Bioregulatory medicine is a mind-body medicine, and as such focuses on the interactions among the brain, mind, body, and behavior, and the powerful ways in which emotional, mental, social, spiritual, and behavioral factors can directly affect health. The mind-body paradigm has been an integral part of most traditional medical systems such as traditional Asian medicine, Ayurveda medicine and Shamanistic medicine.

 

It was also noted by Hippocrates, who recognized the moral and spiritual aspects of healing, and believed that treatment could occur only with consideration of attitude, environmental influences, and natural remedies. 

 

While this integrated approach was maintained in traditional healing systems in the East, developments in the Western world by the 16th and 17th centuries led to a separation of human spiritual or emotional dimensions from the physical body.

 

This separation began with the redirection of science, during the Renaissance and Enlightenment eras, with a new focus on trying to enhance humankind's control over nature. Technological advances developed and appeared to further separate the physical body and cellular world from the world of belief and emotion. 

 

However, moving in full circle over the past 50 years, mind-body medicine has provided considerable evidence that psychological factors can play a substantive role in health as well as the development and progression of disease. From this line of inquiry developed the science of psychoneuroimmunology.

Hippocrates recognized the moral and spiritual aspects of healing, and believed that treatment could only occur with consideration of attitude, environmental influences, and natural remedies.

Psychoneuroimmunology is the study of the interactions among behavioral, neural and endocrine, and immune processes. The brain communicates with the immune system through autonomic nervous system and neuroendocrine activity. Both pathways generate signals that are perceived by the immune system via receptors on the surface of lymphocytes and other immune cells. Conversely, an activated immune system generates chemical signals (cytokines) that are perceived by the nervous system. In turn, the brain releases its own cytokines that signal the central nervous system to initiate a cascade of responses such as fever and listlessness that, theorists believe, help the body adapt by reducing energy output.

 

Psychoneuroimmunology researchers are, in fact, increasingly interested in cytokine activity because it represents an immune response that can go awry. Thus, bidirectional pathways connect the brain and the immune system and provide the foundation for behavioral influences on immune functions. For many years, the immune system was considered a stand-alone, autonomous mechanism. This, as we now know, is not the case. The brain speaks regularly and eloquently to the cells of the immune system and vice versa.

 

One of the major philosophical aspirations in contemporary consciousness research is to find a framework of explanation that can successfully address the problem of mind-body relations. Recent findings in psychoneuroimmunology have shown that somato-psychic mechanisms exist through which bodily stimuli are translated into neuropsychological events resulting in alterations in certain behavioral patterns. 

How an individual interprets and responds to the environment determines responses to stress, influences health behaviors, contributes to the neuroendocrine and immune response, and may ultimately affect health outcomes. There are now enough data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. Health psychology interventions are designed to modulate the stress response and improve health behaviors by teaching individuals more adaptive methods of interpreting life challenges and more effective coping responses. Positive and negative affective states probably create different neuroimmune responses in the body and thus influence health and recovery from illness. Two competing responses, the stress response and the relaxation response, counterbalance each other on an ongoing basis.

Psychoneuroimmunology researchers began their studies in the 1960s making associations between stress and immune functioning. In 1964, George F. Solomon coined the term psychoimmunology and published a landmark article: “Emotions, Immunity, and Disease: A Speculative Theoretical Integration”.

 

Robert Ader is widely considered to be the father of modern psychoneuroimmunology. His early research, involving conditioning in rats, opened the scientific inquiry for the study of brain-immune communication. Robert Ader and Nicholas Cohen's (1975) landmark article showed that immune function could be classically conditioned.

 

This report was viewed with considerable skepticism initially; in fact, several laboratories designed replications of the original experiment, assuming that the original data were erroneous. The reliability of the phenomena has now been demonstrated by several laboratories.

In 1981, David Felten made the next major discovery. He uncovered a network of nerves that led to blood vessels and, importantly, cells of the immune system. Felten's team found nerves in the thymus and spleen that terminated near clusters of important immune system components: 
lymphocytes, macrophages and mast cells.

In 1985, Candace Pert, former chief of the Brain Biochemistry Section of the National Institute of Mental Health and co-discoverer of the brain's opiate receptors, found neurotransmitter and neuropeptide receptors on the cell walls of the immune system and the brain. This discovery showed that the communication chemicals of the nervous system could also speak directly to the immune system. What made this finding particularly fascinating was the discovery of neuropeptide links to the immune system. 

 

Over the past 40 years, researchers have followed the footsteps of these researchers and have uncovered a large body of evidence explaining how the mind and body connect. Evidence from randomized controlled trials and, in many cases, systematic reviews of the literature, suggest that:

 

  • Mechanisms exist by which the brain and central nervous system influence immune, endocrine, and autonomic functioning, which is known to have an impact on health.

  • Multicomponent mind-body interventions that include some combination of stress management, coping skills training, cognitive-behavioral interventions, and relaxation therapy may be appropriate adjunctive treatments for coronary artery disease and certain pain-related disorders, such as arthritis.

  • Multimodal mind-body approaches, such as cognitive-behavioral therapy, particularly when combined with an educational/informational component, are effective adjuncts in the management of a variety of chronic conditions.

  • An array of mind-body therapies (e.g., imagery, hypnosis, relaxation), when employed presurgically, improve recovery time and reduce pain following surgical procedures.

