The implications of psychoneuroimmunology cover the length and breadth of medical research.
Over the last few decades, the intriguing and pervasive links between neuroscience and the immune system have slowly been uncovered.
What might seem, at first, like an uneasy marriage between the brain and immunity has steadily grown into a fully fledged interdisciplinary area of study.
This field is known as psychoneuroimmunology (PNI).
It is well established, in the minds of most people, that stress can induce illness and that, conversely, a fun-filled occasion with loved ones can soothe aches and pains and stave off the very same illness.
What might have been referred to as pseudoscience a few decades ago now finds strong support from many quarters. PNI has deep ramifications for the future of medical research, the treatment of diseases and our attitude toward handling stress.
In this article, we will take a look at the birth of PNI, how the immune and nervous systems interact and some of the ways in which these communication pathways affect us all.
The mind's impact on health
First, we will take a very brief look at a few examples of how psychology has been shown to influence the immune system:
- Bereavement: stories of recently bereaved individuals dying soon after their partner are common. These tales are not just apocryphal. A study that followed 95,647 recently widowed individuals found that during the first week after bereavement, mortality was twice the expected rate. There is more to this than a metaphorical "broken heart"
- The gut: it is now fairly well established that there is a strong association between sustained stressful life events and the onset of symptoms in functional gastrointestinal disorders, inflammatory bowel disease and irritable bowel syndrome
- Cancer: health professionals working with cancer patients know only too well that a patient's outlook and their quantity and quality of psychological support can hugely impact the outcome of their disease
- HIV (human immunodeficiency virus): studies have found significant evidence that elevated levels of stress and diminished social support accelerates the progression of HIV infection
- Skin complaints: psoriasis, eczema and asthma are all known to have psychological aspects to them. A stressful day at the office can have you scratching as you reach for the asthma pump
- Wound healing: the speed at which a surgical patient heals has been linked to psychological factors. For instance, increased levels of fear or distress before surgery have been associated with worse outcomes, including longer stays in the hospital, more postoperative complications and higher rates of re-hospitalization. In one study on patients with chronic lower leg wounds, those who reported the highest levels of depression and anxiety showed significantly delayed healing.
Despite first-hand accounts of stressful or exhausting psychological events negatively impacting physical well-being, the scientific evidence behind these stories was not initially forthcoming.
How could neural activity influence the activity of the immune system? The immune system's classical messaging system - the lymph system - is not present in the central nervous system, so conversations between the two were considered impossible.
What sounds like medieval quackery is now considered science fact; the mechanisms that underpin immune-brain interactions are steadily being uncovered.
As with so many scientific discoveries, it was a chance observation that got the ball rolling.
The birth of psychoneuroimmunology
Robert Ader is widely considered to be the father of modern PNI. His early research, involving conditioning in rats, opened the floodgates for the study of brain-immune communication.
Experiments into psychological conditioning accidentally stumbled upon the brain-immune interaction.
Ader, a psychologist by trade, worked closely with Nicholas Cohen, an immunologist.
Their specialties made them the perfect team for the job, even though they did not realize it at the time.
Their landmark discovery was courtesy of science's old friend - serendipity.
Ader was working on variations of the classic Pavlov's dogs experiment: salivation in dogs was conditioned by an auditory stimulus - such as a metronome - before they were fed each day. Consequently, the stimulus induced salivation without the presence of food.
In Ader's version of the experiment, he fed rats different quantities of saccharin solution and simultaneously injected them with Cytoxan - a drug that induces gastrointestinal distress and suppresses the immune system. The rats were conditioned to avoid drinking the solution, as predicted.
Ader then ceased injecting the rats but continued to present the saccharin-laced water. The rats avoided the solution but, strangely, some of them died. He noted that the avoidance response and the level of mortality varied depending on the amount of saccharine water they had been presented with.
The results intrigued Ader; it seemed that the avoidance response had been conditioned as expected, but, unexpectedly, so had the corresponding drop in immunity. In an interview in 2010, he explained:
"As a psychologist, I was unaware that there were no connections between the brain and the immune system, so I was free to consider any possibility that might explain this orderly relationship between the magnitude of the conditioned response and the rate of mortality.
A hypothesis that seemed reasonable to me was that, in addition to conditioning the avoidance response, we were conditioning the immunosuppressive effects [of Cytoxan]."
