From serendipity to clinical relevance: How clinical psychology and neuroscience converged to illuminate psychoneuroendocrinology.

Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues.

Emil Kraepelin's habilitation and his thesis: a pioneer work for modern systematic reviews, psychoimmunological research and categories of psychiatric diseases.

OBJECTIVES: Although Kraepelin and his oeuvre have been in scientific focus over the past decades, main aspects have still been neglected. Thus the exact circumstances under which and on what topic Kraepelin wrote his habilitation thesis and qualified as university lecturer (in Germany the prerequisite to be appointed as professor) are still widely unknown. METHODS: This study reconstructs his habilitation at the Medical Faculty of Leipzig University in 1882. RESULTS: The study reveals the difficulties he had to habilitate on a topic from Wilhelm Wundt's experimental psychology and the opposition he faced from Paul Flechsig. Yet Kraepelin succeeded, mainly due to a positive review by neurologist Wilhelm Erb on his study "On the Influence of Acute Diseases on the Development of Mental Illnesses" (1881/82). CONCLUSIONS: This work must be regarded as his actual habilitation thesis. It provides an update of organic psychiatric disorders following acute inflammatory diseases and a meta-analysis on the basis of raw data. In addition it discusses possibilities to categorize and understand the pathophysiological mechanism of these disorders and to classify them into those appearing when the fever rises and those occurring when it falls, which has a high impact from a very modern psychoimmunological viewpoint.

The psychoneuroimmunology of depression.

Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, acts as a trigger for anxiety and depression. There is experimental and clinical evidence that the rise in the concentration of pro-inflammatory cytokines and glucocorticoids, which occurs in a chronically stressful situation and also in depression, contribute to the behavioural changes associated with depression. A defect in serotonergic function is associated with these hormonal and immune changes. Neurodegenerative changes in the hippocampus, prefrontal cortex and amygdalae are the frequent outcome of the changes in the HPA axis and the immune system. Such changes may provide evidence for the link between chronic depression and dementia in later life.

Human psychoneuroimmunology: 20 years of discovery.

An important component of psychoneuroimmunology research is to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. Research in human psychoneuroimmunology has shown that immunoregulatory processes are an integral part of a complex network of adaptive responses. As such, this review provides a perspective from our laboratory over the last 20 years to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.

Understanding the interaction between psychosocial stress and immune-related diseases: a stepwise progression.

For many years, anecdotal evidence and clinical observations have suggested that exposure to psychosocial stress can affect disease outcomes in immune-related disorders such as viral infections, chronic autoimmune diseases and tumors. Experimental evidence in humans supporting these observations was, however, lacking. Studies published in the last 2 decades in Brain, Behavior and Immunity and other journals have demonstrated that acute and chronic psychological stress can induce pronounced changes in innate and adaptive immune responses and that these changes are predominantly mediated via neuroendocrine mediators from the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal axis. In addition, psychological stress has predicted disease outcomes using sophisticated models such as viral challenge, response to vaccination, tracking of herpesvirus latency, exploration of tumor metastasis and healing of experimental wounds, as well as epidemiological investigations of disease progression and mortality. These studies have contributed significantly to our understanding that the neuroendocrine-immune interaction is disturbed in many pathophysiological conditions, that stress can contribute to this disturbance, and that malfunction in these communication pathways can play a significant role in the progression of disease processes. There are, however, significant gaps in the extant literature. In the coming decade(s), it will be essential to further analyze neuroendocrine-immune communication during disease states and to define the specific pathways linking the central nervous system to the molecular events that control important disease-relevant processes. This knowledge will provide the basis for new therapeutic pharmacological and non-pharmacological behavioral approaches to the treatment of chronic diseases via specific modulation of nervous system-immune system communication.

Psychosocial influences on immunity, including effects on immune maturation and senescence.