  • Neurochemical and anatomical bases clearly exist for some of the effects of mind-body approaches.

 

There is considerable evidence that many mind-body interventions have positive effects on psychological functioning and quality of life and may be particularly helpful for patients coping with chronic illness and in need of palliative care.

 

The articles listed here are a small sampling of the hundreds if not thousands of articles that have been published on the subjects Mind-Body Medicine and Psychoneuroimmunology. 

Robert Ader is widely considered to be the father of modern psychoneuroimmunology.

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Mind-Body Medicine

Astin, John A., Shauna L. Shapiro, David M. Eisenberg, and Kelly L. Forys. Mind-body medicine: state of the science, implications for practice. The Journal of the American Board of Family Practice 16, no. 2 (2003): 131-147.

Background: Although emerging evidence during the past several decades suggests that psychosocial factors can directly influence both physiologic function and health outcomes, medicine had failed to move beyond the biomedical model, in part because of lack of exposure to the evidence base supporting the biopsychosocial model. The literature was reviewed to examine the efficacy of representative psychosocial–mind-body interventions, including relaxation, (cognitive) behavioral therapies, meditation, imagery, biofeedback, and hypnosis for several common clinical conditions. Methods: An electronic search was undertaken of the MEDLINE, PsycLIT, and the Cochrane Library databases and a manual search of the reference sections of relevant articles for related clinical trials and reviews of the literature. Studies examining mind-body interventions for psychological disorders were excluded. Owing to space limitations, studies examining more body-based therapies, such as yoga and tai chi chuan, were also not included. Data were extracted from relevant systematic reviews, meta-analyses, and randomized controlled trials. Results: Drawing principally from systematic reviews and meta-analyses, there is considerable evidence of efficacy for several mind-body therapies in the treatment of coronary artery disease (e.g., cardiac rehabilitation), headaches, insomnia, incontinence, chronic low back pain, disease and treatment related symptoms of cancer, and improving postsurgical outcomes. We found moderate evidence of efficacy for mind-body therapies in the areas of hypertension and arthritis. Additional research is required to clarify the relative efficacy of different mind-body therapies, factors (such as specific patient characteristics) that might predict more or less successful outcomes, and mechanisms of action. Research is also necessary to examine the cost offsets associated with mind-body therapies. Conclusions: There is now considerable evidence that an array of mind-body therapies can be used as effective adjuncts to conventional medical treatment for a number of common clinical conditions.

 

Astin, John A. Mind–body therapies for the management of pain. The Clinical journal of pain 20, no. 1 (2004): 27-32.

Abstract: This paper reviews the evidence for mind-body therapies (eg, relaxation, meditation, imagery, cognitive-behavioral therapy) in the treatment of pain-related medical conditions and suggests directions for future research in these areas. Based on evidence from randomized controlled trials and in many cases, systematic reviews of the literature, the following recommendations can be made: 1) multicomponent mind-body approaches that include some combination of stress management, coping skills training, cognitive restructuring and relaxation therapy may be an appropriate adjunctive treatment for chronic low back pain; 2) multimodal mind-body approaches such as cognitive-behavioral therapy, particularly when combined with an educational/informational component, can be an effective adjunct in the management of rheumatoid and osteoarthritis; 3) relaxation and thermal biofeedback may be considered as a treatment for recurrent migraine while relaxation and muscle biofeedback can be an effective adjunct or stand alone therapy for recurrent tension headache; 4) an array of mind-body therapies (eg, imagery, hypnosis, relaxation) when employed pre-surgically, can improve recovery time and reduce pain following surgical procedures; 5) mind-body approaches may be considered as adjunctive therapies to help ameliorate pain during invasive medical procedures.

Davidson, Richard J., Jon Kabat-Zinn, Jessica Schumacher, Melissa Rosenkranz, Daniel Muller, Saki F. Santorelli, Ferris Urbanowski, Anne Harrington, Katherine Bonus, and John F. Sheridan. Alterations in brain and immune function produced by mindfulness meditation. Psychosomatic medicine 65, no. 4 (2003): 564-570.

Objective: The underlying changes in biological processes that are associated with reported changes in mental and physical health in response to meditation have not been systematically explored. We performed a randomized, controlled study on the effects on brain and immune function of a well-known and widely used 8-week clinical training program in mindfulness meditation applied in a work environment with healthy employees. Methods: We measured brain electrical activity before and immediately after, and then 4 months after an 8-week training program in mindfulness meditation. Twenty-five subjects were tested in the meditation group. A wait-list control group (N  16) was tested at the same points in time as the meditators. At the end of the 8-week period, subjects in both groups were vaccinated with influenza vaccine. Results: We report for the first time significant increases in left-sided anterior activation, a pattern previously associated with positive affect, in the meditators compared with the nonmeditators. We also found significant increases in antibody titers to influenza vaccine among subjects in the meditation compared with those in the wait-list control group. Finally, the magnitude of increase in left-sided activation predicted the magnitude of antibody titer rise to the vaccine. Conclusions: These findings demonstrate that a short program in mindfulness meditation produces demonstrable effects on brain and immune function. These findings suggest that meditation may change brain and immune function in positive ways and underscore the need for additional research. 

