Humans share such solid bonds with family, friends and community that we can scarcely imagine what it might be like to be a tiger, or a spider or any of the myriad of Earth’s creatures that lead solitary lives. Many mammals leave their kin forever after weaning and, aside from sporadic encounters with mates, live out their entire lives in solitude. In what seems to us an utterly alien life cycle, the hatchlings of some species are left to their own devices at birth: emerging from the safety of the egg, they confront the wide world all alone.

Relationships are so fundamental to our nature that, since the dawn of child psychology, researchers have wondered at the immensely powerful innate attachment of infants and parents, the very first social link forged in human life. Arnold L. Gesell, M.D., Ph.D., the prolific scientist and scholar who founded the Yale Child Study Center, used the relatively new medium of cinematography to analyze infant behavior beginning in the 1920s; he noted that even a newborn baby will turn its head toward the sound of its mother’s voice and, when lifted from the crib, will naturally mold its tiny body to conform to hers.

As Fred R. Volkmar, M.D., the Irving B. Harris Professor of Child Psychiatry, Psychology and Pediatrics in the Child Study Center, says, “Gesell saw that, for the child, the parent’s face and voice are the most important things in the world.”

However, in a now-classic 1943 article, the Johns Hopkins psychiatrist Leo Kanner, M.D., described a group of children who were puzzling exceptions to this rule. These children, whom Kanner dubbed “autistic,” had marked difficulties with language; engaged in repetitive, bizarre behavior; and—most poignantly—were inexplicably inclined toward aloneness. Kanner’s autistic patients were largely indifferent to their parents and, as they grew, to people in general. Instead, they seemed inexorably drawn to objects.

“Every one of the children, upon entering the office, immediately went after blocks, toys or other objects, without paying the least attention to the persons present,” Kanner wrote. “It would be wrong to say that they were not aware of the presence of persons. But the people, so long as they left the child alone, figured in about the same manner as did the desk, the bookshelf or the filing cabinet.”

Sixty years on, autism remains among the most mysterious and intractable of psychological disorders. Most psychological treatments depend on communication, and the insistent inwardness at the core of the condition has stymied generations of researchers and therapists.

But a newfound hopefulness is in evidence at the Child Study Center. Volkmar, an expert on the diagnosis and classification of autism, is also something of a scientific impresario: over the past several years he has assembled an autism research team as diverse and productive as any in the world. The group’s efforts received recognition from the National Institutes of Health in 2002, in the form of a $5 million grant as part of the NIH’s Studies to Advance Autism Research and Treatment (STAART) initiative. Buoyed by a surge in federal funding and public awareness and inspired by new findings on the effectiveness of early intervention and the changeability of the human brain, these Yale researchers are using cutting-edge technologies—functional neuroimaging studies, eye-tracking devices and specially designed computer games—to shed new light on the riddle of autism.

“Refrigerator mothers” no more

The Yale Child Study Center is set back some distance from South Frontage Road at the northern fringe of the medical school campus, hard by the noise and bustle of Route 34. Only a small sign and an unassuming brick facade are visible from the road, so Volkmar urges visitors to watch for “the Mayan temple,” his fanciful name for the colossal parking garage just across the street.

But the center is a landmark of the first order in the study of child development. Since its founding in 1911 by Gesell, the father of the field in America, the center’s mission has been to bring child psychiatrists, pediatricians and psychologists together under one roof—an all-embracing approach to child development in which research is tightly intertwined with protecting children’s health and welfare.

The melding of research and treatment infuses day-to-day life at the center with a distinctive vigor. It is a place where children—patients, research subjects or both—chat excitedly in waiting rooms piled with toys and backpacks, while scientists, physicians, parents and staff hustle through a multistory warren of offices, labs and clinics.

One particularly circuitous corridor in the center leads to Volkmar’s office, a spacious, book-lined room with a wall of windows that looks out onto a sunlit courtyard. An affable man who favors hiking boots and a slightly loosened tie, Volkmar led the group that redefined autism in the latest edition of the American Psychiatric Association’s Diagnostic and Statistical Manual, or DSM, the bible of psychiatric diagnosis.

