The Inflamed Mind

by Edward Bullmore

  We must dare to think differently.

  One day in 1989, when I was training as a physician, just before I started to specialise in psychiatry, I saw a woman in her late fifties with an inflammatory disease called rheumatoid arthritis. I’ll call her Mrs P. She had been arthritic for many years. The joints in her hands were painfully swollen and disfigured by scarring. The collagen and bone in her knees had been destroyed so that the joints no longer worked smoothly and she found it difficult to walk. Together we talked through the long list of physical signs and symptoms that are diagnostic of rheumatoid arthritis. She ticked all the boxes. Then I asked her a few questions that weren’t on the standard checklist. I asked about her state of mind, her mood, and over the course of the next 10 minutes or so she quietly but clearly told me that she had very low levels of energy, nothing gave her pleasure any more, her sleep was disturbed and she was preoccupied by pessimistic and guilty thoughts. She was depressed.

  I was pleased with myself. I thought I had made a minor medical discovery by doubling her diagnoses. She had come to see me with rheumatoid arthritis; I had added depressive disorder. I rushed to tell my senior physician this important news: “Mrs P is not only arthritic, she’s also depressed.” He was not impressed by my diagnostic acumen. “Depressed? Well, you would be, wouldn’t you?”

  We could both recognise that Mrs P was depressed and she was inflamed. However, the conventional medical wisdom of the time was that she was depressed because she knew she had a chronic inflammatory disease. It was all in the mind. It did not occur to either of us that it might originate in the body. That Mrs P might be depressed - not because she knew she was inflamed - but simply because she was inflamed. Mrs P left the clinic no less likely to be depressed or fatigued than she was when she’d arrived. We’d not dared to think differently and we’d done nothing to make a difference.

  About 30 years down the road, we are becoming much more fluent in a new way of thinking scientifically about the links between depression and inflammation, between mind and body, as I recently discovered for myself after a visit to the dentist.

  Root canal blues

  A few years ago I had an old filling in one of my molars that had gone rotten, become infected, and my dentist needed to drill out the cavity all the way to the tips of the roots of the tooth. Undergoing root canal surgery is not my favourite way to while away an hour or so but I knew it had to be done. I was cheerful enough when I obediently hopped up on the chair and opened wide. But as soon as it was all done, I wanted to go home, to go to bed and not talk to anyone. And when I was alone at home I found myself cogitating gloomily on the grave until I went to sleep.

  The next morning I got up, went to work and forgot about mortality. I had endured some drilling of my tooth, some bruising of my gums, and I had briefly experienced some mental and behavioural symptoms: lethargy, social withdrawal, morbid rumination. You could say I had been a bit depressed: but - hey - who likes going to the dentist?

  There seems to be nothing out of the ordinary about this sequence of events - and there isn’t - but the ordinary explanation for it turns out to be not the only one.

  The traditional way of thinking about this tiny episode of illness starts with my body’s immune response to infection and injury. My tooth had been infected by some bacteria; my gums had become inflamed in response to that infection; the dentist’s drilling and scraping, although intended to achieve a long-term surgical cure, had the short-term disadvantage of making my gums even more inflamed and increasing the risk of the bacteria spreading from my tooth into my bloodstream. The reason I went to the dentist, and what happened to me when I got there, amounted to a challenge to my body’s integrity, a threat to my survival and a clarion call to my immune system to step up its inflammatory response.

  Working out this mechanistic chain of cause and effect, which leads from a physical attack, like an injury or an infection, to an inflammatory response from the immune system, is one of the truly game-changing triumphs of scientific medicine. This is the triumph of immunology, the science that now permeates our understanding of almost all diseases, and underpins the therapeutic success of vaccination, transplant surgery and successful new drugs for diseases like rheumatoid arthritis, multiple sclerosis and increasingly more kinds of cancer. This immensely powerful science can provide a minutely detailed explanation for how infection in my tooth could cause local inflammation of my gums, and how surgery could exacerbate the inflammation acutely.

  But immunology has not yet had nearly so much to say about what inflammation feels like for the inflamed patient, or how inflammation can have effects on thoughts and behaviour. Why did I want to be by myself? Why did I want to go to bed and stay there? Why was I so gloomy? The answers to questions like these have traditionally come from psychology, rather than immunology.

  Thus I told myself a psychological story, that my close encounter with the dentist must have reminded me that I was literally getting long in the tooth. And this concrete affirmation of a well-worn metaphor for mortality must have triggered a period of rational pessimism as I calculated how much longer I might have to live. To paraphrase my self-diagnosis, to put it another way: I became momentarily depressed because I thought about the implications of my root canal surgery. My mental state was a reflection or meditation on my physical state, rather than directly caused by my physical state.

  To the extent that you are still unsurprised by this story, you are a dualist. Because the conventional medical explanation for what happened to me is dualist - it exists in two domains - physical and mental - with only a nebulous point of connection between them. Everything that happened up to and including my visit to the dentist is precisely explained in the physical domain, by the biological science of infection and immunity. Everything that happened to my mood and behaviour after I went to the dentist is explained in the mental domain, by the psychologically meaningful story I told myself about getting long in the tooth.