Studies investigating the influence of psychosocial factors on immunity played a critical and formative role in the field of psychoneuroimmunology (PNI), and have been a major component of articles published in Brain, Behavior and Immunity (BBI). An analysis of papers during the first two decades of BBI from 1987-2006 revealed three behavior-related topics were most prominent: (1) stress-induced changes in immune responses, (2) immune correlates of psychopathology and personality, and (3) behavioral conditioning of immunity. Important subthemes included the effect of early rearing conditions on immune maturation in the developing infant and, subsequently, psychosocial influences affecting the decline of immunity in the senescent host. The responsiveness of cell functioning in the young and elderly helped to validate the view that our immune competence is malleable. Many technical advances in immune methods were also evident. Initially, there was a greater reliance on in vitro proliferative and cytolytic assays, while later studies were more likely to use cell subset enumerations, cytokine quantification, and indices of latent virus reactivation. The reach of PNI extended from the traditional clinical entities of infection, autoimmunity, and cancer to attain a broader relevance to inflammatory physiology, and thus to asthma, cardiovascular and gastrointestinal disease. There continue to be many theoretical and applied ramifications of these seminal findings. Fortunately, the initial controversies about whether psychological processes could really impinge upon and modify immune responses have now receded into the pages of history under the weight of the empirical evidence.

Brain-immune communication pathways.

Communication between the central nervous and immune systems lies at the heart of the neuroimmune axis. We trace here some of the major conceptual hurdles which were raised, first against the acceptance of a neuroimmune axis and later in understanding it. We review the major concepts formulated and established during the last two decades and focus on four pathways that have been proposed as important in communication: the neural route, circumventricular organs, blood-brain barrier transport of cytokines, and secretions from BBB cells. These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another.

Psychoneuroimmunology--cross-talk between the immune and nervous systems.

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.

Depressive disorders and immunity: 20 years of progress and discovery.

Since the inception of Brain, Behavior and Immunity twenty years ago, many exciting developments have occurred regarding the relationship between depression and the immune system. These developments have increasingly put the field of psychoneuroimmunology into a clinical context with important translational implications. Initial studies focused on the impact of depression on relatively narrowly defined immunologic endpoints, which ultimately found their relevance in studies examining the effect of depression on immunologically-based diseases including infectious illnesses, autoimmune disorders, and cancer as well as more recently cardiovascular disease. Mechanistic studies have also greatly contributed to an understanding of those facets of depression, which might mediate these effects. More recently, the reciprocal influences of the immune system on the brain and behavior including depression have taken center stage. Increasing data now indicate that activated inflammatory processes can influence multiple aspects of CNS function including neurotransmitter metabolism, neuroendocrine function, and information processing leading to behavioral changes in humans that bespeak depression. These latter developments have intrigued scientists investigating the pathophysiology of depression and warrant consideration as some of the most exciting new developments in psychiatry in the past 20 years. What the future holds is a world of promise as multiple translational targets derived from the cytokine model of depression work their way into the clinical arena as drug targets for further development. Moreover, the work has served to instantiate brain-immune interactions as an essential component in psychiatric and medical co-morbidities and their impact on health and illness.

Role of IL-1 and TNF in the brain: twenty years of progress on a Dr. Jekyll/Mr. Hyde duality of the innate immune system.

The immune-privileged status of the central nervous system (CNS) has changed quite dramatically during the past two decades. Leukocytes have the ability to infiltrate the CNS and cytokines are produced by resident cells, especially during injuries and diseases. Although the cellular source and role of these immune ligands are better known, their exact contribution to brain protection, repair or diseases still remains highly debated today. The ultimate fate of the immune reaction depends on the cytokines involved and the experimental models. It is now generally accepted that microglia play a central role in this response, at least for the production of cytokines participating in the innate immune system. As macrophages, resident microglia produce numerous cytokines and two of them have been largely studied since the beginning of this field of research. Twenty years ago, interleukin 1 (IL-1) and tumor-necrosis factor (TNF) were cloned and recombinant forms were used to investigate their functions ranging from normal neurophysiological responses to pathological conditions. This review presents the history of these two cytokines during immune responses in the brain and where we are now two decades later.

Physiology of psychoneuroimmunology: a personal view.

This article offers a personal view on how the concept of the existence of a network of immune-neuro-endocrine interactions has evolved in the last 30 years. The main topic addressed is the relevance of the exchange of signals between the immune, endocrine and nervous systems for immunoregulation and brain functions. Particular emphasis is given to circuits involving immune cell products, the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. The operation of these circuits can affect immune functions and the course of inflammatory, autoimmune and infectious diseases. We also discuss increasing evidence that brain-born cytokines play an important role in brain physiology and in the integration of the immune-neuro-endocrine network.

Twenty years of psychoneuroimmunology and viral infections in Brain, Behavior, and Immunity.

