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LAB-GROWN MINI BRAINS

HOW EMOTIONS WORK

CRIMINALITY AND BRAIN INJURY BRAIN COVERNEUROSCIENCE STORY

UNLOCKING THE SECRETS O F T H E BRAIN

From autism and schizophrenia to Alzheimer’s, lab-grown mini-brains could be the key to solving the biggest mysteries about human development and disease WORDS: KAT ARNEY ILLUSTRATION: MAGIC TORCH �

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One of Madeline Lancaster’s cerebral organoids, seen here in cross-section

vessels, which tacks of little plastic dishes in a limits how big laboratory incubator, each one they can grow. holding a free-floating blob of Organoids are also might sound like remarkably hardy, as the stuff of science fiction. But long as they’re grown S this is no futuristic flight of the in a scrupulously clean : these strange environment, and can stay creations, known as brain organoids, are already alive for more than a year. being cultivated in labs all over the world, and Lancaster’s mini-brains are researchers believe they could unlock some of the enabling her to prise open the deepest secrets of how our brains grow and what ‘black box’ of human brain happens when they go wrong. development. Because they reflect “I don’t think that any of us set out to try and the cell types and organisation of a grow a brain in a dish,” says Madeline Lancaster, a growing human brain, organoids neurobiologist at the MRC Laboratory of Molecular are opening a window into Biology in Cambridge. “If you’d asked me even just a time of life that has few months before I started working on it, I would A bright-field previously been inaccessible microscopic image have said it was completely nuts – but in my case, it of a cerebral organoid. to science. was an accident!” In real life, this “People have done MRI ‘mini-brain’ is Lancaster’s accidental experiments with organoids 1cm across scanning on children and started when she was a postdoctoral researcher even babies to and look how working in Vienna with molecular biologist Jürgen the brain wiring changes, Knoblich, investigating how the brain forms during but when it comes to those development in the womb. She started by growing early events – how neurons brain stem cells in flat layers in a dish, but soon are made, how many, which realised they lacked many of the key characteristics ventricles that connect the hemispheres of the Cambridge types and where – we can’t of nerve cells in a real brain. In search of a better cerebral cortex in a real brain. Even the layers of neurobiologist answer them, no matter how Madeline Lancaster method she tried a new technique for growing neural cells mimicked the arrangement in normal brain was the first person good our MRI machine is. But I ‘rosettes’ – flat, flower-like circles of cells that were tissue, with stem cells lining the ventricles and to start growing think what’s happening in these more realistic, albeit still two-dimensional. layers upon layers of more specialised cells and ‘mini-brains’ dishes reflects what’s happening in an “When I put the cells in the culture dish, there was neurons built up towards the outside. actual embryo. We know this because the something wrong with the reagents that I was using,” end product looks like a lot like a real brain, so we she says. “Rather than forming these nice flat BUILDING A BRAIN have a tractable system to start asking some of these rosettes, mine were forming these weird, floating Despite their ‘mini-brain’ nickname, these organoids fundamental questions about brain development.” balls. I thought they looked interesting, so I are a long way from being full-size human organs. Lancaster is also using her mini-brains to answer continued growing them.” They’re around half a centimetre in diameter – an even deeper question: what makes a human brain Speaking to other researchers in the field, she roughly the shape and size of the eraser on the end of human? We share more than 95 per cent of our DNA discovered that some of them had also seen these a pencil – and they lack key structures such as blood with our closest primate relatives, such as strange blobs, but had chimpanzees, but our brains are much bigger and thrown them away because undoubtedly different. By comparing brain they looked wrong. But organoids grown from chimp stem cells with those while these brain balls “Despite their ‘mini-brain’ from humans, she and her team are watching how looked curious from the these differences emerge from the earliest stages of outside, what Lancaster The process development. There’s even the possibility of using nickname, these organoids are a of building a found inside was ‘mini-brain’ starts new genetic engineering techniques to switch fascinating. Each was made with a genetically human and chimp genes around in mini-brains – from bulging layers of cells modified human something that would be impossible to do in living long way from being full-size skin cell connected by cavities, just animals – to pin down the precise molecular

like the fluid-filled human organs” PHOTOS: MRC-LMB, SCIENCE PHOTO LIBRARY pathways that make the human brain so special. 2

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2 The brain-like appearance of these organoids is why?,” he asks. “Unlike cancer biologists, who can take raises ethical as well as scientific questions. Can out a tumour, put it in a dish and find ways to treat it, we they think, and are they conscious? According to cannot do that with the brains of our patients with Lancaster, the answer is almost certainly no. mental disorders!” “I think of them as being a bit like brain tumours,” Pasca and his team have managed to grow she says. “Tumours contain many more neurons mini-brains for more than two years – a staggering than our mini-brains in a dish, but no one is 800 days is their current record – and shown that concerned that their brain tumour is thinking or has they can generate most of the same cell types and consciousness, and nobody is sad that it has been structures found in real human brains. They’re taken out and thrown away. That’s what we have using the technique to investigate the roots of here. It’s not an organised network, and it cannot severe autism and epilepsy syndromes, by make a functional thinking circuit – it’s a ball of generating organoids with IPS cells derived from brain tissue, and just because you have neurons skin samples of affected children and then doesn’t mean it can think.” carefully comparing them with cultures grown Today, she and her team are growing mini-brains from healthy cells. from human embryonic stem cell lines – the multi- “We can use electrodes to measure how the purpose cells originally found in very early human cells are talking to each other, and microscopy embryos, but now cultivated in the lab. She’s also to see how the cells move and make using so-called induced pluripotent stem (IPS) cells: connections with each other,” he explains. adult cells that have been pushed back to an “Many of the genes associated with these embryonic state with a cocktail of molecules first disorders are involved in the connections discovered by Nobel Prize-winning Japanese between nerve cells, so we can see how the scientist Shinya Yamanaka. Depending on the exact gene changes in these patients are impairing conditions used, Lancaster can nudge her organoids the communication within the brain in a to develop all kinds of cells, from the fluffy choroid non-invasive way.” plexus (which would connect with blood vessels in a He’s now taking these ideas even further, real brain) to pigmented light-sensing cells that are sticking together organoids that mimic usually found in the at the back of the eye. different regions of the brain and studying “There’s just so many cell types to look for,” she their interactions – a technique he describes says, “But depending on the method we use, every as ‘brain Lego’. The team is using these time we look for something that we know should be hybrids to spy on the brain as it wires itself there, we find it.” up, focusing on what happens to so-called inhibitory neurons that normally help to calm WIRING UP down brain activity but are faulty in people Mini-brains don’t just allow researchers to study with epilepsy and autism. normal developmental processes. Sergiu Pasca, “Inhibitory neurons are not born in the cortex Assistant Professor of Psychiatry and Behavioural on the surface of the brain: they are born in a Sciences at Stanford University in California, is very deep region of the and have to using them to understand what goes wrong in migrate millimetres over many months after autism, schizophrenia, epilepsy and other birth,” Pasca says. “It’s really fascinating to watch neuropsychiatric disorders. in our cultures – they kind of pull themselves up “Most of the psychiatric drugs we have today have and jump along.” been discovered by chance – we know very little But when Pasca and his colleagues looked at about the origins of these disorders and the question organoids grown using cells from patients with a 2

