Different Minds

If there’s one thing Ralph Or not. The fact that there are few An infectious theory Adolphs wants you to under- absolutes is part of why the set of dis- Much of that insight comes from Pat- stand about , it’s this: “It’s orders—autism, Asperger’s, pervasive terson, who pioneered the study of the wrong to call many of the people developmental disorder not otherwise connections between the brain and the on the impaired,” says specified (PDD-NOS)—that fall under immune system in autism, , the Caltech neuroscientist. “They’re autism’s umbrella are referred to as and depression a decade ago. simply different.” a spectrum. As with the spectrum of The main focus of that connection? These differences are in no way insig- visible light—where red morphs into Some kind of viral infection during preg- nificant—they are, after all, why so much orange, which morphs into yellow— nancy, Patterson explains. Or, rather, the effort and passion is being put into un- it is difficult to draw sharp lines immune response that infection inevitably derstanding autism’s most troublesome between the various diagnoses in engenders. traits—but neither are they as inevitably the autism spectrum. To bolster his argument, Patterson devastating as has often been depicted. And, like the autism spectrum itself, points to a recent study by Hjordis O. They are simply differences; intriguing, the spectrum of autism research at Atladottir of Aarhus University, Denmark, fleeting glimpses into minds that work in Caltech also runs a gamut. Adolphs, and colleagues—“an extraordinary look at ways most of us don’t quite understand, for example, studies brain differences over 10,000 autism cases” in the Danish and yet which may ultimately give each between adults on the high-functioning Medical Register, which is a comprehen- and every one of us a little more insight portion of the autism spectrum and the sive database of every Dane’s medical into our own minds, our own selves. general public—the so-called neuro- encounter from cradle to grave—that What makes autism so fascinating, typical population. Neurobiologist John showed a strong epidemiological link Adolphs notes, is what also makes it so Allman’s work on a particular set of neu- between autism in a child and a first- difficult to study, to get a good grasp on: rons is providing insight into a possible trimester viral infection in the mother. the diversity of the population itself. If basis for some of autism’s social quirks. “And we’ve found that if you give a mouse you’ve met one person with autism, the And then there’s neurobiologist Paul the flu during pregnancy, or activate the saying goes, you’ve met one person Patterson, who literally has just finished mother’s immune system directly without with autism. writing the book on the connection a pathogen, the offspring will show a Still, there are characteristic tenden- between the immune system and neuropathology characteristic of autism, cies and traits, gifts and gaps. According autism, and who is collaborating with as well as the three cardinal symptoms to psychiatry’s diagnostic bible, familiarly biologist Sarkis Mazmanian to explore of autism.” known as the DSM-IV, autism involves the connections between gastrointes- In mouse terms, that means exhibit- an “impairment” in social interaction and tinal symptoms and the brain in autism ing repetitive behavior such as excessive communication, as well as “restricted re- spectrum disorders. self-grooming and compulsively and petitive . . . patterns of behavior, interests, They and half a dozen or so of their furiously burying marbles placed on its and activities.” What this means to the colleagues have come together in a bedding. Freaking out, rather than making rest of us is some combination of these: sort of informal Autism Working Group, friends, when faced with an unfamiliar Lousy eye contact. Social awkwardness. which meets regularly to talk about their mouse. And communicating much less Hand flapping.T oe walking. Late-talking individual findings and to brainstorm as a young pup with its mother, or as an babies. Kids who can’t seem to get the together. “People don’t think of Caltech adult with other mice. (Mice “talk” to one hang of playing cops and robbers with when they think about autism research,” another at ultrasonic frequencies, requir- friends, yet can talk for an hour about says Patterson. “But we have a lot go- ing a special microphone and recording Egyptian gods, elevators, or elephants. ing on here; a lot of insight to offer.” equipment to make their conversations Adults who speak in flat tones, who audible to human ears.) come off as rigid, uncomfortable, brilliant.

14 ENGINEERING & SCIENCE winter 2012 Different MinBy Lori Oliwenstein ds

Caltech researchers are gaining insight into what autism is, what autism gives, and where autism lives.

