Professor Robert Zachariae, MDSci, Psychooncology Research Unit, Jens Chr. Skous Vej 4, DK-8000 Århus C, Århus, Denmark. E-mail: email@example.com
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.
Over the past decades there has been increased scientific as well as public interest in the possible influence of psychological and social factors on human physiology, and a growing body of research has provided evidence for psychosocial influences on both the development and the course of a number of medical illnesses. Psychoneuroimmunology, the interdisciplinary area of research examining interactions between brain, behavior, and the immune system, has played a key role in the exploration of behavioral and biological mechanisms linking psychosocial factors, health, and disease (Zachariae, 1996). By challenging the biomedical concept of the immune system as an “autonomous” defense system, psychoneuroimmunology represents a shift from a predominantly biomedical paradigm of health and disease towards an interdisciplinary bio-psycho-social approach (Engel, 1977). In the following, the development of psychoneuroimmunology and some key findings within this field will be described.
The early history of psychoneuroimmunology
The behavior of the immune system, e.g. interactions between antibodies and antigens, can be investigated intelligibly through cloned cells in vitro, i.e. in test tubes outside the living organism, and this has no doubt contributed to the fact that for many decades the dominant “normal” scientific view of the immune system has been one of an “autonomous” defense against external and internal threats to the organism, which is essentially unrelated to other systems and processes of the organism. While historically, the predominant focus of immunological research has been on interactions between the immune system and foreign antigen and between the various components of the immune system itself, a small number of “deviant” studies have appeared over the years. The first study, which reasonably can be termed as “psycho-immunologic”, was published in 1919 and suggested that negative emotions could influence the immune system of patients with tuberculosis (Ishigami, 1919). In the 1920s, a series of animal studies of interactions between the brain and the immune system were conducted in the Soviet Union by pupils of Pavlov (1849–1936), indicating that immune responses could be influenced by classical conditioning. Repeated pairings of a neutral stimulus (e.g. heat) with an immune-stimulating antigen (e.g. inactivated bacteria) were found to result in activation of the immune response when the neutral stimulus was presented alone (Metal’nikov & Chorine, 1926). In the 1950s and 1960s, results from a small number of studies suggested that psychological stress could increase susceptibility to infection (Rasmussen, Marsh & Brill, 1957) and exacerbate autoimmune diseases such as lupus (Fessel & Solomon, 1960) and rheumatoid arthritis (Solomon, Amkraut & Kasper, 1964). The term “psychoneuroimmunology” itself, however, was not coined until 1981, when it appeared as the title of an anthology reviewing the evidence available at the time for associations between behavioral, neural, endocrine, and immune system processes (Ader, 1981). The first official psychoneuroimmunology meeting held in 1986 proposed a number of key questions: (1) Are there interactions between the brain and the immune system? (2) If so, how are they mediated? (3) Are they bi-directional? and (4) are they trivial or important to understanding health and disease? (Cohen, 1987).
The immune system in the living organism: a systemic approach
Posing the first question: is there evidence of interaction between the brain and the immune system, is not possible within the framework of the conventional “autonomous” view of immunology. This requires a broader framework, as provided by a general systems perspective of the organism (von Bertalanffy, 1969). From this perspective, we should expect that the various systems of the organism have developed the ability to interact in a coherent way with the self-regulatory purpose of maintaining a dynamic internal equilibrium while adapting to the challenges posed by changes in the external and internal environment (Zachariae, 1996). While conventional immunology may be able to describe a number of important immunological phenomena independently of other processes, the full understanding of the behavior of the immune system in the living organism requires investigation of both the cooperation between the elements of the immune system itself as well as of their interdependencies with other elements of the system as a whole.
