During a rehearsal one day in 1842, Hungarian composer Franz Liszt was less than thrilled with the performance of the Weimar orchestra, which he directed. “Gentlemen, a little bluer, if you please!” he exclaimed, astounding the musicians. How on earth does one play bluer? Similar requests followed, according to a report in the musical periodical Neue Berliner Musikzeitung. Liszt demanded the orchestra not to go “so rose,” because the music was instead a “deep violet.”

Unlike most—if not all—of the orchestra players, Liszt was a synesthete, someone for whom the stimulation of one sense causes automatic and unusual experiences in another sense. For people like Liszt, sound-to-color synesthetes, musical notes or even the sound of a door slamming or a car honking can trigger seeing colors. Russian composer Nikolay Rimsky-Korsakov famously believed A major to be clear pink and B major a “gloomy dark blue with a steel shine.”

How common synesthesia may be remains a matter of debate. Older estimates put the prevalence at a mere one in 100,000 people, yet more recent work suggests it is far more common—possibly affecting one in 23 people. One reason for the uncertainty is that some experts define the condition more narrowly than others. Beyond sound-to-color synesthesia, researchers have counted more than 60 varieties, and some say there may be 150 kinds.

The most common by far is grapheme-color synesthesia, affecting roughly one in 100 people, which involves experiencing letters as having colors. Russian-born writer Vladimir Nabokov, for example, saw the letter K as having the color of huckleberry, and S to him was “a curious mixture of azure and mother-of-pearl.” (The specific color associated with each letter varies from one synesthete to the next, although many see A as red.) Other people experience smells as having sounds or days of the week as possessing different flavors. Sean Day, synesthesia researcher and president of the International Association of Synaesthetes, Artists, and Scientists, says that for him beef tastes blue. Even rarer types include the sensation that numbers have personalities (for example, “4” was “demure” to one synesthete) or the experience that swimming styles evoke different colors (such as a red butterfly stroke).

Although scientists have been fascinated with synesthesia for at least two centuries, only in the past decade or so has there been an upsurge in research. The first major findings proved definitively that synesthetic experiences are real—something previous generations had debated. More recently, boosted by technological advances such as whole genome sequencing, scientists have begun to unravel the biological basis for synesthesia. As evidence from brain imaging, molecular biology and epidemiology comes together, scientists are focusing on a totally unexpected variable: the immune system.

The Synesthetic Brain

Even a few decades ago synesthesia was not widely accepted as a neurological phenomenon. It could be verified only by self-report and was sufficiently rare that many people were dubious. For that reason, much early research focused on two questions: Was the experience real (as opposed to a creative mind's fancy)? And if so, what was happening during these strange sensations? Neuroimaging helped to answer both.

Using multiple techniques, researchers have discovered that the brain of a synesthete responds differently to sensory stimulation than a typical brain. For example, some scientists have employed magnetoencephalography (MEG), a technique in which patients sit with their head in a tubelike apparatus (similar in appearance to an old-fashioned salon hair dryer) to provide real-time insight into brain activity. In 2010 scientists at the University of California, San Diego, and Vanderbilt University used MEG to study the brains of Nabokov-like grapheme-color synesthetes who looked at white letters on a black background. The team found that an area of the brain called V4, a region of the visual cortex that responds when you see colors, becomes active a mere 110 milliseconds after a synesthete looks at colorless letters. This suggests that the experience of synesthesia is not just real but also automatic.

British synesthete Daniel Tammet has written extensively about his experiences with autism and savant syndrome. French photographer Jérôme Tabet created these images so others could visualize how Tammet sees numbers (clockwise from top): multiplications of 2 and numbers 1 and 11. Credit: JÉRÔME TABET

In a 2013 study, 20 grapheme-color synesthetes and 19 control subjects were asked to watch or listen to episodes of Sesame Street, a children's television show full of letters and numbers, while lying in a functional MRI machine. The results revealed that these synesthetes have greater cross activation between the areas of the brain responsible for letters and those responsible for colors. In other words, for synesthetes, neurons in these two areas are “talking” more with each other than in nonsynesthetes, such that simply hearing a Sesame Street character mention a letter (without actually seeing it) causes visual areas of the brain to light up on a scan.

The brains of synesthetes are also anatomically distinct. If you did a neuroimaging study of Liszt's or Rimsky-Korsakov's brain, you would likely find increased volume of both gray matter (made up largely of nerve cell bodies and glial cells) and white matter (the cells' wirelike axons that carry the brain's signals) in the areas involved in hearing and color. A 2013 MRI study of 10 people with sound-to-color synesthesia and 10 nonsynesthetes found just that. Compared with the controls, the synesthetes had more white matter between visual and auditory areas of the brain, indicating greater connectivity between the two regions.