“Pasca and his team have managed to Sergiu Pasca holding ‘mini- brains’ used to study the development grow mini-brains for more than two of conditions such as autism years – a staggering 800 days is their

current record” SHUTTERSTOCKPHOTO: �

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coming to the scene of a crime after Selina Wray at work in her the criminal is gone, and you’re trying “Mini-brains mimic the very laboratory to piece together a sequence of events at University by looking at the damage that’s been left. College London earliest stages of life, while I want to build models in the lab which will let us look at the very beginning of the dementia is a problem that disease – because if we understand the first things to go wrong, that’s when treatment should be more effective.” takes decades to develop” In a similar way to Pasca and Lancaster, she’s taking samples of skin from patients with dementia, turning them into IPS cells and then “I feel excited by the idea of personalised 2 form of autism that is growing organoids. Wray can spot differences medicine – that you could take somebody’s cells and associated with epilepsy, they compared with organoids from unaffected people grow organoids in the lab, screen a panel of drugs saw a very different picture. The after just a few months, finding increased levels of against them and say, ‘Okay, we think this person inhibitory cells were moving in a the forms of certain molecules that are associated will respond to drugs ABC, but this person will very peculiar way, jumping more with Alzheimer’s disease. respond better to drugs XYZ,’” she says. “That’s often but less efficiently and However, there’s a problem with this approach: happening in cancer biology, this idea of being able One of the cerebral eventually getting left behind. mini-brains mimic the very earliest stages of life, to stratify patients on a molecular basis, and while organoids used by Impressively, the researchers were while dementia is a problem that takes decades to I think we are a long way off, I love the idea of Sergius Pasca in his research into then able to identify a drug that could develop. To solve this, researchers are working on growing someone’s neurons so we can work out neuropsychiatric rescue these lagging cells, correcting the clever hacks to speed up the ageing process. One what therapies we should be giving them.” disorders wiring defect and pointing towards a idea is to add in genetic changes that mimic Sergiu Pasca is similarly enthusiastic about the potential future treatment for children progeria – a rare disorder that causes dramatic potential of mini-brains to change lives. suffering from the same condition. premature ageing. Another approach is to meddle “Our organoids are grown from cells taken from with the structures protecting the ends of DNA real patients,” he says. “These kids have severe INTO OLD AGE inside cells, known as telomeres, which act as a neurodevelopmental disorders that really impair Meanwhile at University College London, kind of countdown clock as we age. their lives, and to think that a few months later you neurologist Selina Wray is using brain organoids to As well as studying the underlying processes that can derive brain tissue from those patients in a dish An X look at neurodegenerative conditions that start at drive dementia, Wray thinks that mini-brains have and start asking questions about how the disease may chromosome: the red areas at the other end of life, including Alzheimer’s disease a lot of potential for helping to identify the right arise – that’s what makes this exciting.” the end of the ‘arms’ and fronto-temporal dementia. treatment for individual patients. are telomeres, which “Normally we have to work with post-mortem Kat Arney is a science writer and broadcaster. Her latest book is play a role in ageing brain tissue from patients, but you’re only ever How To Code A Human. She tweets from @Kat_Arney

looking at the end stages,” she says. “It’s almost like PHOTOS: UCLA, SCIENCE PHOTO LIBRARY, CHARLIE ARBER & CHRIS LOVEJOY/UCL

ALL THE ORGANOIDS It’s not just brains: researchers GUT LUNG BREAST THYMUS HEART Scientists have made are creating three-dimensional Although they’re a long Mammary organoids The thymus gland is the Cardiac organoids are organoid versions of many organoids from many different way from a ‘lung in the lab’, grow the same branching place where infection-fighting revealing hidden regenerative parts of the gastro-intestinal types of tissue, not only to study lung organoids grown using structures that are seen in immune T-cells mature. Thymus pathways that could be tract, from taste buds to the healthy development but also to reprogrammed stem cells from human milk ducts. Because many organoids can produce functional reactivated to treat heart disease. intestines and stomach. Intestinal discover what happens when patients with diseases such as breast cancers start from such human T-cells, which could Researchers also created organoids can be manipulated to things go wrong and to develop chronic asthma and cystic ducts, these organoids are potentially be used to restore organoids with functional, produce insulin, suggesting future therapies. Here are some fibrosis could be useful providing vital insights the immune system in beating chambers, as a possible future treatments of the types they’ve managed to models for finding new into tumour growth. transplant patients. model for studying for diabetes. grow so far… treatments. heart failure.

8 9 COVER STORY

HOW EMOTIONS TRICK YOUR BRAIN

What if happiness doesn’t really exist? New research is uncovering that the way we think about emotions doesn’t match up to what neuroscientists are seeing in our brains and behaviour…

