The Sickening Mind: Brain, Behaviour, Immunity and Disease
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The second, more revealing, approach relies on what are known as functional measures. These assess how well the various cells are performing their immunological functions. Research into the relationships between psychological factors and immunity has tended to rely on two particular functional measures of immune activity: the responsiveness of lymphocytes to stimulation and the cell-killing activity of natural killer cells. Because these two measures are so central to research in this field they warrant closer inspection.
As we have already seen, lymphocytes will respond to antigens by proliferating or producing multiple copies of themselves. This response can also be triggered in a non-specific way (that is, in the absence of the specific antigen) by chemicals known as mitogens. Lymphocyte function can thus be measured in a test tube simply by introducing mitogens to the sample.7 Responsive lymphocytes will proliferate wildly when stimulated with the appropriate mitogen (a Good Thing), while unresponsive lymphocytes will be sluggish (a Bad Thing). Assume this is what I mean when henceforth I refer to lymphocyte responsiveness.
The prime function of natural killer cells is to destroy certain types of virus-infected cells and cancer cells. The obvious method of assessment in this case is to see how effective they are at destroying suitable target cells in the test tube. This is what is meant by natural killer cell activity, the second workhorse measure of immune function that will crop up repeatedly in subsequent chapters.8
It has to be admitted that lymphocyte responsiveness, natural killer cell activity and most of the other measures commonly used to assess immune function are flawed, allowing only a partial glimpse into the complexities of the immune system. Scientists can no more encapsulate the state of an individual’s immune system in a few numbers than they can sum up that person’s behaviour or emotional state with a few numbers.
It is a curious and regrettable fact that scientists tend to place greater faith in measurements of reassuringly physical entities, like the responsiveness of lymphocytes or the activity of natural killer cells, than they do in measurements of supposedly abstract entities like thoughts, emotions or behaviour. There is no rational basis for this prejudice, which is yet another reflection of our propensity to regard mind and body as two fundamentally different sorts of thing.
Despite their appearance of objectivity and precision, immunological measures are not totally reliable and, to a degree, depend upon subjective judgements. Conversely, the common prejudice that all psychological measures are by definition subjective, unreliable and woolly is a gross fallacy. Some are, but others are not. Experimental psychologists and behavioural biologists have been devising valid, reliable ways of measuring behaviour, psychological states and emotions for over half a century.9 Psychological measures are not always perfect, but they are inherently no better or worse than immunological measures in terms of their reliability, validity and objectivity. (Here endeth the lesson.)
The mind – immunity connections
Scientists and doctors have traditionally tended to regard the immune system as an autonomous entity that operates to a large degree independently of the mind and behaviour; an exquisite piece of biological machinery honed by millions of years of evolution to act autonomously in protecting the body from anything the outside world can throw at it. But this view is now known to be fundamentally wrong.
The body’s three main regulatory systems – the central nervous system (which includes the brain), the endocrine system (which produces hormones) and the immune system – do not work in isolation from one another. On the contrary, they are intimately connected and interact with each other in many important ways. Events occurring in the brain can produce changes within the endocrine and immune systems through a variety of routes, including specialized nerve pathways and chemical messengers. The effect may be to impair or enhance aspects of immune function, with potential consequences for health. The central nervous system, immune system and endocrine system are part of an integrated regulatory network that helps to ensure the survival and effective functioning of the whole organism. We are not just a bag of bits.
Another common misconception is that organisms work in a top-down, hierarchical manner with commands flowing in a single direction, from the brain to the rest of the body. In reality, information flows both ways along the various biological pathways that connect the central nervous system, endocrine system and immune system. Activity within the immune system can therefore influence the brain, mental state and behaviour.
Some scientists have likened the immune system to a sort of sensory organ, which is distributed throughout the body and provides the brain and endocrine system with information about the internal and external environment. This analogy makes good biological sense. The immune system detects the presence of antigens, including cells of its own body which have undergone change. It then transmits this information to the central nervous system, together with information about its immune response.
The new field of scientific research which is concerned with the complex inter-relationships between psychological and emotional factors, the brain, hormones, immunity and disease goes by the jaw-bending name of psychoneuroimmunology. In the next chapter we shall examine a few examples of how the brain and immune system interact. Before we do that, however, let us glance at the nature of the mechanisms which connect the brain and the immune system.
Since the 1980s, psychoneuroimmunologists have made considerable progress in understanding the biological pathways by which the brain and immune system influence each other. These pathways are of two basic sorts: electrical pathways using nerve connections, and chemical pathways using hormones, neuropeptides and other chemical messenger molecules. The specialized nature of these mechanisms strongly implies that they have evolved for a purpose – to enable the brain and the immune system to communicate with each other.