For decades, Volkmar says, autistic children and adults were routinely misdiagnosed as mentally retarded or schizophrenic. During the 1950s and 1960s, when psychoanalysis was ascendant, the pain and desperation felt by parents of autistic children were compounded by certain prominent child psychiatrists, most notably Bruno Bettelheim of the University of Chicago’s Orthogenic School, who declared that the condition was caused by inadequate parenting, and in particular by cold, aloof “refrigerator mothers.”

By 1980, when autism was first formally recognized in the DSM, it had become generally accepted that the condition is caused by some breakdown in normal neurological development, but parents’ emotions can still be whipsawed between hope and despair by what Volkmar calls “the flavor of the week”—a regular stream of media coverage of purported cures or breakthroughs. In 1998, for example, it was widely reported that some autistic children experienced dramatic recoveries after receiving injections of synthetic secretin, a gut hormone. However, recent clinical trials of the therapy have been inconclusive at best.

With Volkmar’s guidance, the latest edition of the DSM reflects the current view that autism disorders comprise a spectrum of conditions that fall along a continuum of severity. At one end of the scale is full-blown autism, with major language difficulties; repetitive, sometimes self-destructive behavior; virtually complete social isolation; and profound intellectual disability. At the other end is Asperger’s syndrome, a condition in which patients are verbally fluent and sometimes highly intelligent, but in many cases are so socially disabled that, in Volkmar’s words, “they couldn’t walk into a McDonald’s and get a cheeseburger and change.” Patients whose symptoms fall somewhere in between these two extremes make up the less-well-defined diagnostic realm of PDD-NOS or “pervasive developmental disorders, not otherwise specified.”

The autism spectrum disorders are four times more common in boys than girls. Although many more children are diagnosed with these disorders today than 20 years ago, Volkmar believes the rising number of cases reflects better diagnosis and a higher level of awareness of autism among physicians and the general public rather than a true increase in incidence of the disorder.

Many autistic children and adults possess uncanny abilities, but usually in one narrow—and often quite arcane—realm. Some are musical or artistic prodigies; others can recite from memory the complete train schedules from countries they have never set foot in, or describe what the weather was like in a given place for any day in recorded history. But Volkmar says that few patients have the wide range of extraordinary skills so memorably put to use by Dustin Hoffman in his otherwise accurate portrayal of the autistic Raymond Babbit in the 1988 movie Rain Man.

Finding each patient’s place on the autism spectrum is challenging because the symptoms and developmental course of patients in all three categories vary tremendously. “If you were in a room with 100 autistic patients, first you’d be struck by how different they are from one another, but then you would quickly realize how similar they are,” Volkmar says. And what’s similar in patients across the spectrum is an overpowering disability in social interactions.

Do you see what I see?

The social disabilities at the heart of the autism spectrum are brought vividly to life in a videotape made at the Child Study Center’s developmental disabilities clinic by Ami J. Klin, Ph.D., Harris Associate Professor of Child Psychology and Psychiatry. In one clip, an autistic toddler intently plays with a toy while Klin moves into her field of vision until his face is only inches from her eyes. Because of what Klin calls the “gravitational pull” of objects on the autistic child’s mind, the girl behaves as if she were completely blind to him. But her vision is perfect: we soon see her crawling excitedly toward a tiny orange candy on the floor that she had spied from across the room.

Given the primacy of social interactions in human life, scientists have proposed that we have evolved special brain mechanisms for perceiving faces. In experiments, normal subjects perceive faces more quickly than objects, apparently because faces are seen as wholes, whereas objects are first seen as a collection of component parts. However, it has been known since the late 1970s that autistic subjects see objects just as quickly as faces. For them, it seems, faces have no special status—they hold no more interest than chairs, spoons or airplanes.