While regarded as rather heretical at the time, the immunologist Niels Jerne (1911–1994), in his controversial Network Theory of the immune system (Jerne, 1974), pointed to the apparent functional similarities between the immune system and the brain. Both the brain and the immune system are self-referential, i.e. are involved in the recognition of “self” versus “non-self”, and, according to Jerne, the immune network constitutes the identity of the organism at the molecular level. Similarly, as suggested by more recent developments in neuroscience, neural networks of the brain can be viewed as constituting a neuromatrix, representing the physiological “self” of the organism (Melzack, 1993). Furthermore, both systems involve innate responses as well as characteristics acquired through interactions with the environment, i.e. “learning” and “memory”. Finally, both the brain and the immune system can be described as “sensory organs”. While the five “classical” senses enable us to be cognizant of what we can see, hear, touch, taste, and smell, the immune system can be viewed as a “sixth sense” that enables the organism to recognize bacteria, viruses, cancer cells, and other entities too small to see, touch, taste or smell (Blalock, 1984). While this challenge to the “autonomous” view of the immune system is clearly “meta-theoretical”, it has inspired researchers to pose a number of questions that cannot be asked within conventional immunology. These questions and their answers form the basis of psychoneuroimmunology.
Over the last three decades, psychoneuroimmunology research has provided evidence for extensive bidirectional communication between the brain and the immune system. The evidence stems from several sources. First, early animal studies indicated that left- and right-brain lesions produce different patterns of suppression and activation of various immune measures (Biziere, Guillaumin, Degenne, Bardos & Renoux, 1985). Second, a large body of research has identified “hard-wired” neural connections between the brain and immune system. For example, there is evidence for both sympathetic and parasympathetic innervation of organs and tissues associated with the immune system, including the lymph nodes, thymus, spleen, and bone marrow, and other neural-immune cell associations are found in cutaneous, gastro-intestinal, and mucosal tissue (Bellinger, Lorton, Lubahn & Felten, 2001). Finally, it is now recognized that the nervous and immune systems communicate through a common biochemical language that involves shared neuroendocrine hormones, neurotransmitters, cytokines, and their respective receptors (Carr & Blalock, 1991). Taken together, the available evidence has confirmed the existence of a complex bidirectional brain-immune network, providing a biological basis for the ancient anecdotal notion that the mind can play a role in health and disease by its ability to influence relevant biological processes. Figure 1 summarizes the verified communication pathways between brain and immune system.
The existence of an extensive brain-immune network suggests that the immune system should be under at least partial influence by psychological processes. Examples of psychological phenomena of potential relevance to understanding the brain-behavior-immune connection include learning, psychological stress, emotions, and sensory processes.
Learned immune responses
Learning is a primary function of the brain by which the organism adapts to the environment. One example of the role of the brain in modulating the immune system is provided by studies showing that the immune response can be modified by classical conditioning. The early studies by Soviet researchers described above went largely unnoticed at the time, and the first modern psychoneuroimmunology conditioning experiment was a result of a serendipitous finding by the psychologist Robert Ader. A taste-aversion experiment using a saccharine-flavored drinking solution as the conditioned stimulus (CS) paired with an unconditioned stimulus (UCS) in the form of a tasteless nausea-inducing (and immunosuppressive) agent (cyclophosphamide) revealed that some of the animals died when subsequently presented with the CS alone. This led to the hypothesis that a conditioned immunosuppressive effect of the nausea-inducing agent had taken place, which was confirmed in a subsequent experiment (Ader & Cohen, 1975). In the following years, animal as well as human studies confirmed that a large number of immune parameters can be both suppressed and enhanced using various types of pharmacological and environmental stimuli as UCS (Ader & Cohen, 2001). Cancer patients treated with cytotoxic agents usually experience side-effects in the form of nausea, vomiting, and fatigue as well as immunosuppressive effects (Zachariae, Paulsen, Mehlsen, Jensen, Johansson & von der Maase 2007b). Some patients display anticipatory or conditioned side-effects, with the hospital environment and tastes and odors associated with the treatment serving as CS (Zachariae, Paulsen, Mehlsen, Jensen, Johansson & von der Maase 2007a), and studies using cancer treatment as a natural experiment have shown results suggestive of conditioned immunity (e.g. Bovbjerg, Redd, Maier et al., 1990).
