nowicky A.N. |author4=Kishore U. |author5=Gidron Y. | title = Hemispheric lateralisation and immune function: A systematic review of human research | url =http://eprints.glos.ac.uk/3545/3/Hemispheric%20Lateralisation%20and%20Immune%20Function.pdf | journal = Journal of Neuroimmunology | volume = 240–241| pages = 1–12 | doi=10.1016/j.jneuroim.2011.08.017|pmid=21924504 |date=2011-12-15 |s2cid=10127202 }} [79] => * Immune cells produce cytokines that act on the CNS. [80] => * Immune cells respond to signals from the CNS. [81] => [82] => ===Communication between neuroendocrine and immune system=== [83] => * Glucocorticoids and catecholamines influence immune cells.{{cite journal|vauthors=Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP|title=The pathophysiologic roles of interleukin-6 in human disease|journal=Ann Intern Med|year=1998|volume=128|issue=2|pages=127–137|pmid=9441573|doi=10.7326/0003-4819-128-2-199801150-00009|s2cid=37260638}}{{cite book|last1=Carlson|first1=Neil R.|title=Physiology of behavior|date=2013|publisher=Pearson|location=Boston|isbn=978-0205239399|page=611|edition=11th}} [84] => * Hypothalamic Pituitary Adrenal axis releases the needed hormones to support the immune system.{{Cite web|title=Adrenal Fatigue 101 — Leah Hosburgh Leah Hosburgh Nutritonal Therapy|url=https://www.leahhosburgh.com/blog/2017/4/28/what-is-adrenal-fatigue|access-date=2020-12-07|website=Leah Hosburgh|language=en-US}} [85] => * Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells. [86] => [87] => ===Connections between glucocorticoids and immune system=== [88] => * Anti-inflammatory hormones that enhance the organism's response to a stressor. [89] => * Prevent the overreaction of the body's own defense system. [90] => *Overactivation of glucocorticoid receptors can lead to health risks.{{Cite journal|last1=Janicki-Deverts|first1=Denise|last2=Cohen|first2=Sheldon|last3=Turner|first3=Ronald B.|last4=Doyle|first4=William J.|date=March 2016|title=Basal salivary cortisol secretion and susceptibility to upper respiratory infection|url= |journal=Brain, Behavior, and Immunity|language=en|volume=53|pages=255–261|doi=10.1016/j.bbi.2016.01.013|pmc=4783177|pmid=26778776}} [91] => * Regulators of the immune system. [92] => * Affect cell growth, proliferation and differentiation. [93] => * Cause immunosuppression which can lead to an extended amount of time fighting off infections. [94] => *High basal levels of [[cortisol]] are associated with a higher risk of infection. [95] => * Suppress [[cell adhesion]], [[antigen]] presentation, chemotaxis and cytotoxicity. [96] => * Increase [[apoptosis]]. [97] => [98] => ===Corticotropin-releasing hormone (CRH)=== [99] => Release of [[corticotropin-releasing hormone]] (CRH) from the [[hypothalamus]] is influenced by stress.{{Cite book|last1=Luecken|first1=Linda|title=Handbook of Physiological Research Methods in Health Psychology|last2=Gall|first2=Linda|last3=Nicolson|first3=Nancy|publisher=SAGE Publications|year=2007|isbn=9781412926058|pages=37–44|chapter=Chapter 3: Measurement of Cortisol}} [100] => * CRH is a major regulator of the HPA axis/stress axis. [101] => * CRH Regulates secretion of [[adrenocorticotropic hormone]] (ACTH). [102] => * CRH is widely distributed in the brain and periphery [103] => * CRH also regulates the actions of the [[Autonomic nervous system]] ANS and immune system. [104] => [105] => Furthermore, stressors that enhance the release of CRH suppress the function of the immune system; conversely, stressors that depress CRH release potentiate immunity. [106] => * Central mediated since peripheral administration of CRH antagonist does not affect immunosuppression. [107] => *HPA axis/stress axis responds consistently to stressors that are new, unpredictable and that have low-perceived control. [108] => *As cortisol reaches an appropriate level in response to the stressor, it deregulates the activity of the hippocampus, hypothalamus, and pituitary gland which results in less production of cortisol. [109] => [110] => ===Relationships