One good reason for believing that the brain and the immune system are meant to communicate is that they are hard-wired to each other by nerve connections. The tissues of the immune system are connected to the central nervous system by a rich supply of nerves. These nerve connections are responsible, amongst other things, for helping to regulate the development, activity and movement of lymphocytes and other immune cells.
Immune tissues in the spleen, bone marrow, thymus, lymph nodes, tonsils and gut are all abundantly supplied with nerve endings. Bone marrow, for example, is connected to the central nervous system by nerves emanating from the spinal nerve which supplies that region of the body. Some of the nerve connections in immune tissues do have other purposes, such as helping to regulate the local flow of blood, but some nerves undoubtedly pass information between the immune tissues and the brain. The spleen has a dense network of nerve connections and at least half of them are involved in transmitting information to and from the brain.
The second principal way in which the brain and immune system communicate is through an array of special chemical messenger molecules. The central nervous system and the immune system – the body’s two great regulatory and memory systems – have a lot of chemical communications hardware (or should I say wetware) in common. That such vast numbers of these chemical messengers have been discovered indicates their importance as a mechanism of communication between the central nervous system and the immune system, and also within each system.
Neurotransmitters, hormones and other chemical messenger molecules that were once thought to be restricted to the brain and nervous system are now known to be active within the immune system as well. Conversely, certain immunotransmitters and other chemical messengers that were once thought to be exclusive to the immune system are now known to act on the endocrine and central nervous systems. The brain and the immune system speak the same languages.
Cells of the immune system have special biochemical receptor sites on their surfaces which respond specifically to chemical messengers produced by the central nervous system. Lymphocytes and other immune cells respond to a range of neuropeptides, neurotransmitters and hormones which are either produced directly by the central nervous system, or whose secretion is under its control. These chemical messengers include noradrenaline, corticosteroid hormones, endorphins, encephalins, growth hormone, adrenocorticotrophic hormone (ACTH), prolactin, substance P, substance K, vasoactive intestinal peptide (VIP), angiotensin and somatostatin. A number of these chemical messengers travel to the immune system via the blood circulation; others, like neuropeptides, are also delivered locally from nerve endings.
These chemical messengers are able to modulate aspects of cell-mediated and antibody-mediated immunity. For example, the hormone noradrenaline, which is released from the adrenal glands (under stimulation from the brain) and from nerve endings, has widespread effects on immune function. Noradrenaline can facilitate the production of antibodies in various immune tissues; it can also inhibit the division of lymphocytes and impede the destruction of virus-infected cells or cancer cells by the immune system. Another messenger molecule, substance P, makes lymphocytes more responsive to stimulation, increases the production of certain types of antibody and facilitates the movement of lymphocytes to sites of infection.
We shall see in chapter 5 how psychological stress stimulates the release of hormones, including cortisol, a steroid hormone which suppresses various aspects of immune activity. The stress-induced release of cortisol is controlled by a region of the brain called the hypothalamus. The hormone prolactin is also released in response to psychological stress; unlike cortisol, however, its main effect on immune activity is stimulative.
Chemical communication between the central nervous system and immune system also works both ways. The immune system sends chemical messages to the brain. Immune cells produce neuropeptides, hormones and other chemical messengers, including ACTH, endorphins, encephalins, VIP and growth hormone, which influence both the endocrine and central nervous systems.
Some of the most important messenger molecules mediating the communication between the central nervous system and immune system are the cytokines. These were originally thought to be exclusive to the immune system, but they are now known to act on the central nervous system and endocrine system as well. Scientists have found that cells in several regions of the brain and central nervous system either contain cytokines or have receptor sites for them. When cytokines are released by activated immune cells they can have widespread effects on an organism’s nerves, hormone levels and psychological state. For example, when an infection occurs the cytokine interleukin-1 (IL-1) acts on the brain to induce slow-wave sleep and loss of appetite; IL-1, acting in concert with interleukin-6 (IL-6), induces fever by modulating the temperature control centres in the brain – in effect, putting the body’s thermostat on a higher setting. IL-1 and IL-6 help to make you feel hot, sleepy and indifferent to hunger when you are ill. Cytokines are also active within the endocrine system. The cytokines IL-1, IL-2, IL-6, interferon-gamma and tumour necrosis factor (TNF) are all capable of influencing the release of hormones by the pituitary and adrenal glands.
