Psychoneuroimmunology (PNI) is the study of the interaction between psychological processes and the nervous and immune systems of the human body.^[1] PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.

The main interests of PNI are the interactions between the nervous and immune systems and the relationships between mental processes and health. PNI studies, among other things, the physiological functioning of the neuroimmune system in health and disease; disorders of the neuroimmune system (autoimmune diseases; hypersensitivities; immune deficiency); and the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.

PNI may also be referred to as psychoendoneuroimmunology (PENI).

History

Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine.

Walter Cannon, a professor of physiology at Harvard University, looked at the need for mental and physical balance throughout the organism and coined the term, Homeostasis in his book The Wisdom of the Body,1932, from the Greek word homoios, meaning similar, and stasis, meaning position.

In his work with animals Cannon observed that any change of emotional state in the animal, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach. These studies into the relationship between the effects of emotions and perceptions on the autonomic nervous system, namely the sympathetic and parasympathetic responses that initiated the recognition of the 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. Dr. Cannon’s seminal work, Bodily Changes in Pain, Hunger, Fear and Rage was published in 1915.

Picking up on Cannon's work was Hans Selye. Selye experimented with animals putting them under different physical and mental adverse conditions and noted that under these conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of Dr. 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 ulcerations.

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.^[2]

Mid 20th century studies of psychiatric patients reported immune alterations in psychotic patients, including numbers of lymphocytes ^[3][4] and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects.^[5] In 1964 George F. Solomon et all. coined the term "psychoimmunology" and published a landmark paper: "Emotions, immunity, and disease: a speculative theoretical integration."^[6]

Birth of psychoneuroimmunology

In 1975 Robert Ader and Nicholas Cohen at the University of Rochester advanced PNI with their demonstration of classic conditioning of immune function, and coined the term "psychoneuroimmunology".^[7][8] Ader was investigating how long conditioned responses (in the sense of 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 of saccharine-laced water (the conditioned stimulus) and the drug Cytoxan which unconditionally induces nausea and taste aversion and suppression of the immune system. Ader was surprised to discover that after conditioning, just feeding the rats saccharine-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.

In 1981 David Felten, then working at the Indiana University of Medicine, 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 lymphocytes, macrophages and mast cells, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs.

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. An updated fourth edition was released in 2006.

In 1985, research by neuropharmacologist Candace Pert revealed that neuropeptide-specific receptors are present on the cell walls of both the brain and the immune system.^[9][10] The discovery by Pert et al. that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions 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 has had an enormous impact on how we understand emotions, as well as disease.

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.

The Immune-Brain Loop

PNI research is looking for the exact mechanisms by which specific brainimmunity effects are achieved. Evidence for nervous system–immune system interactions exists at several biological levels.

The immune system and the brain talk to each other through signaling pathways. The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the Hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS). The activation of SNS during an immune response might be aimed to localize the inflammatory response.

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. 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.

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 the brain. Immune cells including macrophages, create these molecules and experiments showed that they can act directly inside the brain by creation of microglia and astrocytes (both types of glial cells) to trigger a sickness response. Cytokines are also locally produced in the brain, especially in the hypothalamus, thus contributing to the development of behavioural effects.^[11]

Cytokines mediate and control immune and 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^[12]:

• the acute-phase reaction
• Sickness behavior
• the pain program
• the stress response

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.

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, in addition to autoimmune hypersensitivity and chronic infections.

Chronic secretion of 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 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.

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.

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.

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 chemokines also modulate central nervous system (CNS) function in the absence of overt immunological, physiological, or psychological challenges.^[13]

Psychoneuroimmunological effects

There is 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 disregulation is highlighted by increased risks across diverse conditions and diseases.