between prefrontal cortex activation and cellular senescence=== [111] => * Psychological stress is regulated by the [[prefrontal cortex]] (PFC) [112] => * The PFC modulates vagal activity{{cite journal | vauthors = Thayer JF, Ahs F, Fredrikson M, et al | title = A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health | journal = Neurosci Biobehav Rev | volume = 36 | issue = 2 | pages = 747–756 |date=December 2012 | pmid = 22178086 | doi = 10.1016/j.neubiorev.2011.11.009 | s2cid = 2512272 }} [113] => * Prefrontally modulated and vagally mediated cholinergic input to the spleen reduces inflammatory responses{{cite journal | vauthors = Williams DP, Koenig J, Carnevali L, et al | title = Heart rate variability and inflammation: A meta-analysis of human studies | journal = Brain Behav. Immun. | volume = 80 | pages = 219–226 |date=August 2019 | pmid = 30872091 | doi = 10.1016/j.bbi.2019.03.009| s2cid = 78091147 }} [114] => [115] => ==Pharmaceutical advances== [116] => {{further|Neuropsychopharmacology}} [117] => [118] => [[Glutamate|Glutamate agonists]], cytokine inhibitors, [[TRPV1|vanilloid-receptor agonists]], catecholamine modulators, [[Ion channel|ion-channel blockers]], [[anticonvulsants]], [[GABA|GABA agonists]] (including [[opioids]] and [[cannabinoids]]), [[Cyclooxygenase|COX inhibitors]], [[Acetylcholine|acetylcholine modulators]], [[melatonin]] analogs (such as [[Rozerem|Ramelton]]), [[Adenosine receptor|adenosine receptor antagonists]] and several miscellaneous drugs (including biologics like [[Passiflora edulis]]) are being studied for their psychoneuroimmunological effects. [119] => [120] => For example, [[SSRI]]s, [[SNRI]]s and [[tricyclic]] [[antidepressants]] acting on [[serotonin]], [[norepinephrine]], [[dopamine]] and [[cannabinoid receptor]]s have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psychoneuroimmunological process.{{cite journal |vauthors=Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M | date = Apr 2001 | title = Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio | journal = J Clin Psychopharmacol | volume = 21 | issue = 2| pages = 199–206 | doi=10.1097/00004714-200104000-00012 | pmid=11270917| s2cid = 43429490 }}Maes M."The immunoregulatory effects of antidepressants". ''Hum Psychopharmacol.'' 2001 Jan;16(1) 95-103Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E."The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". ''Int Immunopharmacol.'' 2005 Mar;5(3) 609-18.{{Cite journal|last1=Smaga|first1=Irena|last2=Bystrowska|first2=Beata|last3=Gawliński|first3=Dawid|last4=Pomierny|first4=Bartosz|last5=Stankowicz|first5=Piotr|last6=Filip|first6=Małgorzata|date=2014|title=Antidepressants and Changes in Concentration of Endocannabinoids and N-Acylethanolamines in Rat Brain Structures|journal=Neurotoxicity Research|volume=26|issue=2|pages=190–206|doi=10.1007/s12640-014-9465-0|issn=1029-8428|pmc=4067538|pmid=24652522}} Antidepressants have also been shown to suppress TH1 upregulation.{{cite journal |vauthors=Diamond M, Kelly JP, Connor TJ | date = Oct 2006 | title = Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade | journal = Eur Neuropsychopharmacol | volume = 16 | issue = 7| pages = 481–90 | doi=10.1016/j.euroneuro.2005.11.011 | pmid=16388933| s2cid = 12983560 }}{{cite journal |vauthors=Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB | date = Jun 2006 | title = A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice | url =https://www.arca.fiocruz.br/bitstream/icict/2741/1/Brustolim_Ribeiro_Kast_etal.pdf | journal = Int Immunopharmacol | volume = 6 | issue = 6| pages = 903–7 | doi=10.1016/j.intimp.2005.12.007 | pmid=16644475}} [121] => [122] => Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown [[analgesic]] properties additionally.