Your brain could be controlling how sick you get — and how you recover

Hundreds of scientists around the world are looking for ways to treat heart attacks. But few started where Hedva Haykin has: in the brain. Haykin, a doctoral student at the Technion — Israel

Institute of Technology in Haifa, wants to know whether stimulating a region of the brain involved in positive emotion and motivation can influence how the heart heals. Late last year, in a

small, windowless microscope room, she pulled out slides from a thin black box, one by one. On them were slices of hearts, no bigger than pumpkin seeds, from mice that had experienced heart

attacks. Under a microscope, some of the samples were clearly marred by scars left in the aftermath of the infarction. Others showed mere speckles of damage visible among streaks of

healthy, red-stained cells. The difference in the hearts’ appearance originated in the brain, Haykin explains. The healthier-looking samples came from mice that had received stimulation of a

brain area involved in positive emotion and motivation. Those marked with scars were from unstimulated mice. “In the beginning we were sure that it was too good to be true,” Haykin says. It

was only after repeating the experiment several times, she adds, that she was able to accept that the effect she was seeing was real. Haykin, alongside her supervisors at the Technion —

Asya Rolls, a neuroimmunologist, and Lior Gepstein, a cardiologist — are trying to work out exactly how this happens. On the basis of their experiments so far, which have not yet been

published, activation of this brain reward centre — called the ventral tegmental area (VTA) — seems to trigger immune changes that contribute to the reduction of scar tissue. This study has

its roots in decades of research pointing to the contribution of a person’s psychological state to their heart health1. In a well-known condition known as ‘broken-heart syndrome’, an

extremely stressful event can generate the symptoms of a heart attack — and can, in rare cases, be fatal. Conversely, studies have suggested that a positive mindset can lead to better

outcomes in those with cardiovascular disease. But the mechanisms behind these links remain elusive. Guardians of the brain: how a special immune system protects our grey matter Rolls is

used to being surprised by the results in her laboratory, where the main focus is on how the brain directs the immune response, and how this connection influences health and disease.

Although Rolls can barely contain her excitement as she discusses her group’s eclectic mix of ongoing studies, she’s also cautious. Because of the often-unexpected nature of her team’s

discoveries, she never lets herself believe an experiment’s results until they have been repeated multiple times — a policy that Haykin and others in her group have adopted. “You need to

convince yourself all the time with this stuff,” Rolls says. For Rolls, the implications of this work are broad. She wants to provide an explanation for a phenomenon that many clinicians and

researchers are aware of: mental states can have a profound impact on how ill we get — and how well we recover. In Rolls’s view, 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, she says. “I think we’re ready to say that psychosomatic [conditions] can be treated differently.” She is part of a

growing group of scientists who 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. This field “has

really exploded over the last several years”, says Filip Swirski, an immunologist at the Icahn School of Medicine at Mount Sinai in New York City. 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 nascent. Rolls, for one, has just begun examining whether the

pathways her team has found in mice are also present in humans. And she has launched a start-up company to try to develop treatments based on her findings. Although these developments are

encouraging to researchers, much is still a mystery. “We often have a black box between the brain and the effect we see in the periphery,” says Henrique Veiga-Fernandes, a neuroimmunologist

at the Champalimaud Centre for the Unknown in Lisbon. “If we want to use it in the therapeutic context, we actually need to understand the mechanism.” A TALE OF TWO SYSTEMS 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 inflammation2. It wasn’t until the late 1990s that researchers in this field began drawing connections to

the body’s master conductor, the brain. Neurosurgeon Kevin Tracey, then 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. How gut microbes could drive brain disorders 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. 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 disappeared3. 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 substances4. 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 brain5. 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 infection6. “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 response7. 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. MIND OVER MATTER Many scientists hope to pin down

how such mental states influence immune responses. Rolls and Fahed Hakim, a paediatrician and director of the Nazareth Hospital EMMS in Israel, were inspired to investigate this question

after coming across a 1989 study8 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. ENJOYING OUR LATEST

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