Dobos, Gustav, Nils Altner, Silke Lange, Frauke Musial, Jost Langhorst, Andreas Michalsen, and Anna Paul. Mind-Body Medicine als Bestandteil der Integrativen Medizin. Bundesgesundheitsblatt-Gesundheitsforschung-Gesundheitsschutz 49, no. 8 (2006): 723-728. (Article in German)

Ock, Sun Myeong. Clinical Application of Mind-body Medicine: An Evidence-Based Approach. Journal of the Korean Academy of Family Medicine 27, no. 2 (2006): 79-90. (Article in Korean)

지난 수 십년간 많은 연구들은 정신사회적인 요인들이 생리적 기능과 건강에 직접적으로 영향을 미친다는 많은 근거들 을 제시하여, 일부 만성 질환과 기능성 질환의 관리에 효과적이며 암과 같이 완화적 요법이 필요한 경우에도 긍정적이 라는 근거를 제시하였다. 현대의 대다수의 질병들이 기능성, 만성 퇴행성 질환으로 효과적인 치료를 위해서는 생활 습관 및 스트레스, 정신사회적 요인들에 대한 관리가 필요하다는 점을 고려해 보았을 때 현대 질병의 효율적인 관리, 의료 질의 향상 등을 위해 심신의학의 개입은 필연으로 여겨지고 있다. 본 논문에서는 심신의학의 근거중심적인 임상 적용 및 전반적인 개요를 제시하였다.

Pelletier, Kenneth R. Matters of the heart: an evidence-based overview of mind-body medicine in cardiovascular disease. holistic healthcare 3, no. 3 (2006): 39.

For nearly 30 years, my research and clinical practice has focused on understanding the inextricable interaction between mind and body especially with regard to cardiovascular disease. In 1977, I wrote Mind as healer, mind as slayer which is considered a ‘classic’ and was updated in 1992. What struck me about the intervening 25 years was how much the basic sciences had evolved regarding mechanisms. By contrast, the evidence-based interventions were similar to practices in the meditation literature of thousands of years. In 2005 I served as one of the co-authors for the official position paper on CAM and cardiology from the American College of Cardiology. It was very positive in its review of the evidence for mind-body medicine, nutritional supplements, acupuncture, and spirituality. It is my hope that in the next 25 years, we will witness a profound integration of conventional, alternative, and epigenetic medicine into an integrative medicine approach to cardiovascular disease.

Wolsko, Peter M., David M. Eisenberg, Roger B. Davis, and Russell S. Phillips. Use of mind-body medical therapies. Journal of general internal medicine 19, no. 1 (2004): 43-50.

OBJECT: Research demonstrating connections between the mind and body has increased interest in the potential of mind–body therapies. Our aim was to examine the use of mind–body therapies, using data available from a national survey. DESIGN: Analysis of a large nationally representative dataset that comprehensively evaluated the use of mind–body therapies in the last year. SETTING: United States households. PATIENTS/PARTICIPANTS: A total of 2,055 American adults in 1997–1998. INTERVENTIONS: Random national telephone survey. MEASURES AND MAIN RESULTS: We obtained a 60% weighted overall response rate among eligible respondents. We found that 18.9% of adults had used at least 1 mind–body therapy in the last year, with 20.5% of these therapies involving visits to a mind–body professional. Meditation, imagery, and yoga were the most commonly used techniques. Factors independently and positively associated with the use of mind–body therapies in the last year were being 40 to 49 years old (adjusted odds ratio [AOR], 2.03; 95% confidence interval [CI], 1.33 to 3.10), being not married (AOR, 1.78; 95% CI, 1.34 to 2.36), having an educational level of college or greater (AOR, 2.21; 95% CI, 1.57 to 3.09), having used self-prayer for a medical concern (AOR, 2.53; 95% CI, 1.87 to 3.42), and having used another complementary medicine therapy in the last year (AOR, 3.77; 95% CI, 2.74 to 5.20). While used for the full array of medical conditions, they were used infrequently for chronic pain (used by 20% of those with chronic pain) and insomnia (used by 13% of those with insomnia), conditions for which consensus panels have concluded that mind–body therapies are effective. They were also used by less than 20% of those with heart disease, headaches, back or neck pain, and cancer, conditions for which there is strong research support. Mind– body therapies were generally used concomitantly with conventional care: 90% of those using a mind–body therapy in the last year had seen a physician and 80% of mind–body therapies used were discussed with a physician.

Psychoneuroimmunology

Ader, Robert, and Nicholas Cohen. Psychoneuroimmunology: conditioning and stress. Annual review of psychology 44, no. 1 (1993): 53-85.

During the past 10-15 years, psychoneuroimmunology--the study of the interactions among behavior, neural and endocrine function, and immune processes--has developed into a bona fide field of interdisciplinary research (Ader 1981a, 1991a). Previously unknown and unsuspected connections between the brain and the immune system provide a foundation for the now numerous observations both (a) that the manipulation of neural and endocrine functions alters immune responses, and the antigenic stimulation that induces an immune response results in changes in neural and endocrine function and (b) that behavioral processes are capable of influencing immunologic reactivity and, conversely, the immune status of an organism has consequences for behavior. This new research indicates that the nervous and immune systems, the two most complex systems involved in the maintenance of homeostasis, represent an integrated mechanism contributing to the adaptation of the individual and the species. Psychoneuroimmunology emphasizes the functional significance of the relationship between these systems--not in place of, but in addition to the more traditional disciplinary analysis of the mechanisms governing functions within a single system. The range of phenomena that bears on the relationship between behavior and immunity is quite broad, and no attempt will be made to provide even a cursory summary of all this literature. We focus here on animal studies of the effects of conditioning and stress in the modulation of immune function. There are several more or less programmatic lines of research in humans that the reader may wish to explore. These deal with the immunologic correlates of emotional states (primarily depression), personality traits as modulators immune function, and the effects of stress on immune function. Few generalizations are possible based on currently available data. Although there is no definitive evidence for the implied chain of events, the hypothesis that immune function may mediate the effects of psychosocial factors on the susceptibility to or progression of some disease processes remains tenable. We confine this review, however, to the experimental literature on the modulation of immunity by stress and conditioning. 