{{cite journal |vauthors=Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A | date = Spring 2007 | title = Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society | journal = Pain Res Manag | volume = 12 | issue = 1| pages = 13–21 | pmid = 17372630 | pmc = 2670721 | doi=10.1155/2007/730785| doi-access = free }}{{cite journal |vauthors=Jones CK, Eastwood BJ, Need AB, Shannon HE | date = Dec 2006 | title = Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition | journal = Neuropharmacology | volume = 51 | issue = 7–8| pages = 1172–80 | doi=10.1016/j.neuropharm.2006.08.005 | pmid=17045620| s2cid = 23871569 }} According to recent evidences antidepressants also seem to exert beneficial effects in experimental autoimmune [[neuritis]] in rats by decreasing [[Interferon-beta]] (IFN-beta) release or augmenting NK activity in depressed patients. [123] => [124] => These studies warrant investigation of antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal [[pharmacotherapy]] in many diseases.{{cite journal |vauthors=Kulmatycki KM, Jamali F | year = 2006 | title = Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response | journal = J Pharm Pharm Sci | volume = 9 | issue = 3| pages = 292–306 | pmid = 17207413 }} Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.{{cite journal |vauthors=O'Brien SM, Scott LV, Dinan TG | date = Aug 2004 | title = Cytokines: abnormalities in major depression and implications for pharmacological treatment | journal = Hum Psychopharmacol | volume = 19 | issue = 6| pages = 397–403 | doi=10.1002/hup.609 | pmid=15303243| s2cid = 11723122 }} [125] => [126] => The [[endocannabinoid system]] appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery. The [[Endocannabinoids|endocannabinoid]]-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system, by which cannabinoid [[Cannabinoid receptor type 1|CB1]] receptors modulate the excitability of [[Dorsal raphe nucleus|dorsal raphe]] serotonin [[neuron]]s.{{Cite journal|last1=Haj-Dahmane|first1=Samir|last2=Shen|first2=Roh-Yu|date=September 2011|title=Modulation of the Serotonin System by Endocannabinoid Signaling|journal=Neuropharmacology|volume=61|issue=3|pages=414–420|doi=10.1016/j.neuropharm.2011.02.016|issn=0028-3908|pmc=3110547|pmid=21354188}} Data suggest that the endocannabinoid system in [[Cortex (anatomy)|cortical]] and subcortical structures is differentially altered in an animal model of depression and that the effects of chronic, unpredictable stress (CUS) on CB1 receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not. [127] => [128] => The increase in amygdalar CB1 receptor binding following imipramine treatment is consistent with prior studies which collectively demonstrate that several treatments which are beneficial to depression, such as [[Electroconvulsive therapy|electroconvulsive shock]] and tricyclic antidepressant treatment, increase CB1 receptor activity in [[Cerebral cortex|subcortical]] [[Limbic system|limbic structures]], such as the [[hippocampus]], [[amygdala]] and [[hypothalamus]]. And preclinical studies have demonstrated the CB1 receptor is required for the behavioral effects of [[noradrenergic]] based antidepressants but is dispensable for the behavioral effect of serotonergic based antidepressants.{{Cite journal|last1=Hill|first1=Matthew N. |last2=Carrier|first2=Erica J.|last3=McLaughlin|first3=Ryan J.|last4=Morrish|first4=Anna C.|last5=Meier|first5=Sarah E.|last6=Hillard|first6=Cecilia J. |last7=Gorzalka|first7=Boris B.|date=September 2008|title=Regional Alterations in the Endocannabinoid System in an Animal Model of Depression: Effects of Concurrent Antidepressant Treatment|journal=Journal of Neurochemistry|volume=106|issue=6|pages=2322–2336|doi=10.1111/j.1471-4159.2008.05567.x |issn=0022-3042 |pmc=2606621|pmid=18643796}}{{Cite journal|last1=Hill|first1=Matthew N.|last2=Barr|first2=Alasdair M.|last3=Ho|first3=W.-S. Vanessa|last4=Carrier |first4=Erica J.|last5=Gorzalka|first5=Boris B.|last6=Hillard|first6=Cecilia J.