The strength of learned associations depends on several factors. Certain personality traits related to sensory perception and imaginative involvement such as hypnotizability and absorption (Zachariae, Jorgensen & Christensen, 2000b) have been associated with both increased conditionability (Zachariae et al., 2007a) and increased reactivity of the autonomic nervous and immune systems (Ehrnrooth, Zachariae, Svensen et al., 2002; Zachariae, Jorgensen, Bjerring & Svendsen, 2000a; Zachariae, Jorgensen, Christensen & Bjerring, 1997). The term state-dependent learning (SDL) describes the phenomenon that behavior learned in one physiological state is better remembered when retention is tested in the same state (Overton, 1991). Although the concept of SDL generally applies to human memory and behavior, the hypothesis that SDL also applies to the memory and behavior of the immune system has been confirmed in an experiment showing that the so-called delayed-type hypersensitivity (allergic) response (DTH) was stronger when the individual had been sensitized to an experimental allergen and later exposed to a challenge with the same allergen under similar psychophysiological conditions of either relaxation or no-relaxation (Zachariae et al., 1997).
Stress and immunity
The available evidence shows that acute stressors generally are associated with enhanced immunity and long-term or chronic stressors with suppressed immune function (Dhabhar & McEwen, 1997). While it makes sense from an evolutionary perspective that stress is associated with enhanced immunity thereby preparing the organism to deal more effectively with potential infections, it seems more puzzling that under long-term stress, the same brain-immune mechanisms are associated with suppression of some immune parameters, e.g. antibody production, and enhancement of others, e.g. allergic and inflammatory responses (Dhabhar & McEwen, 2001). The currently best explanation seems to be that the immune system has developed the ability to selectively up- and down-regulate its responses under different conditions, e.g. up-regulate during infection and down-regulate to avoid autoimmune reactions when the upregulated immune response is no longer needed. The concept of “allostasis” represents the processes involved in the adaptive responses to stressful situations, e.g. increased number of circulating immune cells and enhanced cell-mediated immunity, while “allostatic load” represents the physiological costs to the organism, e.g. in terms of suppressed immunity to antigens or chronic inflammation, when these mechanisms are activated frequently over longer periods of time. The different immune response patterns depend on the timing and duration of the stressor and are modulated by stress-hormones such as glucocorticoids and catecholamines.
While the research demonstrating effects of various types of stressors on immune and inflammatory processes (Herbert & Cohen, 1993b) has provided evidence for potential mechanisms linking stress with increased risk of a number of diseases, including infections, allergies, autoimmune diseases, and even cardiovascular diseases, the current evidence for a link between stress and cancer is less convincing. One reason could be the limited focus of the research so far. The prognosis of many cancer patients is not only related to the cancer itself, but also to complications related to the cancer and its treatment, such as infections and postponement of treatment due to immunosuppression (Bovbjerg, Valdimarsdottir & Zachariae, 1999). Stress has been shown to increase susceptibility to infection (Pedersen, Bovbjerg & Zachariae, 2009b), and to influence immuno-competence, e.g. measured as the strength of the immune response to vaccination (Pedersen, Zachariae & Bovbjerg, 2009c). The role of stress for the risk of infection in cancer patients, however, has so far only been explored in one study, which showed that stress measured prior to treatment was associated with increased risk of being hospitalized with infection during treatment (Pedersen, Zachariae, Jensen, Bovbjerg, Andersen & von der Maase, 2009d).
Immune modulation by emotions
Systematic reviews of the literature generally conclude that negative emotions such as depression are associated with increased mortality (Cuijpers & Smit, 2002), and – conversely – that positive well-being may be associated with reduced mortality (Chida & Steptoe, 2008). While there is good evidence of a link between depression and immunity (Herbert & Cohen, 1993a), it is not clear to what extent this link can explain the association between depression and mortality. However, as positive and negative emotions are essential psychological mechanisms, which serve adaptive purposes in the regulation of behavior, we should expect that changes in emotional state be reflected in changes in the immune system. This hypothesis is supported by results from studies showing that experimentally induced emotional states can affect immunological and inflammatory parameters. In one study, experimentally induced negative mood was found associated with suppression and positive mood with enhancement of chemotaxis, a measure of immune function (Zachariae, Bjerring, Zachariae et al., 1991). In another, the inflammatory skin response to histamine, a model of relevance to immediate-type allergic reactions, was found increased after negative mood and suppressed after positive mood (Zachariae, Jorgensen, Egekvist & Bjerring, 2001). It is worth noting that the association between mood valence and the direction of the immune or inflammatory response is not a simple question of positive moods being associated with increase and negative with suppression, but is in concordance with the clinical implications, i.e. that both suppressed chemotaxis and enhanced inflammatory reaction are associated with negative clinical outcomes. Under natural conditions, the associations between immunity and emotions might be mediated by other behavioral factors. Negative affect is thus associated with impaired sleep quality (Thomsen, Mehlsen, Christensen & Zachariae, 2003), which in turn is known to affect immune function (Born, 1999), and other studies have confirmed that the associations found between depression and immune function found in clinical populations, e.g. HIV-infected, are partly mediated by impaired sleep quality (Cruess, Antoni, Gonzalez et al., 2003).
