Self & Other
15. Stress, Loneliness, and the Vagus Nerve
In the early 1970s, a behavioral psychologist named Robert Ader, working at the University of Rochester, was doing a fairly ordinary experiment in classical conditioning. He gave rats saccharin-flavored water at the same time he gave them a drug called cyclophosphamide that caused stomach upset, hoping the rats would, like Pavlov’s dogs with the bell, learn to associate the taste with the nausea and avoid the water. They did. So far, an unremarkable result.
Then some of the rats started dying.
Not from the cyclophosphamide. They had stopped getting the drug. They had only been getting the saccharin water alone, in occasional follow-up sessions, to test how strongly the conditioning had taken. But some of them, given just the flavored water, were dying anyway.
Ader sat with this for a while. Cyclophosphamide, in addition to causing nausea, is an immunosuppressive drug — it dampens the immune system. The rats had been receiving it for weeks. They were probably mildly immunocompromised. And now, when given just the taste they had associated with the drug, they appeared to be — he could hardly bring himself to think it — they appeared to be having an immune response to the saccharin. Their bodies, in some sense, had learned that the taste meant immune suppression, and were producing immune suppression on cue, even without the drug.
Ader collaborated with an immunologist named Nicholas Cohen to confirm this carefully. They demonstrated, in a series of experiments through the late 1970s, that immune responses could indeed be classically conditioned, exactly the way Pavlov had conditioned salivation. Healthy rats, exposed to a flavor that had previously been paired with an immunosuppressive drug, would suppress their own immune systems in response to the flavor alone. The conditioning was specific. It was reproducible. It implied something that, at the time, most immunologists found nearly impossible to believe: that the brain and the immune system were directly connected, in ways that allowed signals to flow between them.
The field this finding launched is called psychoneuroimmunology, which is, frankly, an awful word. The science underneath it is some of the most surprising and humanly interesting in modern biology. The rest of this chapter is about what we now know.
The Wires
For most of the twentieth century, the immune system was thought of as a freestanding system that ran in parallel to the rest of the body, communicating with itself through cytokines but largely independent of the nervous system, the endocrine system, or anything else. We now know this picture was wrong, and not subtly so. The immune system is wired into the brain through several specific routes that we have begun to map in some detail.
The most direct route runs through a long, branching nerve called the vagus. The vagus nerve emerges from the base of the brain and snakes down through the neck, branches into the heart, the lungs, the gut, and almost every internal organ. It is the longest cranial nerve in the body and one of the strangest, because most of its fibers don’t run from the brain outward; they run from the body inward, sending the brain a constant stream of information about what is happening in the organs. About eighty percent of vagus nerve fibers carry signals from body to brain, not the other way around.
In the late 1990s, a neurosurgeon named Kevin Tracey was studying how the body controls inflammation, and he discovered something that nobody had quite predicted. The vagus nerve, he found, can directly suppress inflammation in tissues. When the vagus nerve fires properly, certain immune cells in nearby tissues calm down. They release fewer inflammatory cytokines. The local response is dialed down. Tracey called this the inflammatory reflex.
The implications were strange. It meant that the body had a built-in nerve circuit specifically dedicated to keeping inflammation under control — a hardwired regulator that the brain could use to talk down an immune response. It also meant that, in principle, you could treat inflammatory diseases by stimulating the vagus nerve. By the 2010s, small implantable devices that delivered mild electrical pulses to the vagus nerve were being tested in patients with rheumatoid arthritis. Some of the early trial results were striking: patients with severe disease who had failed other treatments responded to vagus nerve stimulation. The technology is not yet mainstream, but the principle is real, and several pharmaceutical-equivalent approaches — drugs that mimic vagus nerve signaling — are now being developed alongside the implants.
There are other wires too. Sympathetic nerve fibers — the ones associated with fight-or-flight responses — reach into lymph nodes, into the spleen, into the thymus, where they can directly modulate how immune cells behave. The brain releases hormones that affect immune cells throughout the body. Immune cells, conversely, release cytokines that can act directly on the brain, producing the fatigue, fog, and low mood we associate with being sick. The two systems are not isolated. They are in continuous, two-way conversation.
Stress, Acute and Chronic
The most familiar way the brain talks to the immune system is through stress.
Acute stress — the kind that lasts minutes to hours, the kind your ancestors experienced when something dangerous happened and they had to deal with it — actually mobilizes the immune system. The body, sensing threat, shifts immune cells out of organs and into the bloodstream and the skin, where they will be useful if the threat involves injury. Cytokine production temporarily ramps up. Wound healing capacity is, briefly, enhanced. This is the immune system reading a signal from the brain that says: something is about to happen; be ready. It is not a malfunction. It is a feature.