Ader, Robert. Developmental psychoneuroimmunology. Developmental Psychobiology: The Journal of the International Society for Developmental Psychobiology 16, no. 4 (1983): 251-267.

Biondi, Massimo, and Giorgio D. Kotzalidis. Human psychoneuroimmunology today. Journal of clinical laboratory analysis 4, no. 1 (1990): 22-38.

Studies in human psychoneuroimmunology began around 1919, but a systematic approach wasn’t used until the work of Solomon in the 1960s. Recently, the new specialty has achieved relative independence due to considerable data acquisition. Stress research has revealed relationships between neuroendocrine and immune changes. In parallel, increasing evidence of immunological alterations in psychiatric diseases has expanded the field; presently, immunological correlates of psychosomatic diseases and personality are sought. On the other hand, while immunological disease has been psychologically assessed for many years, a clear-cut link between psyche and immunological changes has yet to be shown. This fact, along with the therapeutic implications of advancing knowledge, will influence strongly the future trends of psychoneuroimmunology. Concepts emerging from the study of this field will be of heuristic value to both psychiatry and immunology and will help define new and expanded limits for both disciplines.

Fancourt, Daisy. An introduction to the psychoneuroimmunology of music: History, future collaboration and a research agenda. Psychology of Music 44, no. 2 (2016): 168-182.

During the 1970s, research on music broadened from a predominantly historical and analytical study to one that explored music and psychology. The last two decades in particular have taken us a step further to explore music, psychology and neuroscience. This article explores how we could extend our research again through the exploration of the immunological impact of music. The influence of music on immune function has been reviewed in a recent article that has brought to light an intriguing body of evidence and highlighted the enormous promise of this field for further study. Such study has the potential to influence research in a number of related areas including music psychology, music and health, evolutionary musicology and music performance. However, there are a number of limitations to the current approach to such research; most significantly that studies are almost exclusively happening outside the field of music psychology. Consequently, drawing on theories of collaboration, a model is put forwards for how future studies should be conducted and a research agenda outlined.

Fleshner, Monika, and Mark L. Laudenslager. Psychoneuroimmunology: then and now. Behavioral and Cognitive Neuroscience Reviews 3, no. 2 (2004): 114-130.

Psychoneuroimmunology (PNI) emerged in the neurosciences in the late 1970s to early 1980s and has extended to influence the fields of psychology, psychiatry, endocrinology, physiology, and the biomedical research community. This review documents the journey of PNI from the early 1980s to the present. Today, we recognize that the highly complex immune system interacts with an equally complex nervous system in a bidirectional manner. Evolutionarily old signals continue to play a role in these communications, as do mechanisms for protection of the host. The disparity between physical and psychological stressors is only an illusion. Host defense mechanisms respond in adaptive and meaningful ways to both. The present review will describe a new way of thinking about evolutionarily old molecules, heat shock proteins, adding to a body of evidence suggesting that activation of the acute stress response is a double-edged sword that can both benefit and derail optimal immunity.

Goehler, Lisa E., Mark Lyte, and Ronald PA Gaykema. Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain, behavior, and immunity 21, no. 6 (2007): 721-726.

Infection and inflammation lead to changes in mood and cognition. Although the “classic” sickness behavior syndrome, involving fatigue, social withdrawal, and loss of appetites are most familiar, other emotional responses accompany immune activation, including anxiety. Recent studies have shown that gastrointestinal bacterial infections lead to enhanced anxiety-like behavior in mice. The bacteria-induced signal is most likely carried by vagal sensory neurons and occurs early on (within six hours) during the infection. These signals induce evidence of activation in brain regions that integrate viscerosensory information with mood and potentiate activation in brain regions established as key players in fear and anxiety. The findings underline the importance of viscerosensory signals arising from the gastrointestinal tract in modulation of behaviors appropriate for coping with threats and suggest that these signals may contribute to affective symptoms associated with gastrointestinal disorders.

Jaremka, Lisa M., Monica E. Lindgren, and Janice K. Kiecolt‐Glaser. Synergistic relationships among stress, depression, and troubled relationships: insights from psychoneuroimmunology. Depression and anxiety 30, no. 4 (2013): 288-296.