Until recently, it was difficult to develop these findings further. In collaboration with Warren R. Jones, a graduate student and research associate in the Child Study Center, Klin has probed more deeply into this phenomenon using a technology known as eye tracking, which allows experimenters to precisely monitor where a person is looking at any given time (See sidebar). When Klin and Jones showed emotionally charged excerpts from Mike Nichols’ 1966 film Who’s Afraid of Virginia Woolf?, for example, normal subjects tended to focus on the actors’ eyes. However, autistic viewers fixed their gaze on mouths or, in many cases, on incidental objects in the periphery of the scene; while Richard Burton and Elizabeth Taylor kissed passionately in a Virginia Woolf clip, one autistic viewer pored over a light switch on a distant wall.

For other eye-tracking experiments, Klin and Jones have adapted the motion-capture technique used to create computer-generated characters in motion pictures (such as the Gollum character in the Lord of the Rings movies) to generate minimalist “point-light” animations of actors playing patty-cake or engaged in some other activity that appeals to children. As still images, point-light displays look like star maps, a random collection of white dots on a dark background. But when they move, normal subjects instantly and irresistibly recognize a human figure. Klin and Jones placed a correctly oriented point-light animation side by side with an upside-down animation on a split computer screen, and eye tracking revealed that normal children prefer to watch the correct version. However, autistic children show no preference whatsoever, indicating that they do not recognize the human being represented by the dots.

Our social instincts are so deeply rooted that they can be triggered even in the absence of faces or suggestions of human figures. In a separate line of work from his eye-tracking studies, Klin has been using a short film devised by the psychologists Fritz Heider and Marianne Simmel during the 1940s that features a few simple geometric shapes—a big triangle, a circle, a smaller triangle—moving about the screen. Heider and Simmel discovered that, when asked to describe this film, people almost invariably impose a social interpretation on it; instead of speaking in terms of inanimate shapes passively changing positions, viewers invent stories in which, for example, a chase might be taking place between a bullying big triangle and a terrified little triangle. But according to Klin, autistic subjects do not personify the shapes in the film, and rely instead on purely physical metaphors in their descriptions.

A brain space for faces?

Given the dramatic differences in autistic patients’ behavior compared to that of other individuals, one would expect that there would be conspicuous differences between autistic and nonautistic brains. But according to neuroimaging expert Robert T. Schultz, Ph.D., associate professor in the Child Study Center, finding such markers has been surprisingly difficult, and only a few studies in the neurobiology of autism have stood the test of time.

Neuroscientists have known since 1997 that pictures of faces, but not pictures of simple objects, activate a small patch of the cortex by the right ear that has come to be known as the fusiform face area, or FFA. But when Schultz and his colleagues showed pictures of faces to autistic patients in a 2000 study using functional magnetic resonance imaging (fMRI), they found little activation in the FFA; instead the study revealed a high level of activity in nearby brain regions involved in recognizing objects.

Schultz’s results have since been confirmed by at least six other research teams—a rare instance of consensus in an area where solid findings have been elusive—and they provide the tantalizing beginnings of a neural explanation for the object-centered worldview first described six decades ago by Kanner and so clearly revealed in Klin and Jones’ eye-tracking studies. But Schultz isn’t certain whether the FFA deficit he found actually causes social disability by itself or reflects some wider disturbance in brain circuitry.

In an intriguing new collaboration, Schultz and Klin are using Heider and Simmel’s film of geometric forms in fMRI experiments to sketch out a map of the entire “social brain,” Schultz’s term for an interconnected network of brain regions—including the amygdala, the medial frontal cortex, the superior temporal sulcus and the FFA—that seem to be crucial for normal human social interaction. In a recent study with normal subjects, Schultz and Klin found that perceived social interactions between the geometric forms strongly activate all the components of the brain’s social network, including the FFA—a quite surprising result since the film contains no images of faces. Based on these results, Schultz and Klin believe that “face area” may be a misnomer for the FFA: this brain area may not just be sensitive to faces, but it may be a more general-purpose area for perception of and knowledge about people and social interactions, however abstract. Schultz believes it may occupy a central place in the circuitry of the social brain.