Link between stress and disease

Stressors can produce profound health consequences. In one epidemiological study, for example, all-cause mortality increased in the month following a severe stressor – the death of a spouse.^[14] 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 ^{[15] [16]}. Potential health consequences are broad, but include rates of infection ^{[17] [18]} HIV progression ^{[19] [20]} and cancer incidence and progression.^{[21] [22] [23]}

Stress is thought to affect immune function through emotional and/or behavioral manifestations such as anxiety, fear, 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^[24], but when stress is chronic, the system is unable to maintain equilibrium or homeostasis.

Immune changes in response to very brief stressors have been a central theme in the last decade of PNI research, but older literature also provides early illustrations. In a study published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives.^[25]

Two meta-analyses of the literature show a consistent reduction of immune function in healthy people who are experiencing stress.

In the first meta-analysis by Herbert and Cohen in 1993,^[26] 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 cells (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.

In the second meta-analysis by Zorrilla et al. in 2001,^[27] 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).

Communication between the brain and immune system

• Stimulation of brain sites alters immunity (stressed animals have altered immune systems).
• Immune cells produce cytokines that act on the CNS.
• Immune cells respond to signals from the CNS.

Communication between neuroendocrine and immune system

• Glucocorticoids and catecholamines influence immune cells.^[28]
• Endorphins from pituitary & adrenal medulla act on immune system.
• Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.

Connections between glucocorticoids and immune system

• Anti-inflammatory hormones that enhance the organisms response to a stressor.
• Prevent the overreaction of the body own defense system.
• Regulators of the immune system.
• Affect cell growth, proliferation & differentiation.
• Cause immunosuppression.
• Suppress cell adhesion, antigen presentation, chemotaxis & cytotoxicity.
• Increase apoptosis.

Corticotropin-releasing hormone (CRH)

Release of corticotropin-releasing hormone (CRH) from the hypothalamus is influenced by stress.

• CRH is a major regulator of the HPA axis/stress axis.
• CRH Regulates secretion of Adrenocorticotropic hormone (ACTH).
• CRH is widely distributed in the brain and periphery
• CRH also regulates the actions of the Autonomic nervous system ANS and immune system.

Furthermore, stressors that enhance the release of CRH suppress the function of the immune system; conversely, stressors that depress CRH release potentiate immunity.

• Central mediated since peripheral administration of CRH antagonist does not affect immunosuppression.

Pharmaceutical advances

Glutamate agonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, GABA agonists (including opioids and cannabinoids), COX inhibitors, acetylcholine modulators, melatonin analogs (such as Ramelton), adenosine receptor antagonists and several miscellaneous drugs (including biologics like Passiflora edulis) are being studied for their psychoneuroimmunological effects.

For example, SSRI's, SNRI's and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors 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.^[29][30][31] Antidepressants have also been shown to suppress TH1 upregulation.^{[32][33][34][35][36]}

Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.^[37][38] 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.^[39]

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases.^[40] 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.^[41]

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.

Medical technology is a part of the Health technology which encompasses a wide range of health care products and, in one form or another, is used to diagnose, monitor or treat every disease or condition that affects humans. These innovative technologies (application of science and technology) are improving the quality of health care delivered and patient outcomes through earlier diagnosis, less invasive treatment options and reductions in hospital stays and rehabilitation times.^[1] medical technology is any format of machinery that is used to operate or perform medical procedures Health technology is:

Allied health profession

The term Medical technology may also refer to the duties performed by clinical laboratory professionals in various settings within the public and private sectors. The work of these professionals encompass clinical applications of chemistry, genetics, hematology, immunohematology (blood banking), immunology, microbiology, serology, urinalysis and miscellaneous body fluid analysis. These professionals may be referred to as Medical Technologists (MT) and Medical Laboratory Technicians (MLT) or as Clinical Laboratory Scientists (CLS) and Clinical Laboratory Technicians (CLT) depending on education, certification and/or licensure. The term medical technologist in this sense is sometimes considered a misnomer due to the fact that these professionals do not actually produce novel medical technology but rather apply the ones already in place in conjunction with the knowledge of the scientific principles of clinical laboratory science, which has been considered a more appropriate term for the discipline.