  At the time, about 2013, when I explained my own experience of inflammation and depression in this way, I found it somewhat comforting “to know”. Now, looking back, I am finally surprised. I am surprised to realise how incomplete and convoluted the standard dualist explanation seems to be - now that I know there could be a very different kind of explanation for what happened to me. There is another way of thinking about my root canal blues. I could have been momentarily depressed simply because I was inflamed; not because I thought about the consequences of being inflamed. The brief, transient burst of inflammation in my mouth could directly have caused the changes in my mood, behaviour and cognition that I noticed immediately after the surgery.

  This new explanation is logically simpler than the familiar dualist reasoning I used when I told myself the story about getting long in the tooth. The stream of explanatory narrative doesn’t run into the sand in the physical domain, when I get out of the dentist’s chair, and then miraculously resurface in the mental domain, when I am back at home despondently in bed. Now the chain of cause and effect can run from start to finish in the physical domain - from the initial cause of an infected tooth to the final effect of a depressed mood.

  But causality is tough to nail down, scientifically. To be completely confident that inflammation can cause depression we’d want to know the answers to two big questions:

  How, exactly, step by step, can inflammatory changes in the body’s immune system cause changes in the way the brain works so as to make people feel depressed?

  Why is a depressed patient inflamed in the first place? And why should the body’s inflammatory response, which is supposed to be on our side, which has evolved to help us win the battle against disease, be causing us to feel depressed?

  Back when I met Mrs P, about 30 years ago, these questions about causality were almost unasked and there were no good scientific or medical answers to them.

  By the time of my root canal surgery in 2013, the questions were being asked much more often, and more precisely, and the answe
rs were becoming clearer, thanks to the work of a disruptive new science, which has continued to make rapid progress in the last 5 years.3-6

  Like a lot of new science, this one has emerged at the interfaces between more established domains of knowledge. It exists at the boundaries between immunology, neuroscience, psychology and psychiatry. It goes by a variety of ungainly, often hyphenated names - like neuro-immunology or immuno-psychiatry - that speak to its hybrid origins and its transgressive ambitions to link brain, body and mind by the mechanisms of the immune system. Neuro-immunology investigates how the immune system interacts with the brain or nervous system; whereas immuno-psychiatry is more focused on how the immune system interacts with the mind and mental health.

  Neuro-immunology and immuno-psychiatry

  The first few people brave enough to call themselves neuroimmunologists were a tiny tribe regarded with some condescension and suspicion by more mainstream scientists. It wasn’t considered professionally respectable to investigate connections between the brain - the province of neuroscience - and the immune system - the province of immunology. Not respectable not least because it was well known in the 20th century that the brain and the immune system had nothing to do with each other. The white blood cells and antibodies of the immune system circulated in the bloodstream and could pass through the spleen and lymph nodes and various other immunologically important organs of the body. But the cells and proteins of the body’s immune system couldn’t percolate so freely through the brain because it was protected by something called the blood-brain barrier. The BBB, as it’s also known, was explained to me at medical school in the 1980s as something like a Berlin Wall that kept the immune system completely apart from the nervous system. The solidity of the BBB exposed the nascent theories of neuro-immunology to the withering scorn of more traditionally minded scientists. How could neuro-immunologists seriously propose - as they began to do from about 1990 - that levels of inflammatory proteins measured by a blood test had anything to do with the brain or the mind, when it was well known that proteins couldn’t cross the barrier between blood and brain? It wasn’t just wrong; it was worse than that.

  The Berlin wall concept of the BBB was the physical embodiment of powerful older ideas, the dualist ideas dating back to Descartes, that mind and body, as we now say, or soul and body, as he said, are utterly different. The 17th-century philosophy of Cartesian dualism is the foundational bedrock of Western scientific medicine. And the disembodiment of the brain by the rigid interdiction of the BBB was a concrete realisation of this philosophy. So when the pioneer neuro-immunologists proposed that inflammatory proteins in the blood could get across the BBB to have effects on the mind, they weren’t regarded merely as wrong about the biology but as deeply disrespectful of the philosophical underpinnings of scientific medicine.

  It is now clear that a lot of what I was taught in medical school is wrong. It has become increasingly obvious that the existence of the BBB does not prohibit all immunological cross-talk between the brain and the body. We now know that inflammatory proteins in the blood, called cytokines, can send signals across the BBB, from the body to the brain and the mind. I will say more about cytokines later but if you’ve never heard of them before you can think of them as hormones which circulate in the bloodstream creating powerful inflammatory effects throughout the body, including the brain. So when the dentist started probing my gums and scraping my teeth, she would have caused immune cells in my mouth to produce cytokines, which then circulated throughout my body in my blood and communicated inflammatory signals across the supposedly impermeable BBB to reach the nerve cells in my brain and cause my mind to become inflamed.

  What does an inflamed mind look like?