Stress and depression consistently elevate inflammation. Stress and depression are often experienced simultaneously, which is exemplified by people in troubled relationships. Troubled relationships also elevate inflammation, which may be partially explained by their ability to engender high levels of stress and depression. People who are stressed, depressed, or in troubled relationships are also at greater risk for health problems than their less distressed counterparts. Inflammation, a risk factor for a variety of age-related diseases including cardiovascular disease, Type II diabetes, metabolic syndrome, and frailty, may be one key mechanistic pathway linking distress to poor health. Obesity may further broaden the health implications of stress and depression; people who are stressed or depressed are often overweight, and adipose tissue is a major source of proinflammatory cytokines. Stress, depression, and troubled relationships may have synergistic inflammatory effects; loneliness, subclinical depression, and major depression enhance inflammatory responses to an acute stressful event. The relationship between distress and inflammation is bi-directional; depression enhances inflammation and inflammation promotes depression. Interesting questions emerge from this literature. For instance, some stressors may be more potent than others and thus may be more strongly linked to inflammation. In addition, it is possible that psychological and interpersonal resources may buffer the negative inflammatory effects of stress. Understanding the links among stress, depression, troubled relationships and inflammation is an exciting area of research that may provide mechanistic insight into the links between distress and poor health.

 

Kendall-Tackett, Kathleen. Psychological trauma and physical health: A psychoneuroimmunology approach to etiology of negative health effects and possible interventions. Psychological Trauma: theory, research, practice, and policy 1, no. 1 (2009): 35.

People who have experienced traumatic events have higher rates than the general population of a wide range of serious and life-threatening illnesses including cardiovascular disease, diabetes, gastrointestinal disorders, and cancer. An important question, for both researchers and clinicians, is why this occurs. Researchers have discovered that traumatic events dysregulate the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. More recently, research from the field of psychoneuroimmunology (PNI) suggests that traumatic life events can lead to health problems through dysregulation of another key system: the inflammatory response. Prior trauma “primes” the inflammatory response system so that it reacts more rapidly to subsequent life stressors. Elevated inflammation has an etiologic role in many chronic illnesses. Recent PNI studies also suggest some interventions that can serve as adjuncts to traditional trauma treatment. These treatments include long-chain omega-3 fatty acids, exercise, and sleep interventions. Each of these interventions downregulates inflammation, which will likely halt the progression to chronic disease for some trauma survivors.

 

Kiecolt-Glaser, Janice K. Psychoneuroimmunology: Psychology's gateway to the biomedical future. Perspectives on Psychological Science 4, no. 4 (2009): 367-369.

How do stressful events and negative emotions influence the immune system, and how big are the effects? This broad question has been intensely interesting to psychoneuroimmunology researchers over the last three decades. Many promising lines of work underscore the reasons why this question is still so important and pivotal to understanding and other advances. New multidisciplinary permutations provide fresh vistas and emphasize the importance of training psychologists more broadly so that they will be central and essential players in the advancement of biomedical science.

 

Kiecolt-Glaser, Janice K. Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge. Psychosomatic medicine 72, no. 4 (2010): 365.

 

Inflammation is the common link among the leading causes of death. Mechanistic studies have shown how various dietary components can modulate key pathways to inflammation including sympathetic activity, oxidative stress, transcription factor nuclear factor kappa B (NF-κB) activation, and proinflammatory cytokine production. Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes. If the joint contributions of diet and behavior to inflammation were simply additive, they would certainly be important. However, several far more intriguing interactive possibilities are discussed: stress influences food choices; stress can enhance maladaptive metabolic responses to unhealthy meals; and diet can impact mood as well as proinflammatory responses to stressors. Furthermore, because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation; in turn, both depression and stress have well-documented negative effects on vagal activation, contributing to the lively interplay between the brain and the gut. As one example, omega-3 fatty acid intake can boost mood and vagal tone, dampen NF-κB activation and responses to endotoxin, and modulate the magnitude of inflammatory responses to stressors. A better understanding of how stressors, negative emotions, and unhealthy meals work together to enhance inflammation will benefit behavioral and nutritional research, as well as the broader biomedical community.

 

Kiecolt-Glaser, Janice K., Lynanne McGuire, Theodore F. Robles, and Ronald Glaser. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annual review of psychology 53, no. 1 (2002): 83-107.

Negative emotions can intensify a variety of health threats. We provide a broad framework relating negative emotions to a range of diseases whose onset and course may be influenced by the immune system; inflammation has been linked to a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, Alzheimer’s disease, frailty and functional decline, and periodontal disease. Production of proinflammatory cytokines that influence these and other conditions can be directly stimulated by negative emotions and stressful experiences. Additionally, negative emotions also contribute to prolonged infection and delayed wound healing, processes that fuel sustained proinflammatory cytokine production. Accordingly, we argue that distress-related immune dysregulation may be one core mechanism behind a large and diverse set of health risks associated with negative emotions. Resources such as close personal relationships that diminish negative emotions enhance health in part through their positive impact on immune and endocrine regulation.

 

Kiecolt-Glaser, Janice K., Lynanne McGuire, Theodore F. Robles, and Ronald Glaser. Psychoneuroimmunology: Psychological influences on immune function and health. Journal of consulting and clinical psychology 70, no. 3 (2002): 537.

This review focuses on human psychoneuroimmunology studies published in the past decade. Issues discussed include the routes through which psychological factors influence immune function, how a stressor’s duration may influence the changes observed, individual difference variables, the ability of interventions to modulate immune function, and the health consequences of psychosocially mediated immune dysregulation. The importance of negative affect and supportive personal relationships are highlighted. Recent data suggest that immune dysregulation may be one core mechanism for a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, Type 2 diabetes, certain cancers, and frailty and functional decline; production of proinflammatory cytokines that influence these and other conditions can be stimulated directly by negative emotions and indirectly by prolonged infection.

 

Miller, A. H. Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain, behavior, and immunity 23, no. 2 (2009): 149-158.