Other studies have shown more widespread changes—particularly increased gray matter—in the frontal and parietal lobes of synesthetes, which are considered higher-level brain regions involved in cognition. Given these findings, it is possible that people have a general predisposition to synesthesia rather than a propensity toward just one particular type, whether it is seeing the letter A in red or tasting blue in beef. And this predisposition may be linked to the unusual connectivity in a synesthete's brain—although it is hard to draw a causal conclusion. “It's not entirely clear whether having synesthesia causes altered neural pathways or whether altered neural pathways cause synesthesia,” says Duncan Carmichael, a psychologist at the University of Sussex in England. “It's probably a bit of both.”

Indeed, research confirms that synesthetic experiences are, to some extent, learned [see “So, You Want to Be a Synesthete?]. “We first have to know that A is A and B is B, before we can actually have consistent color experiences with these letters,” says psychologist Nicolas Rothen of the University of Bern in Switzerland. “I could very well imagine that there is a genetic basis that provides a threshold for how much learning needs to occur for someone to get these experiences. For some people it might be very easy to acquire synesthesia, and for other people it might be entirely impossible.”

On a Blue Day

One hint that synesthesia's unusual neural architecture is partially inborn comes from genetics. If there is one synesthete in your family, as many as 40 percent of your first- and second-degree relatives most likely are synesthetes, too. What has been tricky to figure out, at least until recently, is how synesthesia gets inherited and which particular genes are responsible for the ability to, say, perceive the letter K as a huckleberry hue.

The good news is that as the costs of genome-wide studies go down, it becomes easier for researchers to explore the genetic basis of synesthesia. In 2009 a group of British and Italian scientists led by geneticist Julian Asher, then at the University of Oxford, published the first such study. The researchers took DNA samples from 196 synesthetes in 43 different families. Comparing genomes, they confirmed that synesthesia is indeed heritable but did not pinpoint one specific synesthesia gene. Instead Asher and his colleagues linked many different genes to synesthesia, bolstering the idea that some people may have what scientists call a “synesthesia genotype,” a general predisposition stemming from multiple genetic characteristics.

Some of the genes that the researchers identified were found on chromosome 2. These areas were notable because they are also where you can find several genes involved in neural connectivity in the brain. A similar investigation, published in 2011 by researchers at the Baylor College of Medicine, the University of Alabama at Birmingham and the University of Texas Medical School at Houston, showed that genes associated with synesthesia may also be found on chromosome 16, in a region linked to abnormal neural connectivity. Taken together, the two studies suggest that the unusual brain connections of synesthesia most likely involve a genetic component.

In 2015 a team of researchers in Australia asked six synesthetes to illustrate the visual experiences they had in response to a caramel odor (top) or a burnt smell (bottom). Credit: FROM “CHOCOLATE SMELLS PINK AND STRIPY: EXPLORING OLFACTORY-VISUAL SYNESTHESIA,” BY ALEX RUSSELL ET AL., IN COGNITIVE NEUROSCIENCE, VOL. 6, NOS. 2–3; 2015

In addition, the 2009 genome-wide analysis linked synesthesia to a variant on the long arm of chromosome 2, previously implicated in autism. That connection could help explain the famous case of Daniel Tammet, a 37-year-old British man who not only has been able to recite pi to 22,514 decimal places but also managed to learn conversational Icelandic in just one week. Tammet has both autism spectrum disorder and synesthesia. He sees numbers as having colors, sounds and textures. In his memoir Born on a Blue Day, he writes that number 1 is “a brilliant and bright white, like someone shining a flashlight into my eyes. Five is a clap of thunder or the sound of waves crashing against the rocks. Thirty-seven is lumpy like porridge, while 89 reminds me of falling snow.”

Tammet's case was among the first to inspire scientists, such as Simon Baron-Cohen, a developmental psychopathologist at the University of Cambridge, to inquire into the possible links between autism and synesthesia. The conditions share a few resemblances: both are characterized by neural hyper-connectivity, and people with both conditions are more likely than the average individual to have perfect pitch (the ability to instantly name and recognize musical notes).

In 2013 Baron-Cohen and his colleagues found that in a sample of 164 adults with autism and 97 without, there were almost three times as many synesthetes among people with autism as in the second group. Later that year a team of scientists, including neurobiologist Janina Neufeld, then at the University of Reading in England, had similar findings. The prevalence of grapheme-color synesthesia among those on the autism spectrum could be as much as 31 percent higher than in the general population. “If certain genes involved in local brain connectivity are different in a person, he or she might have an increased likelihood to develop both conditions,” Neufeld says. She adds that for autistic people, who often have a strong drive to systemize things, synesthesia could help them “make sense of the world.”

