Placebo health

Since the 1990’s science has known that mental states can have a profound impact on how ill we get — and how well we recover. Working out how this happens could enable physicians to tap into the power of the mind over the body.

Understanding this could help to boost the placebo effect, destroy cancers, enhance responses to vaccination and even re-evaluate illnesses that, for centuries, have been dismissed as being psychologically driven – psychosomatic (psycho: from the brain and somatic: from the body). It appears that we have more control over our bodies than was previously thought – maybe faith can indeed move mountains.

Neurosurgeon Kevin Tracey, at North Shore University Hospital in Manhasset, New York, and his colleagues found something unexpected while investigating whether an experimental anti-inflammatory drug could help to tame brain inflammation caused by stroke. When delivered into the brains of rodents that had experienced strokes, the drug had the expected effect: it reduced neuroinflammation.

As a control, the team injected the drug into the brains of animals that had inflammation throughout their bodies, thinking the drug would work exclusively in the brain. To their surprise, it also worked in the body. “This was a real head-scratcher,” says Tracey, now president and chief executive of the Feinstein Institutes for Medical Research in Manhasset.

Scientists are mapping out the brain’s control over the body’s immune responses. There are multiple lines of communication between the nervous and the immune systems — from small local circuits in organs such as the skin, to longer-range routes beginning in the brain — with roles in a wide range of diseases, from autoimmunity to cancer.

Some parts of the system — such as the vagus nerve, a huge highway of nerve fibres that connects the body to the brain — have inspired treatments for several autoimmune diseases that are currently being tested in clinical trials. Other studies, investigating how to recruit the brain itself — which some think could provide powerful therapies — are still being investigated.

For more than a century, scientists have been finding hints of a close-knit relationship between the nervous and the immune systems. In the late nineteenth and early twentieth centuries, for example, scientists demonstrated that cutting nerves to the skin could curb some hallmarks of inflammation.

It wasn’t until the late 1990s that researchers in this field began drawing connections to the body’s master conductor, the brain.

After months of trying to determine the path of the drug from brain to body, the researchers decided to cut the vagus nerve, a bundle of some 100,000 nerve fibres that runs from the brain to the heart, lungs, gastrointestinal tract and other major organs. With the vagus nerve snipped, the anti-inflammatory effect of the brain-administered drug disappeared.

Inspired by this discovery, Tracey’s group and others have continued to explore other ways in which the vagus nerve — and the rest of the nervous system — directs immune responses. A driving force for these developments, says Swirski, has been the advent of scientific tools that enable scientists to begin to chart the interactions between the nervous and the immune systems in an unprecedented way.

Some researchers are focusing on particular body systems. For instance, a team led by Andreas Habenicht, a cardiologist at LMU Munich, Germany, reported last year that the interaction between immune cells and nerves in the outermost layer of artery walls modulated the progression of atherosclerosis, an inflammatory disease in which vessels become clogged with cholesterol and other substances.

Meanwhile, Veiga-Fernandes and his group have documented clusters of neuronal and immune cells in various tissues and discovered how they work together to sense damage and mobilize immune reactions. His team is now looking at how these little switchboards can be controlled by the brain.

The brain itself is also beginning to give up its secrets. Neuroscientist Catherine Dulac and her team at Harvard University in Cambridge, Massachusetts, have pinpointed neurons in an area called the hypothalamus that control symptoms including fever, warmth-seeking and loss of appetite in response to infection.

“Most people probably assume that when you feel sick, it’s because the bacteria or viruses are messing up your body,” she says. But her team demonstrated that activating these neurons could generate symptoms of sickness even in the absence of a pathogen. An open question, Dulac adds, is whether these hypothalamic neurons can be activated by triggers other than pathogens, such as chronic inflammation.

Just above the hypothalamus sits a region called the insula, which is involved in processing emotion and bodily sensations. In a 2021 study, one of Rolls’s doctoral students, Tamar Koren, found that neurons in the insula store memories of past bouts of gut inflammation — and that stimulating those brain cells reactivated the immune response.

Rolls, Koren and their colleagues suspect that such a reaction might prime the body to fight potential threats. But these reactions could also backfire and start up in the absence of the original trigger. This could be the case for certain conditions, such as irritable bowel syndrome, that can be exacerbated by negative psychological states.

Fahed Hakim, a paediatrician and director of the Nazareth Hospital EMMS in Israel,  investigated this question after coming across a 1989 study reporting that, among women with breast cancer, those who underwent supportive group therapy and self-hypnosis in addition to routine cancer care survived longer than those who received only the latter. Several other studies have documented a similar link between survival and the mental states of people with cancer.

Clinicians have known about the effect of positive thinking on disease progression for a long time, Hakim says. But this evidence has been largely anecdotal or correlational, so being able to identify a pathway through which such an effect occurs — and manipulate it experimentally in animals — makes it much more real, he says.

Neuroscientist Jeremy Borniger at Cold Spring Harbor Laboratory in New York and his colleagues have also found that activating neurons in the mouse hypothalamus can generate an immune response — and are now examining how manipulating these cells can alter the growth of tumours.

Ben-Moshe and Rolls hope to harness existing brain-stimulation technologies, such as transcranial magnetic stimulation, which uses magnetic pulses to alter brain activity, or focused ultrasound, which uses sound waves, to modulate the immune systems of people with cancer, autoimmune diseases or other conditions.

Potential therapies targeting the vagus nerve are nearer the clinic. A company co-founded by Tracey — SetPoint Medical in Valencia, California — is testing pill-sized vagus-nerve stimulators, implanted in the vagus nerve in the neck, in autoimmune diseases including Crohn’s disease, multiple sclerosis and rheumatoid arthritis.

The rheumatoid-arthritis trial is farthest along — the team has shown in a small trial in Europe that its device can reduce disease severity. The technique is currently undergoing a randomised, sham-controlled trial (in which the control group will receive an implant but no active stimulation) in 250 patients in various centres across the United States.

Rolls’s hope is that this work will ultimately help physicians to understand, and act on, the mind–body connections that they see in their practices. The need is clear: when Rolls put out a call to speak to psychologists from the hospital where her lab is based, the meeting room was packed. People from departments ranging from dermatology to oncology were eager to share their stories.

Many clinicians pass people with seemingly psychosomatic issues on to psychologists, saying there is nothing physically wrong, said one attendee. This can be distressing for the person seeking treatment. Even being able to simply tell people that there is a brain–immune connection that is responsible for their symptoms can make an enormous difference.

It’s time that both researchers and clinicians take the link between psychology and physiology seriously, says Rolls. “You can call something psychosomatic, but in the end, it’s somatic. How long can we ignore what is there?”