Work in our laboratory has focused on the mechanisms by which cytokines can influence the brain and behavior in humans and non-human primates. Using administration of interferon (IFN)-alpha as a tool to unravel these mechanisms, we have expanded upon findings from the basic science literature implicating cytokine-induced changes in monoamine metabolism as a primary pathway to depression. More specifically, a role for serotonin metabolism has been supported by the clinical efficacy of serotonin reuptake inhibitors in blocking the development of IFN-alpha-induced depression, and the capacity of IFN-alpha to activate metabolic enzymes (indolamine 2,3 dioxygenase) and cytokine signaling pathways (p38 mitogen activated protein kinase) that can influence the synthesis and reuptake of serotonin. Our data also support a role for dopamine depletion as reflected by IFN-alpha-induced changes in behavior (psychomotor slowing and fatigue) and regional brain activity, which implicate the involvement of the basal ganglia, as well as the association of IFN-alpha-induced depressive-like behavior in rhesus monkeys with decreased cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid. Neuroimaging data in IFN-alpha-treated patients also suggest that activation of neural circuits (dorsal anterior cingulate cortex) associated with anxiety and alarm may contribute to cytokine-induced behavioral changes. Taken together, these effects of cytokines on the brain and behavior appear to subserve competing evolutionary survival priorities that promote reduced activity to allow healing, and hypervigilance to protect against future attack. Depending on the relative balance between these behavioral accoutrements of an activated innate immune response, clinical presentations may be distinct and warrant individualized therapeutic approaches.

 

Shi, Yufang, Satish Devadas, Kristy M. Greeneltch, Deling Yin, R. Allan Mufson, and Jian-nian Zhou. Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology. Brain, behavior, and immunity 17, no. 1 (2003): 18-26.

Psychological and physical stressors best exemplify the intercommunication of the immune and the nervous systems. It has been shown that stress significantly impacts leukocyte cellularity and immune responses and alters susceptibility to various diseases. While acute stress has been shown to enhance immune responses, chronic stress often leads to immunosuppression. Among many criteria examined upon exposure to chronic stress, the reduction in lymphocyte mitogenic response and lymphocyte cellularity are commonly assessed. We have reported that chronic restraint stress could induce lymphocyte reduction, an effect dependent on endogenous opioids. Interestingly, the effect of endogenous opioids was found to be exerted through increasing the expression of a cell death receptor, Fas, and an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte reduction was not affected by adrenalectomy. In this review, based on available literature and our recent data, we will discuss the role of the hypothalamic– pituitary–adrenal axis and endogenous opioids and examine the mechanisms by which chronic stress modulates lymphocyte apoptosis.

Suárez, Andrea L., Jamison D. Feramisco, John Koo, and Martin Steinhoff. Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates. Acta dermato-venereologica 92, no. 1 (2012): 7-18.

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cellnerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

 

Zachariae, Robert. Psychoneuroimmunology: A bio‐psycho‐social approach to health and disease. Scandinavian Journal of Psychology 50, no. 6 (2009): 645-651.

Since the early 1980s, the interdisciplinary field of psychoneuroimmunology has explored the complex bi-directional interactions between brain, behavior, and the immune system. Taken together, this research has expanded the limits of the questions we can ask about the organism by challenging the biomedical paradigm of the immune system as predominantly ‘‘autonomous’’. Psychoneuroimmunology has played a key role in establishing a biological basis for the ancient idea that the mind can play a role in health and disease. This article describes the development of psychoneuroimmunology and reviews a number of key findings concerning psychological phenomena of potential relevance to understanding brain-behavior-immune interactions, including learning, emotions, stress, and the role of sensory processes.

 

Ziemssen, Tjalf, and Simone Kern. Psychoneuroimmunology–cross-talk between the immune and nervous systems. Journal of neurology 254, no. 2 (2007): II8-II11.

Psychoneuroimmunology is a relatively new field of study that investigates interactions between behaviour and the immune system, mediated by the endocrine and nervous systems. The immune and central nervous system (CNS) maintain extensive communication. On the one hand, the brain modulates the immune system by hardwiring sympathetic and parasympathetic nerves (autonomic nervous system) to lymphoid organs. On the other hand, neuroendocrine hormones such as corticotrophin-releasing hormone or substance P regulate cytokine balance. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and immune system-mediated disease.

Psychoneuroimmunology - Epigenetics

Mathews, Herbert L., and Linda Witek Janusek. Epigenetics and psychoneuroimmunology: mechanisms and models. (2011): 25-39.

In this Introduction to the Named Series “Epigenetics, Brain, Behavior, and Immunity” an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin remodeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.

 

 

Psychoneuroimmunology - Pregnancy

Christian, Lisa M. Psychoneuroimmunology in pregnancy: immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development. Neuroscience & Biobehavioral Reviews 36, no. 1 (2012): 350-361.

It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development.

 

Psychoneuroimmunology - Cancer

Bovbjerg, Dana H. Psychoneuroimmunology. Implications for oncology? Cancer 67, no. S3 (1991): 828-832.

Accumulating evidence indicates that the central nervous system (CNS) may regulate the activity of the immune system. Although the overall significance of the immune system in cancer remains controversial, psychosocial influences on immune function could potentially provide a mechanism to account for some of the reports of an association between psychosocial factors and cancer prognosis.