  Mental inflammation, I used to think, without thinking about it too hard, might be similar to physical inflammation. As we have known since Roman times, the body becomes red and swollen when it is inflamed. So I used to imagine the inflamed mind was metaphorically red and swollen, angry and excessive, passionate, out of control and potentially dangerous, closest in psychiatric parlance to a state of mania. But the image of an inflamed mind that I conjure up now is almost the opposite: not a choleric and threatening person but a melancholic and withdrawn one. Like Mrs P, her hands swollen and deformed by inflammatory joint disease, silently wondering why she felt so gloomy and tired. I now think of her as typical of an inflamed mind, not metaphorically speaking, but mechanistically speaking.

  The shift from metaphors to mechanisms of the inflamed mind begins by acknowledging the overwhelming evidence for a strong association between inflammation and depression. Simply recognising this association, which is sometimes hiding in plain sight, is the right place to start. But the crucial questions are about causality. For a new, post-dualist way of thinking to take root it must be scientifically established that inflammation is not merely associated or linked with depression but can directly cause depression.

  One way of teasing apart cause and effect is by looking at the sequence of events in time. Causes must come before effects. So if inflammation is a cause of depressive symptoms, we would expect to find evidence that inflammation can occur before depression; and there is some such evidence from recent research. For example, a 2014 study of 15,000 children in Bristol and south-west England found that children who were not depressed, but were slightly inflamed at the age of nine, were significantly more likely to be depressed 10 years later as 18-year-olds.7 This is one of dozens of human studies, and hundreds of animal studies, that have shown that inflammation can anticipate or precede depression or depressive behaviours.

  But precedence alone is not sufficient for inflammation to be taken seriously as a cause of depression. Sceptical scientists and doctors will need to know how, by what exact biological mechanisms, inflammation can cause depression, step by step from cytokines in the blood to changes in the brain that can in turn cause depressive changes in mood. Here too there is supportive evidence from recent experiments in animals and humans.

  If a rat is experimentally injected with infectious bacteria, it behaves a bit like I did after the dentist. It withdraws from social contact with other animals, it doesn’t move so much, its sleeping and eating cycles are disturbed. In short, infection reliably causes a syndrome in animals - called sickness behaviour - that is roughly recognisable as akin to the human experience of depression. In fact, you don’t even need to infect a rat to see this sickness behaviour. It is enough to inject the rat with cytokines, proving that it is not the germ itself that causes sickness behaviour but the immune response to infection. Inflammation directly causes depression-like behaviours in animals - that is beyond doubt.3

  We also understand how inflammation can have effects on the brains of rats and mice. We know that nerve cells exposed to cytokines are more likely to die and less likely to be regenerated. We know that when nerve cells are inflamed the connections or synapses between them are less capable of learning patterns of information and that inflammation reduces the supply of serotonin as a transmitter between nerve cells. For animals, at least, an explanatory chain is taking shape that can link inflammation of the body directly to changes in how nerve cells work in the brain, that in turn causes sickness behaviour that looks like depression.

  To work out the equivalent chain of connections in humans is not easy. We can’t experimentally infect people with dangerous bacteria, we can’t inject cytokines (or anything else) directly into the brains of healthy people, and it is impossible to see what inflammation does to living human nerve cells, one cell at a time. The vast majority of human nerve cells - about 100 billion of them - are packed together densely in the brain; and the brain is extremely well protected from the outside world by the bony skull. The only way we can “see” what is going on inside the skull of a living human is with brain scanning techniques, like magnetic resonance imaging. And recent fMRI research has begun to produce evidence that inflammation of the body can have a direct causal effect on the human brain and mood. For example, when
healthy young people were injected with a vaccine against typhoid, their immune systems reacted like the immune system of a rat injected with bacteria, and cytokine levels spiked in their blood. The vaccinated volunteers also became mildly depressed and their post-vaccination depression was associated with greater activation of regions of the brain that we know are hard-wired for emotional expression.8

  So the science of immuno-psychiatry has matured to the point that it can help me answer the question of how I became depressed after the dentist in a new and logically seamless way. I don’t need a ghost in the machine. I can plausibly argue that the surge of cytokines caused by my root canal surgery sent an inflammatory signal across the BBB to cause a change in the emotion-processing networks of nerve cells in my brain, which in turn caused an episode of depression that led my mind to dwell on the grave. There is credible experimental evidence for every step of this dualism-defying, extraordinary explanation. But still it is not entirely complete. There are gaps and anomalies in the existing evidence base, to be sure, as there always will be in any rapidly advancing area of science. But even if we had a complete answer to the question “how”, we would still want to know the answer to the question “why”.

  The only scientifically acceptable answer to that question is in terms of evolution. Why does inflammation cause depression? It can only be because of natural selection. There must be some sense in which a depressive response to infection or any other inflammatory challenge is (or was) advantageous for our survival.9, 10 And we must have inherited genes that were naturally selected in previous generations to make us more likely to benefit from a depressive response to inflammation. If I want to, I can reasonably speculate that the reason why I became momentarily depressed after the dentist is because I have inherited genes that helped my ancestors survive infections in the past. This genetic inheritance might well have helped me recover from the minor trauma of root canal treatment by aggressively killing off any infectious germs and by dictating that I should stay in bed and conserve my energy while that happened.