For 20 years, Brain, Behavior, and Immunity has provided an important venue for the publication of studies in psychoneuroimmunology. During this time period, psychoneuroimmunology has matured into an important multidisciplinary science that has contributed significantly to our knowledge of mind, brain, and body interactions. This review will not only focus on the primary research papers dealing with psychoneuroimmunology, viral infections, and anti-viral vaccine responses in humans and animal models that have appeared on the pages of Brain, Behavior, and Immunity during the past 20 years, but will also outline a variety of strategies that could be used for expanding our understanding of the neuroimmune-viral pathogen relationship.

Conceptual development of the immune system as a sixth sense.

Understanding how and why the immune and nervous systems communicate in a bidirectional pathway has been fundamental to the development of the psychoneuroimmunology (PNI) field. This review will discuss some of the pivotal results that found the nervous and immune systems use a common chemical language for intra and inter-system communication. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that provides a common repertoire of receptors and ligands between the two systems. These studies led to the concept that through the sharing of ligands and receptors the immune system could serve as a sixth sense to detect things the body cannot otherwise hear, see, smell, taste or touch. Pathogens, tumors, and allergens are detected with great sensitivity and specificity by the immune system. As a sixth sense the immune system is a means to signal and mobilize the body to respond to these types of challenges. The paper will also review in a chronological manner some of the PNI-related studies important to validating the sixth sense concept. Finally, the review will suggest ways to apply the new found knowledge of the sixth sense to understanding a placebo effect and developing new therapeutic approaches for treatment of human diseases.

Studying the biology of hope: An interview with Lee S. Berk, DrPH, MPH. Interview by Sheldon Lewis.

Dr Lee S. Berk is a pioneering medical researcher studying the neuroendocrine and immune effects of positive emotions. He is an associate professor of Health Promotion and Education, School of Public Health, and associate research professor of Pathology and Human Anatomy, School of Medicine, both at Loma Linda University in Loma Linda, California. Dr Berk is a fellow of the American College of Sports Medicine and the American Association for Integrative Medicine. He is also nationally board certified as a health education specialist and has served as a member of the board of directors for the American College of Lifestyle Medicine in Loma Linda, California. Dr Berk is a member of the editorial board of Advances in Mind Body Medicine. During the Society for Neurosciences' annual 2001 meeting Dr Berk presented and received major media coverage of a landmark paper entitled, "The Anticipation of a Laughter Eustress Event Modulates Mood States Prior to the Actual Humor Experience." More recently Dr Berk presented at the FASEB (Federation of American Societies for Experimental Biology) annual 2006 meeting in the American Physiological Society section another landmark paper entitled, "Beta-Endorphin and HGH Increase are Associated With Both the Anticipation and Experience of Mirthful Laughter," with further major media coverage. Recently, Dr Berk spoke about his work with Sheldon Lewis, editor in chief of Advances.

Healing mysteries: An interview with Howard Hall, PhD, PsyD. Interview by Sheldon Lewis.

Dr Howard Hall is an associate professor in the department of pediatrics at Case Western Reserve University (CWRU) and an attending doctor in the division of behavioral pediatrics at Rainbow Babies and Children's Hospital in Cleveland, Ohio. Dr Hall holds a PhD in Experimental Psychology from Princeton University and a PsyD in Clinical Psychology from Rutgers University. He has conducted research and taught courses in clinical and multicultural psychology and maintains a clinical practice using hypnosis and other mind-body approaches to healing at CWRU. Howard Hall has been recognized as a leader in the field of clinical psychoneuroimmunology and conducted pioneering research on the effects of hypnosis on immune responses. In recent years, he has studied energy-based rapid wound healing as demonstrated by Sufi practitioners. Recently, Sheldon Lewis, Editor-in-Chief of Advances in Mind-Body Medicine, spoke with Dr Hall about his work.

Interdisciplinary research: noradrenergic regulation of adaptive immunity.

To understand the complexity of mechanisms involved in the regulation of adaptive immunity by the sympathetic neurotransmitter norepinephrine and adrenergic receptor stimulation, there must be a rich history of basic science and clinical findings upon which to form hypotheses for testing, as well as a rich supply of individuals trained in two or more disciplines. This review is intended to offer a tour of the past, present, and future discoveries that have been made in the area of adrenergic regulation of adaptive immunity, as well as share a vision of how our field of study will progress years from now, given that every individual who contributes to the interdisciplinary nature of our research is valued. And finally, this review will discuss how the lessons from the past can help us to attain a vision of interdisciplinary research for the future.