winter 2012 ENGINEERING & SCIENCE 15 This is an impor- dysfunction there—then the breakdown tant clue connecting product gets into the bloodstream. And the mother’s im- research has indeed found that this mune reaction to the happens more often in kids with autism fetus’s brain develop- than in typical kids.” ment. It’s known that There’s similarly strong evidence, he the interleukins are says, implicating our normally helpful inflammation-boosters, and cooperative intestinal bacteria—as and inflammation is it turns out, the various types of bacteria all well and good found in the digestive systems of typical when you need to and autism spectrum kids tend to differ. wake up the immune But while the bowel-bacterium-brain system and get it to connection is clear, it’s still not known pour white cells into just how widespread it is. “Estimates an infected area. But of the percentage of people with autism it has its unintended who are affected by these gastro- side effects as well; intestinal differences vary from 20 to Patterson observed the same neuro- the inflammatory response often takes 70 percent,” Patterson says. “Clearly, pathology and behavior in mice who had a scattershot approach, meaning that the science is lagging; there’s still a lot never had an infection, but were instead healthy tissues can also get caught up of work to be done.” given synthetic molecules that mimic in the onslaught. Which is why the science-and- the presence of a virus. In other words, For instance, grad student Elaine advocacy group recently Patterson found that simply mounting Hsiao is finding that IL-6 and other brought Patterson and Mazmanian to- an immune response may be enough cytokines not only work directly on the gether with immunologist Paul Ashwood to steer a fetus down a path that could fetal brain, but can also alter the func- at UC Davis and pediatrician Alessio eventually lead to an autism-like condi- tion of the placenta, which would have Fasano from the University of Maryland tion after birth. indirect effects on fetal development. to explore the gut-brain-immune con- That “may” is key. There is definitely Why does an immune response nections in mice and in kids with autism a connection between infections during sometimes result in a developmental spectrum disorders. pregnancy—especially the early months disability—and sometimes not? Pat- “You have Sarkis’s and Alessio’s of pregnancy—and increased risk of terson thinks it could be the timing of expertise in the human gastrointestinal autism (and, as Patterson has also the infection, or the genetic makeup of system, you have Paul’s expertise in shown, schizophrenia) in the offspring, the mother, or her fetus that modulates children with autism, and then you have he says, but that is not the same as the outcome. our mouse model,” says Patterson. “That saying it’s a direct, 100 percent, if-you- The questions Patterson is asking makes for a pretty exciting consortium. It get-sick-while-you’re-pregnant-your- about inflammation and the brain might should allow us to look at autism in new baby-will-have-autism correlation. apply to other parts of the body as and unprecedented ways.” How does it all work? Patterson thinks well. So he and biologist Sarkis cytokines—proteins produced by the Mazmanian are looking at the gastro- Looking and connecting body in response to an infection—play intestinal problems somewhat com- Ralph Adolphs, too, is looking at autism a role. In fact, grad student Steve Smith monly found in kids with autism, and in new ways—and looking at looking in (PhD ’08) found that giving pregnant how those might be related to the autism as well. mice one cytokine in particular, called development of autism. Adolphs, who runs the Autism and interleukin-6 (IL-6), leads to offspring “The evidence that there are gastro- Asperger Syndrome Research Program who exhibit autistic and schizophrenic intestinal issues in children with autism at Caltech, spends most of his time features. “It was really unexpected that is pretty good,” Patterson notes. “You working with high-functioning adults a single injection of a single cytokine test it by feeding a child a molecule with autism. “We’re exploring the social would exert such a powerful effect,” that gets broken down in the gut; differences people with autism have,” Patterson notes. if the gut is leaky—if there is some says Adolphs. “We’re looking at every-

16 ENGINEERING & SCIENCE winter 2012 thing from eye-tracking, to reasoning, to about what you notice around you, and not only to your emotional awareness complex theory-of-mind stuff, which is how you respond to it, rather than a lack and empathy, but also to your internal about understanding what others feel of caring. “What’s interesting is figuring awareness—of the state of your or think. We hope one day to be able to out what people with autism pay atten- digestive system, the sensation of tell a story about the roles of particular tion to,” says Adolphs. “It’s not that pain, and the like. This fits well with brain areas, and how the white-matter their amygdala doesn’t work, it’s that the known tendency of people with connections between them look abnor- it works differently.” autism to be hypersensitive to sound, mal, and how that causes the effects Neurobiologists John Allman and light, temperature and other stimuli. we see.” Atiya Hakeem (BS ’93) have also been The missed or unusual connec- For example, people with autism look focusing on a component of the brain tions both Adolphs and Allman are at faces differently—focusing not on the that may work differently in people looking at may be a critical part of the other person’s eyes, the way a neuro- with autism. Called the von Economo story, Adolphs adds. Indeed, he says, typical person would, but on the center neurons, these cells are thought to play there’s a sort of “globally abnormal of the face or on a point beside the a key role in your ability to quickly and connectivity in the brains of people face. Several research groups, including intuitively assess a situation—say, for with autism.” Adolphs’s lab, have discovered that this example, when you meet someone for Which is why Adolphs and Caltech is linked to the brain’s amygdala, which the first time, and come to an immedi- psychology researcher Lynn Paul is known to play roles in face recogni- ate conclusion about how to respond have been studying a group of people tion and in the processing of emotions— to their greeting. Those sorts of snap born without a corpus callosum—the both our own and others’. judgments, Allman says, are much bundle of nerve fibers that connects The amygdala is also involved in more difficult for people with autism, the brain’s two hemispheres. Intrigu- social interactions, so Adolphs’s team who tend to have trouble realizing that ingly, a full third of such people also is looking at how being aware of other what you say when you first meet a new meet the diagnostic criteria for having people affects behavior. In one set of client is very different from the way you an autism spectrum disorder. experiments, volunteers were asked should respond upon first meeting your The team recently found that to make charitable donations (with brother’s new girlfriend or your long-lost despite the missing 200 million or their own money!) in the presence or Aunt Sadie. so connections between neurons absence of an observer. As expected, And that, he posits, may well be due that the corpus callosum normally people gave bigger sums to abnormalities in the connections provides, these folks’ left and right when other people were watching. By these neurons make or where they wind hemispheres still manage to carry on contrast, the people with high-function- up in the brain. The latter notion has communications with one another. ing autism gave the same amount either since begun to gain traction else- “This finding really amazed us,” says way. “For most of us, when other people where—a recent study led by Micaela Adolphs, “and it shows that you can are watching, we act differently,” he Santos of the Mount Sinai School of generate remarkably normal func- says. “But we’ve found that people with Medicine in New York has found that tional networks that communicate autism lack that behavioral change. They children with autism have an oversupply between different parts of the brain don’t seem to think about what other of von Economo neurons in the fronto- even when the wiring is all scrambled. people think of them.” relative to another type There must be some fundamental But at its root, this seems to be more of neuron. This brain structure is linked principle about how the brain orga-