ILLUSTRATION: MAGIC TORCH WORDS: DR LISA FELDMAN BARRETT �

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ow do emotions work? This might “Ifaluk people have an seem like an odd question since emotion, ‘fago’, that can we all experience emotions every day: happiness mean love, empathy, pity, at seeing an old friend, sadness sadness, or compassion” while watching a tragic film, fear of losing the ones way. Your heart raced, your blood pressure soared, we love. Emotions seem automatic. Your heart and your face formed an expression of fear that’s skips a beat, your nerves do a little dance, your said to be universal across all human cultures. Hface moves in familiar ways, and you are carried In this classical view of emotion, the firing fear away by the experience. Nevertheless, from a circuit, the bodily changes, and the facial expression scientific standpoint, what are emotions really? supposedly form a distinct, detectable ‘fingerprint’ For centuries, famous thinkers like Plato, that distinguishes fear from all other emotions. Aristotle, Darwin and Freud, as well as countless BELOW: The That fingerprint was presumably passed down to amygdala is other scientists, have tried to explain emotion involved in humans through evolution, along with fingerprints using common sense. Emotions feel natural and thinking, for other emotions. memory, uncontrollable, the reasoning went, so they surely empathy and must be built into us from birth. In recent years, emotion. It is CHANGING TIMES however, the field of neuroscience – the study of seen here as As compelling and intuitive as the classical view two orange how the human brain creates the human mind – has structures, may be, it can’t possibly be correct. Scientists have surged. With this interest has come intense research connected to the been searching for emotion fingerprints in the and renewed debate on the nature of emotions. hippocampus face, body and brain for over 100 years without A few decades ago, scientists could success. Occasionally, you’ll see a news story that only guess how the brain creates scientists have found fingerprints of happiness, our emotional experiences. sadness, anger, fear, or other emotions in humans Now, though, we can or other animals, but when other scientists retest use brain-imaging to those claims, they invariably don’t hold up. For harmlessly peer inside example, for many years, scientists believed that a head. This allows the brain’s ‘fear circuit’ was a region called the us to observe neural amygdala. If you google ‘amygdala fear’ you can activity, moment by still find thousands of articles that make this moment, inside living claim. Nevertheless, it’s not true. We now know angry. Another study on babies showed that their ABOVE: The simply perceive the person is laughing. They don’t Himba people people. And when definitively that some people who lack an amygdala facial movements are pretty much indistinguishable do not associate perceive laughter in mental terms. Throughout the it comes to emotion, can still feel fear. Not only that, but the amygdala in fear and anger. No emotion has a single fingerprint laughter with an world, the sheer variety of emotional life is vast what we see in those is involved in dozens of other mental functions in the body. Instead, variety is the norm. emotion – they – too vast to be explained by the classical view. Amygdala simply perceive brains seems to defy location (such as thinking, memory, empathy and all other Not only that, but different cultures have different the person as common sense. Emotions emotions), so it’s clearly not a fear circuit. The same emotions. For example, the German language laughing SO, HOW ARE EMOTIONS MADE? are not what most people is true of every other brain area that has ever been contains three distinct angers with different The answer of how emotions are made flies in think they are. claimed as the home of an emotion. meanings, while Russian has two and Mandarin the face of common sense, because the human Here’s what I mean. Suppose The main problem with the classical view has five. Plenty of cultures have emotions that brain is a master of deception. Like a magician, you’re walking in the woods of emotion is that emotional life has too much don’t translate into English. The Ifaluk people of it creates incredible experiences as diverse as and you see a bear, and you variety to be shoehorned into a bunch of universal Micronesia, for example, have an emotion, ‘fago’, joy, envy, curiosity and wrath without revealing instantly feel afraid. What fingerprints. Do your eyes widen every time you’re that can mean love, empathy, pity, sadness, or how it does so. But thanks to recent advances in happened inside you? The afraid? Do you always gasp? Of course not. People compassion, depending on context. Even more brain imaging, which allows scientists to observe traditional explanation goes who feel fear might scream, cry, laugh, close their intriguing, some cultures don’t have a unified a living brain as it thinks, feels, and perceives its like this. As soon as you saw the eyes, clench their fists, wave their arms, strike out, concept of ‘emotion’ for the events that Westerners surroundings, we now have a pretty good idea of bear, some dedicated part of you faint, or even stand motionless. We also smile only experience as emotional. One example comes the brain’s secret technique for making emotion. – like a ‘fear circuit’ in your brain – about 12 per cent of the time when we’re happy, from the Himba people of Namibia. When you Your brain’s most important job is keeping your sprang into action, triggering your according to a recent statistical analysis of many see somebody laughing, you might perceive that body alive. To accomplish this, it devotes most of

body to react in a predetermined studies, and scowl 28 per cent of the time when GETTY X3 they’re happy or amused, but the Himba would its time to predicting what will happen next, so 2 �

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“When walking in the woods, your brain issues thousands of predictions process that nobody understands, brain predicted someone you know, based on past physical movements inside your experience, and just for a second, you saw them. body become mental. You feel in every moment, based In short, emotions are your brain’s best guesses generally pleasant, unpleasant, for what your body’s sensations mean, based on or anywhere in between. You on past experience. So, if your situation. When your face feels hot as a feel calm or agitated. Your mood driver cuts you off in traffic, you might experience is like a barometer for the health the heat as anger. If you feel the same hot face of your body. It’s with you every a bear shows up, you’re when you’re inches away from having your first moment of your life, though much kiss, you might experience it as excitement. Or of the time it’s in the background already starting to run if you feel the same sensation as you walk out and you don’t notice it. of the sea and realise your swimming costume This same process produces and experiencing fear” has fallen down, you might experience it as 2 your emotions completely outside your awareness. Let’s go back to our ‘bear in the woods’ example. When you’re walking in the woods, your brain ABOVE: Brain 2 your body can be ready for any issues thousands of predictions scans show contingency. Studies show that in every moment, based on regions of increased your brain spends 60 to 80 per past experience. It anticipates each activity, which cent of its energy on prediction. In step, the crunch of the dry leaves allows every moment, your brain issues underfoot, and the look of the scientists to improve their thousands of predictions at a time, greenery above you. It forecasts understanding based on past experience, and the the heart rate and breathing of emotions. Here, the ones that win are (usually) the ones that you’ll need to keep up the subjects (male that fit the situation in the next pace. Your brain even issues on the left, moment. When you walk, for example, each time predictions about animals appropriate to the female on the right) are you lift your foot to take the next step, your brain setting, such as bears, and prepares your body to experiencing anticipates how your foot will land. If your brain deal with them. It sends signals to your heart to jealousy, gets this wrong, you might trip. If you’ve ever beat faster, your lungs to breathe deeper, and so on, and the hypothalamus been in an airport on a moving walkway, and and prepares your body to run. At the same time, is glowing red have stumbled as you stepped off (or the last step your brain guesses how you will feel in a moment RIGHT: Your just feels weird), you know how prediction error from now when you start running and produces an brain makes feels. Your brain also makes predictions about agitated mood. This entire collection of predictions predictions other people in the world. Studies show that when comes from your past experiences of fear. So, if based on past experiences. you meet strangers, you like and trust them more an actual bear shows up in the next moment, But it can get it when their facial movements (like smiles or scowls) you’re already starting to run and experiencing wrong, which is match your brain’s guesses. Remarkably, you even fear. That’s why fear feels so automatic in that why you may stumble when consciously see their face more quickly! situation, like a reflex. Your brain explains your stepping off Along with predictions about the world, your body’s sensations and launches your movements a moving walkway. The brain also makes them about your body so you before you’re consciously aware. same can stay alive and healthy. It forecasts when your heart happen with should speed up or slow down, when your blood MORE THAN A FEELING your emotions pressure should rise and fall, when your breathing But what if there’s no bear? That’s a prediction should deepen, and when you need more salt, error, and you’ll be left with an agitated feeling sugar, water or hormones, and attempts to meet with no apparent cause. If you’ve ever walked in those needs before they arise. It’s like running a the woods at night and have suddenly startled for budget for your body, but instead of money, the no apparent reason, you’ve experienced this. There’s currency is biological. even a curious third possibility that there’s no bear This budgeting process continues through present, but you see a bear anyway, for a moment. your entire life, and most of the time, you aren’t You’ve probably experienced this too. Have you aware of it. But it produces something you know ever seen a person that you thought you knew,