 

Kiecolt-Glaser, Janice Kay, and Ronald Glaser. Psychoneuroimmunology and cancer: fact or fiction? European Journal of Cancer 35, no. 11 (1999): 1603-1607.

There is substantial evidence from both healthy populations as well as individuals with cancer linking psychological stress with immune downregulation. This discussion highlights natural killer (NK) cells, because of the role that they may play in malignant disease. In addition, distress or depression is also associated with two important processes for carcinogenesis: poorer repair of damaged DNA, and alterations in apoptosis. Conversely, the possibility that psychological interventions may enhance immune function and survival among cancer patients clearly merits further exploration, as does the evidence suggesting that social support may be a key psychological mediator. These studies and others suggest that psychological or behavioural factors may influence the incidence or progression of cancer through psychosocial influences on immune function and other physiological pathways.

 

Kiecolt-Glaser, Janice Kay, T. F. Robles, K. L. Heffner, T. J. Loving, and R. Glaser. Psycho-oncology and cancer: psychoneuroimmunology and cancer. Annals of Oncology 13, no. suppl 4 (2002): 165-169.

A growing body of research linking psychological and behavioral factors to the incidence and progression of cancer suggests that psychosocial factors may have an impact on some types of cancer [1–6]. In this paper, we suggest that it is through the impact these behavioral and psychological factors have on the cellular immune response, including natural killer (NK) cell function, that they may ultimately affect the occurrence and progression of certain tumors. Our discussion of this link begins with a brief overview of the evidence that psychoneuroimmunology (PNI) research with healthy individuals may be relevant to cancer. Next, to link extant PNI research findings with tumorigenesis, we draw upon two important PNI findings relating psychological distress to two important aspects of carcinogenesis: (i) poorer repair of damaged cellular DNA and (ii) modulation of apoptosis. Finally, we focus on the implications of intervention research in cancer patients for cancer progression and treatment.

Kiecolt-Glaser, Janice K., and Ronald Glaser. Psychoneuroimmunology: Can psychological interventions modulate immunity? Journal of Consulting and Clinical Psychology 60, no. 4 (1992): 569.

Objective: Although psychological modulation of immune function is now a well-established phenomenon, much of the relevant literature has been published within the last decade. This article speculates on future directions for psychoneuroimmunology research, after reviewing the history of the field. Methods: This review focuses on human psychoneuroimmunology studies published since 1939, particularly those that have appeared in Psychosomatic Medicine. Studies were clustered according to key themes, including stressor duration and characteristics (laboratory stressors, time-limited naturalistic stressors, or chronic stress), as well as the influences of psychopathology, personality, and interpersonal relationships; the responsiveness of the immune system to behavioral interventions is also addressed. Additionally, we describe trends in populations studied and the changing nature of immunological assessments. The final section focuses on health outcomes and future directions for the field. Results: There are now sufficient data to conclude that immune modulation by psychosocial stressors or interventions can lead to actual health changes, with the strongest direct evidence to date in infectious disease and wound healing. Furthermore, recent medical literature has highlighted a spectrum of diseases whose onset and course may be influenced by proinflammatory cytokines, from cardiovascular disease to frailty and functional decline; proinflammatory cytokine production can be directly stimulated by negative emotions and stressful experiences and indirectly stimulated by chronic or recurring infections. Accordingly, distress-related immune dysregulation may be one core mechanism behind a diverse set of health risks associated with negative emotions. Conclusions: We suggest that psychoneuroimmunology may have broad implications for the basic biological sciences and medicine.

Maier, Steven F., Linda R. Watkins, and Monika Fleshner. Psychoneuroimmunology: The interface between behavior, brain, and immunity. American psychologist 49, no. 12 (1994): 1004.

Psychoneuroimmunology is the study of interactions between behavior, the brain, and the immune system. This article is designed to provide an overview of this new field for the general psychologist. The existence of bidirectional communication pathways between the brain and the immune system and the implications of this network for behavior are emphasized. Implications are that behavioralpsychological processes ought to be capable of altering immune function and that events that occur as part of immune responses should modulate behavior. Evidence for influences in both of these directions is reviewed. The discussion of psychological modulation of immunity focuses on classical conditioning and stress, whereas that of immune modification of behavior highlights behavioral effects produced by substances released by the immune system. Finally, the adaptive role that such changes might play is considered.

 

Psychoneuroimmunology - Sleep

Irwin, Michael R. Why sleep is important for health: a psychoneuroimmunology perspective. Annual review of psychology 66 (2015): 143-172.

Sleep has a critical role in promoting health. Research over the past decade has documented that sleep disturbance has a powerful influence on the risk of infectious disease, the occurrence and progression of several major medical illnesses including cardiovascular disease and cancer, and the incidence of depression. Increasingly, the field has focused on identifying the biological mechanisms underlying these effects. This review highlights the impact of sleep on adaptive and innate immunity, with consideration of the dynamics of sleep disturbance, sleep restriction, and insomnia on antiviral immune responses with consequences for vaccine responses and infectious disease risk, and on proinflammatory immune responses with implications for cardiovascular disease, cancer, and depression. This review also discusses the neuroendocrine and autonomic neural underpinnings linking sleep disturbance and immunity, and the reciprocal links between sleep and inflammatory biology. Lastly interventions are discussed as effective strategies to improve sleep, and potential opportunities are identified to promote sleep health for therapeutic control of chronic infectious, inflammatory, and neuropsychiatric diseases.