These eye-tracking studies show how we “read” other people’s faces. Left: Neurotypical people look at the eyes. Middle: People with autism tend to focus on or around the bridge of the nose. Right: Superposing the two, with red being the neurotypical folks and blue being people with autism.

winter 2012 ENGINEERING & SCIENCE 17 nizes itself functionally during develop- ity,” says Adolphs. ment, such that it can do so even when “People with autism the corpus callosum is entirely missing.” have strengths and Although the corpus callosum study they have weakness- looked at a specialized population, most es, just as we all do.” of Adolphs’s other findings have come Mapping these about thanks to the cooperation of some peaks and valleys 40 adult volunteers with diagnoses of will not only help high-functioning autism, Asperger’s, or academics like PDD-NOS. Adolphs and his Why study high-functioning adults? Caltech colleagues Adolphs admits that at least some of learn the ins and outs the impetus is purely practical. It’s much of autism, it will help easier to get adults to sit through long society as a whole hours of testing and MRI scanning than understand how it is to get any child—with or without best to help people autism—to do the same. But the payoff is with autism exploit worth it. Those hours they’ve spent lying their strengths and work around their Paul Patterson is the Anne P. and motionless in the MRI mean that Adolphs weaknesses. Benjamin R. Biaggini Professor of knows these people inside and out. And lest anyone think these lessons Biological Sciences at Caltech. His And there are other draws as well. apply only to those with a diagnosis that research on autism and schizophrenia is For one thing, the overwhelming majority falls clearly onto the autism spectrum, funded by Autism Speaks, the of autism research is done on children Adolphs has a few words of caution. International Rett Syndrome Foundation, and is about children. “You hear a great “Autism is just one extreme of this broad the National Institute of Mental Health deal about children with autism, but not spectrum of individual differences that (NIMH), the U.S.-Israel Binational Science so much about adults,” Adolphs says. stretch across the general population,” Foundation, the Simons Foundation, the “In fact, although autism starts to be he says. For instance, in a 2008 paper McGrath Foundation, the Weston Havens noticed in childhood, it’s not a child- published in Current Biology, Adolphs Foundation, the Della Martin Founda- tion, the Department of Defense, and the hood disorder. Instead, it’s a disorder of and colleagues showed that the par- Caltech Innovation Initiative. His book, development, and those children who ents of children with autism—who were Infectious Behavior: Brain-Immune Con- have autism become adults with autism, not themselves autistic—frequently nections in Autism, Schizophrenia, and and eventually elderly adults with autism. respond to faces in a manner similar Depression, was published in September We know extremely little about how to children with autism, spending more by the MIT Press. autism interacts with the aging process, time looking at other people’s mouths for instance.” than at their eyes. Ralph Adolphs is the Bren Professor Indeed, he notes, while some of “It turns out that what we’re learning of Psychology and Neuroscience and autism’s symptoms are most appar- about autism,” Adolphs notes, “may be professor of biology, as well as direc- ent in childhood—delayed speech, for relevant to almost anyone who is a little tor of the Caltech Brain Imaging Center. instance—others don’t make themselves bit different, who does things differently.” His research is supported by grants from known until later in life and are a direct That means you over there in the cor- Autism Speaks, NIMH, and the Simons result of the atypical development that ner, who hates large parties and small Foundation. came before. “Autism affects develop- talk. And you, the person who plugs ment,” Adolphs says, “and in turn, devel- your ears at a concert, because you feel John Allman is the Frank P. Hixon Pro- opment affects autism. And so we want physically assaulted by the noise. And fessor of Neurobiology. His research is to look at the interaction of autism with you, spending hours upon hours fixing funded by the James S. McDonnell Foun- the entire developmental lifespan.” up old computers, or old cars, or orga- dation, NIMH, and the Simons Foundation. They also want to look at the way au- nizing your model-train collection. He and neuropsychiatrist Peter Williamson tism interacts to create not only deficits, Not diseased. Not impaired. Just are the coauthors of The Human Illnesses: but benefits. “One of the things we’re different. Just like you and me. Neuropsychiatric Disorders and the Nature getting with such detailed assessments of the Human Brain, published in January is a profile of peaks and valleys of abil- 2011, by the Oxford University Press.

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