well: your mood. Somehow, through a mysterious but then realised it’s a stranger? Same thing. Your GETTY X2, SCIENCE PHOTO LIBRARY �

14 15 COVER STORY Dictionary corner When you take a look at some of the words used around the world to convey emotions, the traditional concepts of ‘happy’ and ‘sad’ start to look a little one-dimensional. Lisa Feldman Barrett’s lab has started collecting these ‘untranslatable’ words to start a new kind of dictionary. Here are 10 of our favourites. You can find an interactive index of more these words at bit.ly/emotion_dictionary

Jayus. Indonesian / n. / gah-yoose. Age-otori. Japanese / n. / (archaic) A joke that is so unfunny (or told so badly) aa-gey oh-toh-ree. To look worse after a and anxiety are often viewed as ailments of the that you just have to laugh. haircut; styling one’s hair for a mind. But we now know that your brain constantly ~ coming-of-age ceremony, with the regulates your body budget, and when the budget’s Lekker. Dutch / adj. / leh-ker. contrary effect of making oneself look in the red, you feel bad. This suggests that problems Tasty (food); relaxed, comfortable; worse than before. with metabolism, traditionally associated with pleasurable; sexy. ~ the body, are at the core of mood-related mental ~ Mamihlapinatapai. Yaghan / n. / illnesses such as depression and anxiety. It also Gezellig. Dutch / adj. / khe-zell-ikh. ma-mey-la-pin-ought-ta-pay. A look helps explain why physical illnesses like diabetes Cosy, warm, intimate, enjoyable; often a shared by two people, each wishing that and heart disease have persistent mood symptoms. shared experience (with close others). the other would initiate something that The boundary between the physical and the mental ~ they both desire but which neither wants is more porous than previously thought, and Njuta. Swedish / v. / nyoo-ta. to begin. understanding this is key to finding new pathways To deeply enjoy, to profoundly appreciate. ~ for prevention and treatment. ~ Shinrin-yoku. Japanese / n. / shee-n Bēi xî jiāo jí. Chinese / n. / ree-n yoh-koo. Taking in the forest NEW OUTLOOK bay-shee-jeeow-jee. Intermingled atmosphere; forest bathing. This new view of emotion suggests something feelings of sadness and joy. ~ important about artificial intelligence. Is it possible ~ Daggfrisk. Swedish / n. / adj. / to build a machine that can read people’s emotions? Fernweh. German / n. / fiern-vay. daag-frisk. ‘Dew fresh’; the kind of pure, Companies such as Facebook, Google, and Microsoft Far/distant pain/woe. The ‘call of faraway clean feeling one might have from waking are betting that the answer is yes. They’re spending places’; homesickness for the unknown. refreshed in the early morning at sunrise. millions of research dollars to detect emotion via software, by examining faces and bodies as their owners experience emotion. But emotions aren’t readable in the face and body alone, because 2 embarrassment. Your brain makes meaning emotions. I’m not saying this is easy, but it’s possible. emotions have no fingerprints, and variety is the from the identical sensation in different ways, Changing your body budget is the most norm. This means these approaches are asking depending on context. That’s how emotions are straightforward of the three (but again, not easy). fundamentally the wrong questions. Tech companies made. They are not built-in at birth. They are built Eat healthily, get enough sleep, and exercise must include more data about a person’s context, in the moment. regularly, and your brain won’t have to work as hard and embrace the variation in real emotion life. In a sense, your emotions are constructed to keep your body budget in balance. That means ABOVE: Your constructed all sorts of negative explanations that A tougher question is, can we build a computer unconsciously from three ingredients: your body your mood will be less negative and your brain brain has to are deeply personal. To deal with these feelings, we that can feel emotion? Our new view of emotion constantly budget, your current situation, and predictions will have fewer opportunities to create unpleasant balance your took inspiration from the real flu. The influenza offers an intriguing possibility. If emotion is from past experience. If you modify any of these emotions. You can change the second ingredient, body’s budget to virus isn’t personal – it simply takes up residence constructed in part by regulating a body budget, then keep you ingredients, you can take some control over your your current situation, in a variety of ways. You healthy. If in your lungs. Likewise, we worked hard to view for a machine to experience emotion, it must have can directly adjust your surroundings by moving things get out of the wretchedness as purely physical, and to treat something like a body. Not necessarily a human-like to another location, like leaving the room or taking whack, it can the symptoms with naps, walks, exercise, hugs, body, but a set of complicated, interacting systems impact your a walk. If that’s not possible, you can indirectly mood and create or whatever works. By repeatedly reframing the with energy needs that must be kept in balance. (No “Eat healthily, get change your surroundings by paying attention to bad emotions. situation from personal to physical, my family and doubt some clever AI programmers can figure out other things around you – that is, being mindful. Eat healthily, I changed our brains’ future forecasts, making it a solution.) This will bring us closer to creating a get enough enough sleep, and The third ingredient, your predictions from sleep and easier to create the non-personal, non-judgmental, machine that can feel and be empathetic. past experience, is the toughest to alter because exercise emotional flu. This was challenging to do at first, regularly to give it’s impossible to change your past. Yet if you take your brain a but it got easier with practice, and we’ve passed exercise regularly, and action in the present, you can modify your brain’s helping hand the idea along to friends who have also succeeded. predictions in the future, changing your future I’m not saying you can tweak a few predictions and Dr Lisa Feldman Barrett(@LFeldmanBarrett) is a ABOVE LEFT: your brain won’t have emotions. For example, in my family, we came up Typical images cure a serious disorder like anxiety or depression, psychologist and neuroscientist, and the author of with an idea we call the ‘emotional flu’. Have you used in the lab but it’s possible to make tangible improvements How Emotions Are Made: The Secret Life Of The Brain. ever felt wretched, like you’re a horrible person, to test our in your life. That said, this way of thinking about to work as hard to keep perception of DISCOVER MORE everybody hates you, and the world is going to emotions emotion does have implications for understanding end… but in fact, there’s nothing actually wrong mental illness. For hundreds of years, people have Listen to an interview with Dr Lisa Feldman Barrett your body budget with your life? That’s the emotional flu – you’re drawn a boundary between mental and physical don the Science Focus podcast. Visit sciencefocus. having an unpleasant physical feeling, probably illness. Cancer, heart disease and diabetes are com/sciencefocuspodcast or subscribe on iTunes, Acast,