Theories that various types of emotional inhibition, e.g. alexithymia (Jorgensen, Zachariae, Skytthe & Kyvik, 2007) and emotional repression (Jorgensen & Zachariae, 2006) are associated with increased risk of somatic symptoms, have led to the hypothesis that emotional inhibition may be a risk factor for development of cancer (LeShan, 1959). Later findings, however, suggest that the increased level of repression often found in cancer patients may be a coping response to the cancer diagnosis, rather than a premorbid personality trait (Zachariae, Jensen, Pedersen et al., 2004). This does not exclude the possibility that repressive coping could be associated with poorer cancer prognosis. The plausibility of this theory would however be strengthened, if clear associations between emotional inhibition and cancer-relevant immune-measures could be identified. Only few studies have so far addressed this issue with mixed results (e.g. Esterling, Antoni, Kumar & Schneiderman, 1993; Jamner, Schwartz & Leigh, 1988).
Voluntary modulation of the immune system through sensory imagery
While the psychoneuroimmunologic phenomena described above can still be understood as “autonomous”– i.e. non-voluntary – responses to various types of external stimuli (e.g. stressors) and psychological states (e.g. emotions), the idea that the immune system can be influenced by voluntary, conscious processes is more controversial from a conventional biomedical view. Nevertheless, there is growing evidence that this may indeed be possible by altering sensory perception through various psychological techniques such as guided imagery or hypnosis (Zachariae, 2001). The response of the organism to potentially damaging external stimuli is regulated by a number of highly integrated mechanisms, involving both the central and peripheral nervous systems. The two systems interact with the aim of producing those responses of the cardiovascular, endocrine, immune, and sensory nervous (SNS) systems that promote the most adaptive physiological and behavioral reactions under different conditions.
For instance, inflammatory reactions of the skin have been shown to be partly regulated by ascending and descending pathways between the brain and the SNS (Zachariae, 1996). For example, animal studies have shown that lesioning of the sensory nerves suppresses the inflammatory skin reaction to histamine, and, in humans, inflammatory skin reactions can be suppressed by local anesthetics. This suggests that the intensity of a local inflammatory reaction, e.g. to a burn, partly depends on sensory feedback to the brain from the affected area. It is well documented that hypnotic suggestions can alter both the self-reported perception of sensory stimuli such as pain as well as sensory-related brain-correlates (Zachariae & Bjerring, 1994; Zachariae, Andersen, Bjerring, Jorgensen & Arendt-Nielsen, 1998; Zachariae, Bjerring, Arendt-Nielsen, Nielsen & Gotliebsen, 1991a), and in an integrated bio-psycho-social system we should therefore expect that psychologically induced altered perception can reduce local inflammatory reactions. This hypothesis was confirmed in a study showing reduced inflammatory reactions to histamine under a hypnotic analgesia condition, compared to reactions in a control condition, with reductions in pain-evoked brain potentials confirming reduced sensation during hypnotic analgesia (Zachariae & Bjerring, 1990).