Unfriendly Mrs. Monday

In 2008 a woman from Edinburgh participated in one of Carmichael's experiments on synesthesia. She had several variants, including sequence-personality synesthesia (in which one might feel, for example, that Mondays were female and unfriendly). During the study, she underwent an MRI scan, which was then examined by a radiologist. The results were troubling. She had white matter lesions suggestive of multiple sclerosis (MS).

In 2015 Carmichael and his colleagues published a review of various studies on synesthesia in which MS-like lesions had been detected. Admittedly, the overall number of cases was tiny—just three among 234 synesthetes. But that gives a prevalence of 1,282 in 100,000 people, which is nine times higher than what is usually found in the general population. It is possible that MS, which damages the myelin that insulates nerve fibers, could contribute to sensory changes that mimic synesthesia's effects.

MS is not the only malady linked to synesthesia. In 2012 scientists at the University of Manchester in England published a study of 200 patients with irritable bowel syndrome (IBS) and the same number of control subjects. It showed that 9.5 percent of IBS sufferers experienced synesthesia versus just 3 percent in the control group. One patient remembered attending a concert as a child and telling her mother afterward how much she liked the colored laser show that accompanied the music. The mother was baffled. There had been no laser display. The light show was a product of her daughter's synesthesia.

Some migraine sufferers also experience such colorful displays. The connection could be explained by the fact that both people with migraines and those with synesthesia often have what scientists call hyperexcitability of the visual cortex. If you stimulate their brain with a magnetic field by placing a special generator near their head, they will experience visual illusions.

A 2015 study, which analyzed 161 female synesthetes and 92 female nonsynesthetes, showed that migraine with aura (a painful headache preceded by symptoms such as light sensitivity or hallucinations) may be associated with certain types of synesthesia, such as those connected to touch, taste, emotion and personality. According to the study's lead author, Clare Jonas of the University of East London, the aura could be a type of synesthetic experience in itself: “One possibility is that you have some visual disturbance that most people don't have and your synesthetic response to it is a headache, so aura causes pain.”

Inspired by such curious overlaps, Carmichael and Julia Simner, a psychologist at Sussex, have proposed an explanation for how synesthesia comes about. Autism, IBS, migraine and MS are all conditions in which immune system dysfunction plays a role. According to their “immune hypothesis,” synesthesia may arise from a variation in immune-related genes, which in turn results in changes to the brain's connectivity.

Broadly speaking, immune system proteins have a different function in an adult than they do in a developing baby. In adults, they generally tag pathogens so that white blood cells can remove them. But in small children, some of these immune proteins tag brain synapses for removal instead. “When you are born, your brain is essentially like a big block of stone that needs to be sculpted. You have far more synapses and far more connections than you end up using,” Carmichael explains. This abundance of connections sounds like a good thing—but that kind of brainpower comes at a cost, in this case, high-energy consumption. For the sake of efficiency, we have to lose a lot of connections that are not regularly used, a process known as synaptic pruning.

If the immune system proteins do not function properly and do not prune enough synapses, we are left with extra connectivity between brain regions, which could in turn lead to synesthesia. In fact, the two genome-wide studies pinpointed regions of chromosomes that also contain immune function genes.

Does that mean synesthetes should worry about developing migraine or immune disorders such as multiple sclerosis? “Not on the basis of the evidence we have now,” Carmichael reassures. “Just like being a man or being a woman makes you more susceptible to certain medical conditions, being a synesthete might change your risk profile in terms of getting certain medical conditions—but whether this is true, it's too early to say.”

Bern's Rothen, for one, believes that we need to see if large investigations, involving thousands of synesthetes, confirm the high prevalence of immune disorders among such people. “A lot of studies so far have been based on very small samples, so we need to be cautious,” he says.

Matters of Immunity

The immune hypothesis fits into a larger revolution in neuroscience. For decades scientists saw the brain and immune system as distinctly separate entities. Thanks to the powerful blood-brain barrier, the thinking went, the two could not interact. But increasingly, scientists are tearing down the old divide. The central nervous system is not exempt from immune effects. Instead immune proteins play a part in brain development and maintenance.

Even if synesthesia is a by-product of immune-related genes underpruning the brain, it is a positive by-product. Rothen has found a link with a specific profile of enhanced memory, for example, and other studies show synesthetes can be more creative and have improved color perception.

From an evolutionary perspective, all of this shows how synesthesia may have come in handy over the generations. If you were picking berries in a Paleolithic forest, being able to differentiate one type of fruit from another by their shade may have been a matter of life and death—and detecting extrasensory cues would be advantageous. Nowadays, Neufeld says, synesthetic experiences could help us “memorize things like color coding a pin number.” By that logic, “brilliant white of a flashlight, thunderclap, lumpy porridge” could be the buzzer code for a friend's front door and “huckleberry, mother-of-pearl, vulcanized rubber” might serve as the perfect password.