in balance” from a disrupted body budget, and your brain has DR LISA FELDMAN BARRETT X4, GETTY seen as disorders of the body, while depression Stitcher, or your favourite podcast app. �

16 17 COVERPSYCHOLOGY STORY

MY BRAIN MADE ME DO IT A growing body of research has found that head injury can make people more prone to criminal behaviour… WORDS: LINDA GEDDES

he tumour growing in the compulsion to act upon his sexual urges front of the schoolteacher’s – was new. It was certainly plausible, brain was the size of an his doctors concluded. The tumour was T egg. It was the likely source growing in the right lobe of his orbitofrontal of his recent headaches, cortex, which is a brain area linked to balance problems, and difficulties writing social behaviour, judgment and impulse and drawing. But these symptoms paled control. Once the tumour was removed, in comparison to the personality change his deviant urges apparently disappeared, that the tumour apparently brought about. and his drawing, writing and balance Several months earlier, the man had been improved. He successfully completed a arrested after making sexual advances Sexaholics Anoymous programme, and towards his prepubescent stepdaughter; he was allowed home. But the following year, had also amassed a trove of pornography, he began secretly collecting pornography including indecent images of children. again, and a brain scan showed the tumour He knew his urges were unacceptable, was regrowing. Once more, he underwent yet claimed that his ‘pleasure principle’ surgery to have it removed. overrode his restraint. He also insisted We often assume that paedophiles or 2 GETTY that this interest in children – and his people who commit other atrocious

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18 19 COVER STORY

2 acts are nothing like us; they were either born BOTTOM: Phineas Gage its constituent parts. For instance, the frontal lobes bad or became that way because of maltreatment survived after an iron rod – which include the orbitofrontal cortex, where COULD VIRTUAL REALITY (held by Gage in this image) during their own childhood. Increasingly though, was blasted through his the schoolteacher’s tumour was growing – sit just brain injury – caused by a blow to the head, a brain. His skull (below) is on beneath the forehead and are thought to be where HELP CURE BAD URGES? display in Harvard Medical stroke, or a tumour pressing on neighbouring brain School. The hole is where the many higher functions such as planning, problem tissue – is being recognised as another factor that iron rod exited through the solving and decision-making take place. These can predispose to or trigger criminal behaviour. top of his skull regions also regulate impulses and social behaviour. Inside a small room at a high stimulus than using 2D pictures.” Sometimes these injuries bring about personality Craig and his colleagues have also studied the brains security hospital in Montreal, He believes virtual reality could changes so obvious that they raise immediate alarm of people with seemingly more innate antisocial Canada, synthetic animations of also play a role in the rehabilitation bells, but more often the personality change is subtler, personality traits, such as psychopathy. They naked children and adults are of sex offenders. It could be used to and the brain injury goes undetected. recently discovered abnormalities in the uncinate projected onto a screen. The men teach offenders about how their It’s not only serious crimes like paedophilia or fasciculus – the ‘wires’ connecting the frontal lobe watching them are wired up to brain responds to certain situations, murder that are being linked to brain injury: a recent to the emotion-regulating amygdala – in psychopaths devices that track their eye-gaze, or to help them develop skills study of 613 men who were screened upon admission convicted of violent crimes including rape and the electrical activity of their brains, they’re deficient in, such as to Leeds Prison revealed that 47 per cent of them murder, compared to non-psychopaths. “We found and the flow of blood to their empathy. Already, this is being had experienced at least one traumatic brain injury that it was bumpier or less well-formed than it was penises in order to build up a more tested in the context of domestic – a serious blow to the head where they’d either lost in people who didn’t have psychopathy,” Craig says. accurate picture of their sexual violence. At the University of consciousness or felt very dazed or confused – with The worse their antisocial behaviour, the greater the preferences than they might be Barcelona, first-time offenders most of them being injured before committing their abnormality seemed to be. prepared to admit themselves. undergoing a rehabilitation first offence. Other researchers have reconstructed the injuries Each year, Dr Patrice Renaud and programme are offered a session in sustained by Gage using modern imaging and his team assess some 70 to 80 sex which they embody a female avatar computer software, discovering that he too must offenders this way, to help judges who encounters an aggressive have sustained damage to the uncinate fasciculus, establish the risk they pose to male. He criticises their appearance, “BRAIN INJURY as well as to the prefrontal lobes. The uncinate society before deciding their smashes a phone against the wall fasciculus is composed of white matter, which sentences. For instance, not all child and then advances towards them. coordinates the flow of information between different molesters are sexually attracted to After the session, the perpetrators’ CAN PREDISPOSE brain regions. Some of Craig’s colleagues have children – sometimes their offence ability to recognise signs of fear in also identified abnormalities in the grey matter is prompted by another mental female faces improved. TO OR TRIGGER of psychopaths’ brains, which is involved in the health problem – an important “An important aspect of treating processing of information. “There is a developing distinction to make in terms of their someone is that they will be able to idea that it is not so much one region or another treatment. “Virtual reality enables use the skills you teach them in the CRIMINALITY” [that governs antisocial behaviour], but networks you to simulate every possible real world,” explains Renaud, who of regions that are important,” Craig explains. In context that you could imagine, isn’t involved in the Spanish Not only could the diagnosis of such brain damage the case of the uncinate fasciculus, it forms part which is a major asset when you’re research. “If you learn in virtual result in more effective rehabilitation programmes of the – a network of different brain talking about criminal behaviour,” reality that you can feel something that reduce reoffending, but by studying the affected regions involved in our emotional and behavioural Renaud says. “When the avatar is for an avatar, or that you can’t get brain networks scientists are gaining new insights responses to the world around us. mimicking a child, the individual too close to an environment or a into the nature of criminality itself. If it’s damage to entire brain networks rather that we assess has the impression bad thing will happen, then the than specific regions that matters, this could help of being seated in front of a real trainee is more likely to transfer DAMAGED BRAIN explain a puzzling finding: “As a neurologist, one child, which is more potent as a those lessons into real life.” The idea that brain damage could trigger personality of our dirty little secrets is that often the location of change has a long history. One of the first documented brain damage doesn’t link up with where we think cases was that of Phineas Gage, a 25-year-old American the symptoms are coming from,” says Dr Michael railway construction worker who, in 1848, survived Fox, an associate professor of neurology at Harvard an accident which saw an iron rod driven through his Medical School in Boston, US. Take Broca’s , left cheek and out of the top of his head, destroying a condition in which people struggle to speak much of his brain’s left frontal lobe. fluently, often as the result of a stroke. It is assumed “Gage purportedly changed from being to result from damage to Broca’s area, a region in a relatively nice chap to somebody with more the brain’s left anterior frontal lobe, involved in antisocial personality traits,” says Dr Michael language processing. Yet when you scan the brains Craig, a consultant psychiatrist and reader in of people with Broca’s aphasia, the damage is often forensics and neurodevelopmental sciences at elsewhere. Importantly, these various brain lesions King’s College London. He became stubborn, foul- all connect to the left anterior frontal lobe. mouthed, and quick-tempered; friends said they no longer recognised him as Gage. “From that came the MAPPING THE MIND general idea that there are regions of the brain that, In recent years, Fox has linked many such medical if affected by an injury, surgery or a tumour, can symptoms to different brain networks, using a map actually change someone’s personality,” Craig adds. of the human brain’s connections called the Human Since then, scientists have discovered much more Connectome. More recently, he and his colleagues ABOVE: Offenders can be given a virtual reality avatar to help them develop skills and learn 2 about how the brain works and the relative role of ALAMY X2, WIKIPEDIA COMMONS, DR PATRICE RENAUD turned their attention to criminal behaviour. The more about their brain in a safe environment �

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“VIEWING AN INMATE’S SLEEPWALKING SUSPECTS BEHAVIOUR THROUGH THE Can you be guilty for a murder you committed in your sleep? In 2008, when Brian Thomas strangled his wife, LENS OF BRAIN INJURY CAN Christine, he claimed to have been in the throes of a nightmare about a ‘boy racer’, who he was fighting off BE HELPFUL” after he broke into the campervan that they were sleeping in. At trial, the judge said Thomas bore no responsibility for his actions, and he was released. He was, however, was the underlying reason many of them had previously undiagnosed injuries to advised to seek treatment for his ‘night terrors’; a disorder for their criminal behaviour. their brains. This doesn’t necessarily excuse their bad in which people experience sudden and intense dread However, it doesn’t always behaviour; after all, there are plenty of people with during sleep, and which, in the most severe cases, is work in their favour: in a US brain injuries who don’t commit crimes. “Brain injury associated with injury to themselves or other people. case, a man called Richard does not inject criminality or antisocial behaviour, Thomas was also a frequent sleepwalker. Hodges arrived at court to but what it can do is remove some of the inhibitors,” In such cases, perpetrators can use a legal defence plead guilty to burglary explains Pitman. called automatism, which means they had no control over and cocaine possession, but Even so, viewing an inmate’s behaviour through the their body at the time of the crime. When people are appeared lost, confused, and lens of brain injury can be helpful. “It means that we can sleepwalking, their prefrontal cortex – the area of the asked irrelevant questions. start to look at things much more functionally: not that brain responsible for planning, judgment and impulse This prompted the judge this person is bad, or is trying to upset or annoy you, but control – is effectively sleeping, even though other areas to order a brain scan and actually, perhaps this person doesn’t quite understand are wide awake. neuropsychiatric assessment. what is expected of them, and doesn’t quite understand The automatism defence can’t be used if someone did 2 team searched the medical literature for case ABOVE: White The conclusion: Hodges was faking it. the things that you understand,” says Pitman. matter fibres, as something that caused them to lose control over their reports of patients who had been normal, law-abiding seen in this 3D It also has implications for their treatment. People body, however. For instance, when a British man called citizens until experiencing a brain injury, such as scan, coordinate PRISONS AND PRISONERS with brain injuries can often come across as quite Zack Thompson raped a woman while holidaying in a stroke, brain bleed or tumour, which apparently the flow of Yet research like Fox’s could prompt questions normal during conversation, but they may struggle to information Portugal, his claim that he was sleepwalking was prompted them to start committing crimes. They between different about how to handle criminals with more subtle fully comprehend what people are saying to them. They undermined by the fact that he had drunk seven or eight identified 17 case reports where the brain images areas of the abnormalities in their brain networks – perhaps may also find it difficult to multitask, set goals or make brain. Flaws in pints before falling asleep. were good enough that they could be mapped onto the white matter arising during development, or as a result of childhood decisions – a phenomenon called the frontal-lobe paradox. Human Connectome. Although the damage affected have been linked neglect. “Do we treat them as criminals who need When someone who hasn’t committed a crime different brain regions in the various individuals, to psychopathic to be locked up and isolated from society, or do sustains a brain injury, they will be assessed by a traits their lesions all mapped onto a common network: we treat them as patients in need of treatment to team of psychologists, occupational therapists and one which becomes active when healthy people make improve their symptoms?” asks Fox. physiotherapists to identify such deficits and develop moral decisions, such as whether it’s okay to steal For now, that question remains a largely theoretical strategies to help them function in everyday life. Such a loaf of bread if your family is starving. one: there isn’t yet an effective treatment for adult assessments aren’t usually done when someone is sent Although the schoolteacher’s case wasn’t included psychopathy, for instance. But as we learn more about to a secure hospital or prison, but their treatment and in their analysis, Fox says he is aware of it: “His lesion the changes underpinning antisocial behaviour, the rehabilitation often hinges on psychological interventions location showed exactly the same connectivity profile chances of us finding one grow stronger. Similar – such as relaxation techniques and talking therapies as all of the other lesions that were included in our questions often cross Dr Ivan Pitman’s mind. As – which require engagement if they’re to be effective. network,” he says. So too, did the injuries sustained a clinical psychologist who has spent his career “We have to acknowledge that this way of treating them by Gage. But Fox cautions that many more patients working with offenders – some of them detained may not work very well because they’re not able to learn need to be examined before they can be sure of the in Ashworth Hospital in Merseyside – his research and respond in the way that healthy people are,” says existence of a brain network that can be reliably suggests that undiagnosed brain injury may be a Pitman. “Our job is to identify the obstacles they face ABOVE: Brian Thomas and his wife Christine prior to the tragedy associated with criminal behaviour. However, if contributing factor in more criminal cases than and find ways of overcoming them.” BELOW: Brian Thomas leaves court accompanied by his two their finding holds true, it could have profound is widely recognised. It may also be impeding Pitman’s current focus is on the general prison daughters, after being found not guilty of the murder of his wife social and legal implications. Already, there have rehabilitation efforts. population. As his study of inmates at Leeds Prison been a handful of British court cases in which a Ashworth houses some of the UK’s most violent revealed, up to half of prisoners may have experienced defendant’s brain injury or medical condition has prisoners; men whose criminality is judged to stem a brain injury in their past. And although many of these been used as a mitigating factor when determining from mental illness – a chemical imbalance in the injuries are mild, an estimated 15 per cent are moderate their sentence or their entitlement to compensation. brain, which could potentially be corrected with or severe, which means those affected may be struggling A reliable test would make such decisions easier. drugs. Pitman wonders if in some cases, it might with everyday tasks. “In theory, you could take our network and say arise from a physical brain injury, which is less Brain injuries can’t be fixed, but given the right ‘does the lesion fall within this network or does it reversible. “Once brain tissue is dead, it’s dead. The environment, people can learn to work around them to not,’ and if it doesn’t, it would certainly decrease brain copes by finding new pathways for signals some degree. As Pitman says, “By failing these people, the chances that that lesion was contributing to the to go around, but it is never as effective as it was there’s a risk of further victims being created.” criminal behaviour,” says Fox. before,” he says. Around the world, courts are now turning to He and his colleagues began reassessing some of neuroscientific evidence as growing numbers of Ashworth’s most difficult inmates using a combination Linda Geddes is a freelance science journalist, who writes about