The increased longevity of humans over the past century can be significantly attributed to advances resulting from medical research. Among the major benefits have been vaccines for measles and polio, insulin treatment for diabetes, classes of antibiotics for treating a host of maladies, medication for high blood pressure, improved treatments for AIDS, statins and other treatments for atherosclerosis, new surgical techniques such as microsurgery, and increasingly successful treatments for cancer. New, beneficial tests and treatments are expected as a result of the human genome project. Many challenges remain, however, including the appearance of antibiotic resistance and the obesity epidemic.

Most of the research in the field is pursued by biomedical scientists in cooperation with molecular biologists.

Preclinical research

Preclinical research is research in basic science, which precedes the clinical trials, and is almost purely based on theory and animal experiments. Much of these experiments involve preclinical imaging modalities to aid in vivo, longitudinal studies.

New treatments come about as a result of other, earlier discoveries — often unconnected to each other, and in various fields. Sometimes the research is done for non-medical purposes, and only by accident contributes to the field of medicine (for example, the discovery of penicillin). Clinicians use these discoveries to create a treatment regimen, which is then tested in clinical trials.

Clinical trials

A clinical trial is a comparison test of a medication or other medical treatment, versus a placebo, other medications and devices, or the standard medical treatment for a patient's condition. Clinical trials vary greatly in size: from a single researcher in one hospital or clinic to an international multicenter trial with several hundred participating researchers on several continents. The number of patients tested can range from as few as a dozen to several thousands.

Every new drug formulation used in a clinical trial has to first undergo rigorous tests in a laboratory. Once the results from those tests confirm that the formulation is safe to be taken by humans, the drug is given to healthy volunteers in what are called Phase I clinical trials.^[1]

Funding

Research funding in many countries comes from research bodies which distribute money for equipment and salaries. In the UK, funding bodies such as the Medical Research Council derive their assets from UK tax payers, and distribute this to institutions in a competitive manner.

In the United States, the most recent data from 2003^[2] suggest that about 94 billion dollars were provided for biomedical research in the United States. The National Institutes of Health and pharmaceutical companies collectively contribute 26.4 billion dollars and 27.0 billion dollars, respectively, which constitute 28% and 29% of the total, respectively. Other significant contributors include biotechnology companies (17.9 billion dollars, 19% of total), medical device companies (9.2 billion dollars, 10% of total), other federal sources, and state and local governments. Foundations and charities, led by the Bill and Melinda Gates Foundation, contributed about 3% of the funding.

In Australia, medical research is funded mostly by the National Health and Medical Research Council (NHMRC), whos expenditure on research was nearly $AUD700 million in 2008-09.^[3]

The enactment of orphan drug legislation in some countries has increased funding available to develop drugs meant to treat rare conditions, resulting in breakthroughs that previously were uneconomical to pursue.

Regulations and guidelines

Medical research is highly regulated. National regulatory authorities oversee and monitor medical research, such as for the development of new drugs. In the USA the Food and Drug Administration oversees new drug development, in Europe the European Medicines Agency (see also EudraLex), and in Japan the Ministry of Health, Labour and Welfare (Japan). The World Medical Association develops the ethical standards for the medical profession, involved in medical research. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) works on the creation of rules and guidelines for the development of new medication, such as the guidelines for Good Clinical Practice (GCP). All ideas of regulation are based on a country's ethical standards code. This is why treatment of a particular disease in one country may not be allowed, but is in another.

Conflicts of interest

In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies in the U.S. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.

Medical nutrition therapy (MNT) is a therapeutic approach to treating medical conditions and their associated symptoms via the use of a specifically tailored diet devised and monitored by a registered dietician. The diet is based upon the patient's medical and psychosocial history, physical examination and dietary history.

The role of MNT is to reduce the risk of developing complications in pre-existing conditions such as diabetes as well as ameliorate the effects any existing conditions such as high cholestorol.