Small changes to the structure of the brain will produce corresponding changes within the immune system, thus providing further evidence of communication between the two. Highly localized damage (or lesions) to parts of the brain, including the limbic forebrain, hypothalamus, brain stem and cerebral cortex, can bring about specific changes in immune function. Small lesions in the anterior hypothalamus produce reductions in lymphocyte responsiveness, natural killer cell activity and antibody production, while lesions in limbic forebrain structures such as the hippocampus and amygdala can increase the responsiveness of T-lymphocytes. Brain lesions can even modify certain immune-mediated diseases. For example, tiny lesions in the anterior hypothalamus alter the growth of tumours and allergic responses. In addition, animals with certain hereditary defects in their central nervous system are more vulnerable to immunologically-mediated disorders such as arthritis.
A final and fundamental point, to which we shall be returning in subsequent chapters, is that the electrical and chemical communication pathways between the central nervous system and the immune system operate in both directions. Information about the state of the immune system can be passed up to the brain and hence influence the organism’s psychological state.
There is abundant experimental evidence that changes in immune activity are accompanied by corresponding changes in hormone levels, nerve activity and psychological state. Experiments have further revealed that patterns of electrical and chemical activity in the hypothalamus, limbic forebrain and other brain regions are linked to changes in immune activity which occur during the course of an immune response. For example, the peak production of antibodies in reaction to an immunological challenge (inoculation) is accompanied by changes in the electrical activity of nerve cells in the hypothalamus and other parts of the brain. Our brains appear to know, at least to some extent, what is going on within our immune systems.
In conclusion, then, we have seen that our psychological and emotional state can shape our perception of health and hence our sickness-related behaviour. At the extremes we may, like Colin Craven, feel ill and demand medical attention even though we have no disease; or, like Henry Earlforward, we may deny the reality of our symptoms and allow a serious disease to advance unchecked.
But our minds do far more than alter our perception of reality: they alter reality itself. The mind can affect our susceptibility to real physical diseases by modifying our behaviour or by directly influencing our immune defences, to which it is connected via electrical and chemical communications pathways.
By means of these psychological and biological mechanisms our minds really can make us ill.
4 Mind and Immunity
O the mind, mind has mountains; cliffs of fall
Frightful, sheer, no-man-fathomed. Hold them cheap
May who ne’er hung there.
Gerard Manley Hopkins, No worst, there is None (1885)
Evolution has equipped our bodies with psychological and biological mechanisms which enable the brain and immune system to talk to each other. Let us now examine what happens when these mechanisms operate in practice. In this chapter we shall look at what the immune system can do to the mind and, conversely, what the mind can do to the immune system. We shall see that changes in a person’s mental state can affect their immune function and vice versa. Then we have the remarkable phenomenon of immune conditioning, which teaches the immune system to respond to purely psychological stimuli. We shall explore the curious connections between left-handedness, developmental learning disorders and immunological diseases. To round off the story we shall study in closer detail one specific instance of how mind, body and health interact, by considering herpes virus infections.
What can the mind do to the immune system?
Let us start with the most basic of psychoneuroimmunological questions. (The question is much simpler than its epithet.) What effects do psychological factors actually have on the immune system?
Probably the first ever scientific account of a psychoneuroimmunological phenomenon appeared in 1919, when a Japanese scientist called Ishigami published the results of his research on tuberculosis in schoolchildren. Ishigami observed that an increase in tubercular illness coincided with a period when the children and their teachers were experiencing high levels of ‘emotional excitement’. Using a crude immunological measure – the ability of white blood cells to destroy foreign bacteria – Ishigami was able to relate this upsurge in disease to a decline in immune function. He concluded that the emotional stress was responsible for the decline in immunity which, in turn, led to the increased incidence of disease.
Since Ishigami’s day, and especially since the 1980s, scientists have accumulated a huge and varied pool of evidence that psychological and emotional factors influence the immune systems of humans and other species, with consequential effects on physical health.1 It is time to look at a few examples.
BEREAVEMENT AND NUCLEAR DISASTERS
The death of a spouse or partner is one of the most devastating forms of psychological and emotional disturbance anyone can experience. It is also surprisingly common, affecting more than 800,000 people each year in the USA alone. By the age of sixty-five over 50 per cent of American women have been widowed at least once.
Bereavement considerably heightens the risks of death and disease for the surviving partner. The risks are particularly great if the surviving partner is male: widowed men in their twenties have a mortality rate seventeen times higher than comparable married men. Moreover, the increased mortality rates among widowers persist for several years after the death of their wife.
One factor in this increased disease and mortality among the bereaved may be that they undergo changes in their immune function. A number of surveys have found that the death of a spouse is followed by measurable reductions in the immune function of the surviving partner.
In a pioneering 1970s study of this phenomenon, scientists at the University of New South Wales in Australia took blood samples from recently bereaved people and measured how responsive their lymphocytes were to stimulation by mitogens. The results were compared against the immune function of non-bereaved individuals who were matched for age, sex and other relevant factors. Several weeks after the death of their spouse the bereaved subjects’ T-lymphocytes were significantly less responsive.