defendants’ claim that a brain injury or disorder GETTY, SHUTTERSTOCK, ATHENA PICTURE LIBRARY X2 of cognitive tests and brain scans: this revealed that biology, medicine and technology. She tweets from @LindaGeddes �

22 23 COVERPSYCHOLOGY STORY LIFE WITH NO MIND’S EYE Some people cannot imagine their best friend’s face, or even their own house. This lack of mind’s eye is called ‘aphantasia’, and researchers are only just starting to unravel the science behind it WORDS: DR LUCY MADDOX ILLUSTRATIONS: JAMES MINCHALL

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icture an apple. What colour is it? What about calling to mind “HE SAID THAT READING WAS HYPERPHANTASIA your mother’s face? What is her expression? How about your last DIFFERENT; PREVIOUSLY HE USED Some people’s mind’s eye is so holiday? Can you picture where you stayed? For some people, this vivid that the lines between is impossible. They cannot recall TO ENTER A VISUAL WORLD AND reality and imagination can Pimages of familiar objects or people to their ‘mind’s eye’. In effect they don’t have one. This crucial become blurred… difference in the way people see the world has only THAT NO LONGER HAPPENED” started to be researched in the last few years. How have we gone for so long ignoring this variation in Zeman searched the literature on visual imagery At the other end of the spectrum to aphantasia is how we experience our internal worlds? loss and found there was little out there. “It’s weird, hyperphantasia. People with hyperphantasia describe pictures it’s just a sort of gap,” he says. Back in the 1880s, so vivid that they can find it hard to be sure whether an image MIND BLIND Victorian polymath had published was perceived or imagined. Although this sounds pleasurable, it Aphantasia is the name given to the inability to call a paper on mental imagery, where he reported that can potentially be confusing, and might make individuals more an image to mind. The name was coined in 2015 a small number of people couldn’t visualise. Since susceptible to symptoms such as flashbacks in post-traumatic by Prof Adam Zeman, a cognitive and behavioural then, researchers have continued to study visual stress disorder (PTSD). “Maybe it’s a bit harder to live in the neurologist at the University of Exeter. Zeman first imagery but haven’t paid attention to the extreme present if you have very vivid visual imagery,” says cognitive became aware of the phenomenon when he was ends of the visualisation spectrum. Before Zeman and behavioural neurologist Prof Adam Zeman. Yet just like referred a patient who had ‘lost’ his visual imagery started studying it, there wasn’t even a name for with aphantasia, he doesn’t think this end of the spectrum has after a heart operation. the experience. Zeman and a classicist friend came to be problematic. “My feeling is that there are pros and cons to “He had vivid imagery previously,” recalls Zeman. up with ‘aphantasia’, based on Aristotle’s term for being at either end.” “He used to get himself to sleep by imagining friends the ‘mind’s eye’. Hyperphantasia is more common than aphantasia, but is still and family. Following the cardiac procedure, he Zeman’s assessment of his patient raised more a more extreme experience than most people have. “It’s possible couldn’t visualise anything, his became questions than answers. The man could describe a to bring to mind strong and clear images of people, places and avisual, he said that reading was different because castle, and could say whether grass or a pine tree brain imaging suggested he couldn’t access visual things,” says hyperphantasic artist Clare Dudeney. “It’s not previously he used to enter a visual world and that was darker green, but he reported knowing these areas when he tried to imagine or remember images. always possible to hold them for long in the day because of the no longer happened. We were intrigued.” answers, not imagining the objects. Functional Zeman’s case study about his patient was written distractions of everything else happening around. But at night about in Discover magazine by science journalist you can get lost in an imagined world that feels real. Sometimes Carl Zimmer. Over the next couple of years, 20 the only way I can tell it’s a is when I’m doing something people got in touch with Zeman to say they’d read I can’t normally do, like fly, or breathe underwater. I used to the article and had the same absence of imagery, annoy my husband by getting my sketchbook out on holiday at but they had experienced it for their entire lives. As every incredible scene. Now I’ve realised that I can relax, take it more was written about the findings, more people in and paint it later from memory.” got in touch. Zeman now has 12,000 aphantasic Although she wouldn’t change it if she could, sometimes volunteers. He estimates that about 2 per cent of hyperphantasia can be tricky: “When people describe some the population have little or no visual imagery. terrible accident, I visualise it so strongly that I feel it’s Yet not all experiences of aphantasia are alike. happening to me,” she explains. “I can watch gruesome things on Many people have had aphantasia since birth, but TV and be fine, but a passage in a book can bring to mind such others have acquired it following a brain injury, or vivid images that I faint.” sometimes after periods of depression or psychosis. Some individuals don’t dream in images, like Zeman’s first patient, but others can, even though they are unable to visualise while they’re awake. Brain scanner studies on people have demonstrated a network of brain areas involved in visualisation. These include the primary visual cortex and an area in the fusiform that’s close to a region involved in face recognition. The network also includes parts of the frontal and parietal lobes, which are usually involved in decision-making, working memory and attention. Memory areas, including the hippocampus and medial temporal lobe, also seem to be important. As well these specific brain regions, the ‘default node