Other studies have confirmed that hypnotic suggestions to suppress or enhance reactions of the skin can alter both inflammatory skin reactions associated with immediate-type allergic reactions and delayed-type immune reactions of relevance to eczemas, psoriasis and other skin diseases (Zachariae, Bjerring & Arendt-Nielsen, 1989). Further results indicate that the immune system is susceptible to psychological influences both during the sensitization or “learning” phase of the immune response and during the later challenge or “retention” (Zachariae & Bjerring, 1993; Zachariae et al., 1997). The available results suggest that voluntary changes of local immune reactions require sufficiently strong sensory pathways (Locke, Ransil, Zachariae et al., 1994b), and that effects on specific immune components of skin and mucosa are likely to be mediated through neural influences on local vascular processes, rather than through direct differential effects on specific types of immune cells (Zachariae, Oster & Bjerring, 1994). This was supported by results of a study comparing effects of non-specific instructions to relax and guided imagery instructions to imagine enhancement of specific immune cells (Zachariae, Hansen, Andersen et al., 1994). While both interventions may influence the function of various immune cells in the blood stream when compared to no intervention, the results of this study showed no difference between the effects of relaxation and guided imagery, suggesting that effects on cells in the peripheral blood stream are probably due to more general non-specific effects of relaxation and stress-reduction through altered autonomic nervous system activity. Few studies have explored the clinical applicability of these findings, but preliminary results indicate that patients with immune-related skin diseases such as psoriasis may benefit from psychological intervention (Zachariae, Oster, Bjerring & Kragballe, 1996).
As expected from theories of living systems, the pathways between the brain and the immune system are unlikely to be unidirectional, and there should be at least some form of “feedback-loop” from the immune system to the brain (Zachariae, 1996). This has been demonstrated most clearly by studies of so-called cytokine-induced sickness behavior during infection (Dantzer, 2001). At the behavioral level, infected individuals show depressed activity, loss of interest in the environment, and reduced food intake, and, subjectively, infection is associated with fatigue, depressed mood, and increased pain sensation. These changes can be experimentally induced in healthy animals and humans by injections of proinflammatory cytokines (e.g. interleukin-1) that are normally released by activated immune cells during the response to bacterial or viral infections. It could be argued that the sickness behavior pattern induced by the immune system is the expression of a motivational state, rather than the consequence of physiological weakness, and that it represents a response that promotes behaviors that support the adaptive physiological changes that occur during infection. For instance, the increase in body temperature that is needed to produce fever leaves little room for costly activities that are of no use in fighting the infectious pathogens, and the reduced level of activity characteristic of sickness behavior can thus be seen as a highly organized strategy that is critical to the survival of the organism (Dantzer, 2001).
This perspective on cytokine-induced sickness behavior could potentially lead to new psychoneuroimmunologic perspectives on cancer. Cancers are often associated with increased inflammation, and the high prevalence of depression found among cancer patients (Christensen, Zachariae, Jensen et al., 2009) could, at least partly, represent a cytokine-induced sickness syndrome (Raison & Miller, 2003). As increased inflammation has been associated with poorer prognosis, this could theoretically explain the links found between depression and increased cancer mortality. Another area of potential interest is the common complaint of impaired cognitive function following cancer treatment, often referred to by patients as “chemo brain”. As such cognitive complaints are less likely to be due to the chemotherapy itself (Mehlsen, Pedersen, Jensen & Zachariae, 2009; Pedersen, Rossen, Mehlsen, Pedersen, Zachariae & von der Maase, 2009a), they could perhaps be due to cancer-induced immune-influences on the brain.
As reviewed above, psychoneuroimmunologic research over the last three decades has confirmed the existence of bi-directional interactions between the brain and the immune system, and results from a growing number of studies indicate that negative psychosocial factors such as depression and stress are associated with increased morbidity and mortality. Still lacking, however, is sufficiently convincing evidence that the links between psychosocial factors and health and disease are mediated by the identified brain-immune pathways, and further research is needed. Psychoneuroimmunologic research has revealed the high degree of complexity of the brain-immune interactions, and the adaptive function of many of these interactions is as yet far from fully understood. This makes it difficult to interpret various immune outcomes in studies of psychosocial factors and immunity and also underscores that the promises of a “strengthened immune system” frequently promoted by proponents of complementary and alternative treatments are only metaphors that make little sense from a scientific perspective (Zachariae, 1996). Although the field of psychoneuroimmunology has provided promising results, the critical question of whether behavioral manipulation, e.g. stressors or intervention, can affect immunity so as to influence health and survival, still remains to be answered.