His next study, published in 1975, proved beyond doubt that his hunch, although surprising and openly mocked by other scientists, was spot on.
The game truly had changed. A neural signal (taste) had managed to trigger a conditioned reduction in the immune system. The results were replicable, and although the theory received more than its fair share of flack, there seemed no other way to explain it.
All of a sudden, the central nervous system and immunity were bedfellows.
Evidence for brain-immune interactions mount
Following on from those seminal experiments, science began to build a picture of this new and unexpected interaction.
The brain and immune system are now known to have a myriad of functional connections.
If the immune system was in cahoots with the nervous system, there must be points where they intersect. Soon, this too was demonstrated.
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 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.
The role of neuropeptides
Neuropeptides are the latest molecules to join the ranks of the neurotransmitters. Neurons use them to communicate between themselves and, to date, more than 100 distinct neuropeptides appear to be utilized by the nervous system.
Rather than classic neurotransmitter's relatively short-lived action, neuropeptides have longer-lasting effects and can influence a number of operations, from gene expression to the building of new synapses.
Interestingly, neuropeptides are implicated in a wide array of functions involving an emotional aspect. For instance, neuropeptides are known to play a part in reward-seeking, social behaviors, reproduction, memory and learning.
How does the brain talk to the immune system?
As the field of PNI grows and develops, many discrete pathways of chatter between psychology and immunity are being discovered.
Over the past few decades, the depth of integration between the nervous system and immune system has slowly been unpicked.
For the sake of brevity, we will mention just one of the better-understood networks at play: the hypothalamic-pituitary-adrenal (HPA) axis and the impact that psychological stress has on that particular network.
The HPA axis involves three small endocrine glands - glands that secrete hormones directly into the blood. The glands in question are the hypothalamus and the pituitary, which are neurological neighbors, and the adrenal glands, situated on top of the kidneys.
This triumvirate of tissues control reactions to stress and regulate processes including digestion, the immune system, sexuality, mood and energy usage.
The hypothalamic-pituitary-adrenal axis plays a vital role in immune-brain interaction and stress.
One chemical of note involved in the HPA axis' work is corticotropin-releasing hormone (CRH). The hypothalamus releases CRH in response to stress, illness, exercise, cortisol in the blood and sleep/wake cycles. It peaks soon after waking and slowly declines throughout the rest of the day.
In a stressed individual, however, cortisol levels are elevated for prolonged periods of time.
During stress, the body believes it is in imminent danger, so cortisol triggers a number of metabolic changes to ensure that enough energy is available in case a fight or flight is necessary.
One of these energy-saving tactics is to suppress the metabolically expensive immune system, saving vital glucose for the approaching life-threatening event.
Of course, in modern humans, stress levels can soar for a number of reasons. Very few of these situations involve a genuine threat to life, but the HPA axis evolved long before dissertation deadlines and job interviews.
In this way, ongoing stress can reduce the capabilities of the immune system as the body saves its energy for a physical exertion that never comes.
Conversely, there is some evidence that oxytocin, produced during positive social interactions, helps dampen the activity of the HPA axis. This has been shown to promote health benefits, such as increasing the speed of wound healing.
The interaction between the hypothalamus, pituitary and adrenal glands is complex, as is the influence of other brain centers on each of them. Although we have a picture of some of its workings, we are a long way from charting the entire range of influences and influencers. And, the HPA axis is but one of the systems PNI has uncovered.
Different stress, different immune response
A meta-analysis of 300 empirical studies found that certain types of stress altered different aspects of the immune system. They compared brief stressors, like exams, with chronic stressors - events that change a person's entire life, like caring for a partner with dementia.
Brief stressors tended to suppress cellular immunity (the type that deals with cellular invaders, like viruses) while preserving humoral immunity (normally dealing with pathogens outside of cells, such as parasites and bacteria).
Chronic stressors tended to suppress both types of immunity.
Stress has a measurable effect on the strength of the immune system and therefore its ability to protect us. In a very real way, managing levels of stress can help maximize the virility of your immune system.
Research has shown time and time again that people in stressful situations have measurable changes in physical responses to injury. Whether it is slowed wound healing, a higher incidence of infection or a worse prognosis for cancer survival.
It rams home the message that managing stress is an important ability to learn and that supporting those in stressful situations is just as important.
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.
Stress is both psychological and physical.