ILLUSTRATION (RIGHT): CLARE DUDENEY network’ or ‘daydreaming’ network is involved. 2 �

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visualising is a ‘top down’ process that’s driven to work in academic and computer-related careers, by the cortex. He thinks this is likely to cause the and for those at the other end of the spectrum to dissociation between some people’s visualisation work creatively. But there are exceptions. There are abilities while dreaming and waking. aphantasic artists, who either depict objects they But what’s going on in the brains of see, or use images they make on the paper people with lifelong aphantasia? There as a stimulus to engage with. “It’s perfectly have not yet been any published studies, possible to be creative and imaginative but scientists are hoping to have some “IT’S PERFECTLY without visualisation,” says Zeman. answers soon. Zeman’s team has just Zeman doesn’t think aphantasia needs finished studying 20 people with high POSSIBLE TO BE diagnosis and treatment. “It’s an intriguing visual imagery, 20 people with no visual variation in human experience, not a imagery and 20 people in the middle, disorder,” he says. Indeed, the scientist using neuropsychological tests and brain CREATIVE AND Craig Venter, the first person to decode imaging. “So in a few months’ time we the human genome, has described his might have an answer,” Zeman says. IMAGINATIVE aphantasia as useful in helping him to Whatever is happening neurally, it does concentrate on scientific problems. seem to be heritable to some degree, with The presence of a large and previously people with aphantasia more likely to WITHOUT hidden aphantasic community reveals how have a close relative (parent, sibling or it is possible for all of us to be seeing the child) who also struggles to visualise. VISUALISATION” world differently without even realising. One reason aphantasia may have gone Brain imaging can help us understand nameless and unstudied for so long is neurodiversity of all sorts, but we’ll only because it isn’t necessarily a problem. know there’s difference to be investigated While it makes drawing objects from if we don’t assume that you see what I see, imagination impossible, and visualisation strategies and instead we ask curious questions. LIVING WITH cannot be used for memorising, there are other ways to mentally represent information. Some APHANTASIA Dr Lucy Maddox is a clinical psychologist , lecturer and writer. people use words or symbols, others report having a good ‘mind’s ear’ or ‘mind’s nose’ instead of a Dame Gill Morgan recalls her 2 These areas are usually active in the resting ‘mind’s eye’, or say that they have kinaesthetic DISCOVER MORE brain and when we are being introspective. As experience of lacking a mind’s eye (movement-based) imagery. From January 2019 there will be an exhibition of art by Zeman says: “If you just chill in a scanner, that’s While there are individuals with aphantasia people with aphantasia and hyperphantasia, held at the set of areas that is most active. It turns out to who report memory difficulties, this is not true for Glasgow University and then Exeter University. For more Dame Gill Morgan realised she saw things differently in be a kind of daydreaming network, active when everyone. There is a trend for people with aphantasia information visit sites.exeter.ac.uk/eyesmind/ her 30s while participating in a management course. The you think about the past, or anticipate the future.” facilitator asked the group to imagine a beautiful sunrise. Zeman thinks it might be involved in visual imagery “I had no idea what a sunrise looked liked. I know it when because when we visualise we are paying attention I see it, I could explain and describe it, but I couldn’t imagine to internal stimuli instead of the outside world. it at all. I thought, ‘Everybody’s having them on, nobody can “So we know that there’s this big network: visual, see this damn thing.’” Afterwards, in the bar, she mentioned decision-making, working memory, attention, long- it to her colleagues: “I said, ‘That was daft wasn’t it?’ And term memory and introspection,” summarised they all went, ‘What do you mean? We can imagine…’ But I Zeman. “Where there’s a network, you could predict can’t. I can’t at all.” that it might break down in a number of different Until then, she had thought ‘the mind’s eye’ was just an ways, which helps to explain why there’s more expression. She hadn’t realised that people actually could than one sort of aphantasia.” visualise. “I don’t think it’s been different for me at all,” she For example, Zeman’s initial patient had normal says. “You’d think I’d be no good at faces or names, but I’m brain activation when he looked at faces but couldn’t okay. I haven’t really noticed it apart from the fact I can’t activate these same brain areas when he tried to draw. If you said, ‘draw a cow’, I would have no idea. I know imagine faces. For him, perhaps there was a loss it’s got four legs and a head, but I couldn’t tell you what was of connectivity between decision-making areas different about the head of a cow compared with the head and visual areas. This might have occurred as a of a horse. I can’t imagine a cow or a horse but I know them consequence of a small stroke during his heart when I see them.” operation. For other people with aphantasia, the She doesn’t notice any effect on her ability to empathise neural basis is likely to be different. or remember; in fact, she thinks her memory may be better in order to compensate. She has had a long, successful career DREAM WORLD and has a happy family life. What about those people who can dream in pictures Yet the first time she really missed visualising images was but cannot call images to mind when they’re awake? after her parents’ death. “Other people, if you talk to them Zeman doesn’t think this is as odd as it might about their parents, they can pull up a picture in their mind’s sound. “What the brain is doing in wakefulness eye. The only way I can do that is to look at a photograph.” and dreaming are different,” he says. Zeman describes dreaming as a ‘bottom up’ process that’s organised from the brainstem, whereas consciously �

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