|date=2007-10-01|title=Electroconvulsive shock treatment differentially modulates cortical and subcortical endocannabinoid activity|journal=Journal of Neurochemistry|volume=103|issue=1 |pages=47–56 |doi=10.1111/j.1471-4159.2007.04688.x |pmid=17561935|issn=1471-4159|doi-access=free}} [129] => [130] => Extrapolating from the observations that positive emotional experiences boost the immune system, Roberts speculates that intensely positive emotional experiences—sometimes brought about during mystical experiences occasioned by psychedelic medicines—may boost the immune system powerfully. Research on salivary IgA supports this hypothesis, but experimental testing has not been done.{{cite book |last=Roberts |first=Thomas B. |year=2006 |chapter=Chapter 6. Do Entheogen-induced Mystical Experiences Boost the Immune System?: Psychedelics, Peak Experiences, and Wellness |title=Psychedelic Horizons |place=Westport, CT |publisher=Praeger/Greenwood}} [131] => [132] => ==See also== [133] => {{col-begin}} [134] => {{col-break}} [135] => [136] => ===Branches of medicine=== [137] => * [[Biological psychiatry]] [138] => * [[Psychoneuroendocrinology]] [139] => * [[Neuroanatomy]] [140] => * [[Neurobiology]] [141] => * [[Neurochemistry]] [142] => * [[Neurophysics]] [143] => {{col-break}} [144] => [145] => ===Neuroanatomy=== [146] => * [[Locus ceruleus]] [147] => * [[Pedunculopontine nucleus]] [148] => * [[Raphe nucleus]] [149] => * [[Reticular activating system]] [150] => * [[Suprachiasmatic nucleus]] [151] => {{col-break}} [152] => [153] => ===Related topics=== [154] => * [[Allostatic load]] [155] => * [[Fight-or-flight response]] [156] => * [[Healing environments]] [157] => * [[Immuno-psychiatry]] [158] => * [[Neural top down control of physiology]] [159] => * [[PANDAS]] [160] => * [[Post-traumatic stress disorder]] [161] => * [[Cholinergic anti-inflammatory pathway]] [162] => * [[Ecoimmunology]] [163] => {{col-end}} [164] => [165] => ==References== [166] => {{Reflist|3}} [167] => [168] => ==Further reading== [169] => [170] => * Berczi and Szentivanyi (2003). ''NeuroImmune Biology'', Elsevier, {{ISBN|0-444-50851-1}} (Written for the highly technical reader) [171] => * Goodkin, Karl, and Adriaan P. Visser, (eds), ''Psychoneuroimmunology: Stress, Mental Disorders, and Health'', American Psychiatric Press, 2000, {{ISBN|0-88048-171-4}}, technical. [172] => * Maqueda, A. "[http://www.maps.org/news-letters/v21n1/v21n1-15to16.pdf Psychosomatic Medicine, Psychoneuroimmunology and Psychedelics]", ''Multidisciplinary Association for Psychedelic Studies'', Vol xxi No 1. [173] => * Ransohoff, Richard, et al. (eds), ''Universes in Delicate Balance: Chemokines and the Nervous System'', Elsevier, 2002, {{ISBN|0-444-51002-8}} [174] => * Robert Ader, David L. Felten, Nicholas Cohen, ''Psychoneuroimmunology'', 4th edition, 2 volumes, Academic Press, (2006), {{ISBN|0-12-088576-X}} [175] => * Hafner Mateja, Ihan Alojz (2014). ''[https://www.dropbox.com/s/huahvkb01d3qr6v/AWAKENING_trailer.pdf?dl=0 AWAKENING: Psyche in search of the lost Eros - psychoneuroimmunology]'', Alpha Center d.o.o., [http://zase.si/?izdelki&vec=124 Institute for preventive medicine], {{ISBN|978-961-6070-26-3}}. [176] => [177] => ==External links== [178] => * [http://www.pnirs.org/ Psychoneuroimmunology Research Society] [179] => * [http://www.urmc.rochester.edu/GEBS/faculty/Robert_Ader.htm Home page of Robert Ader - University of Rochester] [180] => * [https://www.semel.ucla.edu/cousins Cousins Center for Psychoneuroimmunology] [181] => * [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.3767 Biochemical Aspects of Anxiety] [182] => * [https://web.archive.org/web/20140322114912/http://www.psiconeuroinmunologia.com/portal/index.php/recursos-cientificos/ Peruvian Institute of Psychoneuroimmunology] [183] => * [http://www.zase.si Institute for preventive medicine], Ljubljana, Slovenia [184] => [185] => [[Category:Branches of immunology]] [186] => [[Category:Neurology]] [187] => [[Category:Mind–body interventions]] [188] => [[Category:Behavioral neuroscience]] [189] => [[Category:Somatic psychology]] [190] => [[Category:Psychoneuroimmunology]] [] => )
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Psychoneuroimmunology

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine.

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