Similar conclusions emerged from a prospective study which investigated the immune function of men whose wives had terminal breast cancer. During the weeks immediately following bereavement the widowers’ lymphocytes were not as responsive as they had been beforehand. In the majority of cases their lymphocyte function eventually returned to normal, but some men were still exhibiting reduced immune function a year later. The changes in lymphocyte responsiveness could not simply be explained away as by-products of behavioural changes which might also have followed bereavement, such as disrupted sleep, inadequate diet or increased smoking.
Bereavement is also followed by a drop in natural killer cell activity. Scientists have found reductions in the natural killer cell activity of women whose husbands have died from lung cancer within the previous few months and in women whose husbands are in the final stages of lung cancer.
The death of a partner is obviously not the only way in which marriages or long-term relationships are disrupted. Separation and divorce also result in the severing of ties and can have an effect on the partners’ immune function and health. Indeed, the health risks arising from separation and divorce are, if anything, worse than those associated with bereavement.
The stress which attends the loss of a partner is as old as the human race, but the twentieth century has ushered in new anxieties, such as the prolonged fear of exposure to dangerous radiation following a nuclear accident. Sadly, this is now a well-documented phenomenon. One of the most detailed scientific investigations of chronic stress has been conducted on people living near the damaged Three Mile Island nuclear power plant in Pennsylvania.
On 28 March 1979 the Three Mile Island reactor suffered a serious accident. Fortunately, the damage was contained and there was no significant release of radiation into the surrounding environment. However, the accident understandably generated great anxiety and distress among local inhabitants. In its immediate aftermath there was panic and confusion; saturation reporting by the media fanned the flames of fear that the reactor core would melt down and cause a massive release of radiation. Even after the initial crisis had passed, locals were painfully aware of the long-term clean-up operation and the continuing threat posed by the damaged reactor. Fear, anxiety and stress persisted for years.
Six years after the Three Mile Island incident American scientists measured the immune functions of people living within a five-mile radius of the damaged reactor. Compared with matched control subjects living further away, those living near Three Mile Island had markedly impaired immune systems. To be specific, they had fewer circulating B-lymphocytes, fewer natural killer cells, fewer suppressor/cytotoxic T-lymphocytes and a reduced immunological control over latent herpes viruses. And to round off the picture, they also showed a higher degree of anxiety and psychological distress; higher blood pressure; higher average pulse rates; and higher levels of the stress hormones adrenaline, noradrenaline and cortisol.
The Three Mile Island incident demonstrated quite clearly that, irrespective of whether or not there is a release of harmful radiation, the psychological stress which attends a nuclear accident can still have a major impact on mental and physical wellbeing. A further general conclusion from this and similar studies is that the immune system does not always adapt to long-term stress. Prolonged stress can produce a prolonged depression in immune function. It can also have some subtle effects on disease patterns.
The plot thickened. Three years after the original accident a team of researchers from Columbia University discovered an unusually high incidence of cancers among local inhabitants. In 1982 the incidence of all types of cancer among those living near the plant was 50 per cent above the historical norm. However, the cancer rate then started to fall, and by 1985 it had dropped below the long-term average. Meanwhile, cancer rates among the control subjects living further away from the plant had remained roughly constant. What was going on?
A number of fine minds were brought to bear on this problem. They concluded that subtle psychological processes lay at its root. All the evidence indicated that this peculiar blip in the cancer rates was not merely a consequence of exposure to radiation released from the damaged reactor. For a start, very little radiation had been released and the levels were too low to have caused a measurable increase in cancer. Moreover, there was no discernible association between the recorded levels of radioactivity and the pattern of cancer occurrences in the Three Mile Island area. The consensus among scientists was that the cluster of cancers around Three Mile Island could not be attributed directly to radiation.
Instead, it appeared that the transient increase in cancer rates probably stemmed from the high degree of psychological stress local residents were experiencing. Psychological surveys confirmed that the closer a subject lived to the plant, the higher on average their levels of anxiety and distress.
Psychological stress could have generated the apparent rise in cancer rates in two distinct ways. First, the local population had been bombarded with publicity about the potentially dire health consequences of the incident. They were more anxious about their health in general and particularly concerned about the dangers of radiation-induced cancer. It is therefore probable that they would have paid closer attention to their own health – especially to any possible symptoms of cancer – and would have sought medical attention at an earlier stage than individuals who were less concerned. This process would explain why cancer rates initially rose and then fell below the long-term average. The overall long-term incidence of cancer stayed roughly constant, but in the years immediately after the accident cancers were being diagnosed at an earlier stage in the disease – hence the blip.