 

Psychoneuroimmunology - Depression

Corwin, Elizabeth J., and Kathleen Pajer. The psychoneuroimmunology of postpartum depression. Journal of women's health 17, no. 9 (2008): 1529-1534.

Postpartum depression (PPD) is a potentially debilitating disorder that develops in a significant percentage of women during the first year after giving birth. Women afflicted with PPD experience long-term consequences, including sadness, guilt, and despair. Offspring may be affected as well. Several investigators have tested psychosocial risk factors for the development of PPD; however, substantial amounts of variance in PPD have gone unexplained with regression on psychosocial variables alone. Likewise, interventions for PPD that have focused on psychosocial risk factors alone have been largely unsuccessful. The unexplained variance and disappointing treatment success could well be due to investigators’ failure to address relevant biological changes occurring during the postpartum period. Two biological systems that are affected significantly and remain in flux during the postpartum period are the innate immune system and the hypothalamic-pituitary-adrenal (HPA) axis. Bidirectional interactions between these two systems are well established, and it is generally acknowledged that dysfunction in either system can lead to depression in nonpregnant, nonpostpartum populations. To date, little research has pursued the contribution of these interacting systems to the development of PPD. The purpose of this paper is to review the psychoneuroimmunology of PPD. The central hypothesis presented is that dysregulation in either system individually or in their bidirectional interaction is associated with the development of PPD.

Irwin, Michael. Psychoneuroimmunology of depression. In Psychoneuroimmunology: The Fourth Generation of Progress, pp. 983-398. Raven Press, NY, 1995.

The central nervous system is hypothesized to have a role in the modulation of immune function. This chapter provides an overview of the association between psychological factors and immunity, concentrating on the immunological alterations of depression. In addition, experimental evidence is reviewed of the neural and endocrine mechanisms that have been proposed to alter immune function in depression. Finally, because psychological distress has recently been associated with an increased susceptibility to infectious disease and possibly risk of cancer, the possible health implications of depression or stress-associated immune changes are discussed. Before describing the interactions between the brain, behavior, and immunity, a brief overview of the immune system is provided.

 

Irwin, Michael. Psychoneuroimmunology of depression: clinical implications. Brain, Behavior, and Immunity 16, 
1–16
 
(2002).

Psychoneuroimmunology is a field that investigates the interactions between the brain and the immune system. One important goal of this field of research is to translate basic research in order to understand how behavior affects health and resistance to disease in humans. This review evaluates the impact of depression on morbidity and mortality risk and asks whether neuroimmune mechanisms contribute to this association. Examples are drawn from three diseases: cardiovascular disease, infectious disease, and rheumatoid arthritis. Finally, the potential for biobehavioral interventions to impact psychological adaptation and the course of immune related disease is discussed.

 

Psychoneuroimmunology - Heart Disease

Ho, R. C., Li Fang Neo, A. N. Chua, A. A. Cheak, and Anselm Mak. Research on psychoneuroimmunology: does stress influence immunity and cause coronary artery disease. Ann Acad Med Singapore 39, no. 3 (2010): 191-6.

This review addresses the importance of psychoneuroimmunology (PNI) studies in understanding the role of acute and chronic psychological stressors on the immune system and development of coronary artery disease (CAD). Firstly, it illustrates how psychological stressors change endothelial function and lead to chemotaxis. Secondly, acute psychological stressors lead to leukocytosis, increased natural killer cell cytotoxicity and reduced proliferative response to mitogens while chronic psychological stressors may lead to adverse health effects. This will result in changes in cardiovascular function and development of CAD. Thirdly, acute and chronic psychological stressors will increase haemostatic factors and acute phase proteins, possibly leading to thrombus formation and myocardial infarction. The evidence for the effects of acute and chronic psychological stress on the onset and progression of CAD is consistent and convincing. This paper also highlights potential research areas and implications of early detection of immunological changes and cardiovascular risk in people under high psychological stress.

Psychoneuroimmunology - Autoimmune Diseases

Kern, S., and T. Ziemssen. Brain—immune communication psychoneuroimmunology of multiple sclerosis. Multiple Sclerosis Journal 14, no. 1 (2008): 6-21.

The central nervous system (CNS) and the immune system are two extremely complex and highly adaptive systems. In the face of a real or anticipated threat, be it physical (eg, infection) or psychological (eg, psychosocial stress) in nature, the two systems act in concert to provide optimal adaptation to the demanding internal or environmental conditions. During instances of well being, the communication between these two systems is well tuned and balanced. However, a disturbed crosstalk between the CNS and the immune system is thought to play a major role in a wide series of disorders characterized by a hyporesponsive or hyperresponsive immune system. In multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease, an excess of inflammatory processes seems to be a hallmark and there is growing evidence for a disturbed communication between the CNS and the immune system as a crucial pathogenic factor. While the exact mechanisms for these phenomena are still poorly understood, the young discipline of psychoneuroimmunology (PNI), which focuses on the mechanism underlying the brain to immune crosstalk, might offer some insights into the existing pathogenic mechanisms. Findings from the field of PNI might also help to gain a better understanding regarding the origin and course of MS clinical symptoms such as fatigue and depression.

Psychoneuroimmunology - Neuropsychopharmacology

Haroon, Ebrahim, Charles L. Raison, and Andrew H. Miller. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37, no. 1 (2012): 137.

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

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