Schultz’s former Yale colleague Isabel Gauthier, Ph.D., now at Vanderbilt University, has also argued for a broader view of the FFA. Gauthier has shown that, in people who have special expertise, such as car enthusiasts or bird-watchers, the FFA can be activated by pictures of the objects of their affection, whether they be T-birds or warblers. Moreover, along with Michael J. Tarr, Ph.D., of Brown University, Gauthier has shown that this “expertise effect” can be produced in normal adults by intensively training them to recognize subtle differences between previously unfamiliar objects. Gauthier and Tarr used “Greebles,” doll-like objects that look almost identical to the casual observer. As one would expect, when the experiment began, pictures of Greebles did not activate the FFA, but once Gauthier and Tarr’s subjects were “Greeble experts” who could quickly and reliably tell one Greeble from another, the FFA was significantly activated whenever they saw a picture of a Greeble.

In the clinic, a social-skills primer

Gauthier and Tarr’s Greeble work elegantly demonstrates that the FFA is a changeable structure, which may have direct implications for the treatment of autism. Schultz believes that by adulthood the components of the social brain in autistic patients may be severely weakened by a lifetime of social deprivation, but inspired by Gauthier’s work, he is working with colleagues at a STAART-funded clinic housed in the Temple Medical Center in New Haven to find out whether very early intervention and social training can head off some of this cumulative neurological fallout.

“We are betting on brain plasticity,” says Katarzyna Chawarska, Ph.D., an associate research scientist who heads up an ambitious screening program at the clinic. Chawarska is refining eye-tracking techniques to diagnose autism during infancy in the hope that the brains of very young autistic children might still be malleable enough to absorb what she calls “pivotal” social skills. “We treat each and every child as a child with endless potential,” she says.

As newly diagnosed children enter treatment at the STAART clinic, Associate Research Scientist Cheryl Klaiman, Ph.D., will eventually teach them to use Let’s Face It!, a computer game created in collaboration with James W. Tanaka, Ph.D., of the University of Victoria in Canada, that has been specially designed to hone autistic kids’ face-recognition skills. Because it is difficult to perform fMRI studies with very young children, especially autistic children, Klaiman and Schultz plan to assess whether Let’s Face It! is inducing brain changes by measuring event-related potentials, electrical signals that are detectable on the scalp with equipment similar to that used in the more familiar EEG technique. At the same time, Klin and Jones plan to use eye tracking to see whether tools such as Let’s Face It! can change young autistic children’s performance on their face-perception and point-light display tasks.

The team hopes that developing “social expertise” through early intervention might gently steer autistic children away from isolation and coax them toward the rich social world that is their human birthright. With an optimism tempered by decades of grappling with this most stubborn of disorders, Volkmar says frankly, “We don’t know if it will work, but we’re going to give it our best shot.”

Keeping science grounded

Science proceeds deliberately, and it will be some time before the members of the group know whether they can make a real impact on autism by transforming the social brain. In the meantime, autistic children and their families remain locked in a difficult daily struggle. Lawrence D. Scahill, Ph.D., an associate professor in the Child Study Center and the School of Nursing and a pioneer in pediatric psychopharmacology, has focused his energies on rigorously testing existing drug treatments for autism. Scahill and his colleagues recently published a landmark clinical study of risperidone, an antipsychotic drug, which provided the first conclusive evidence that the drug can successfully control violent tantrums in autistic children.

Scahill says that the $5 million STAART grant is “a real shot in the arm” that buys much-needed certainty in his field, which has long been plagued by studies too small and too poorly designed to draw firm conclusions. “The government is now funding autism research at a level where we can get sample sizes that are respectable,” Scahill says. “That’s a real first. Now we can not only answer the primary scientific questions, but we may finally be able to provide real guidance to clinicians on how to treat these kids.”

Klin would agree. The greatest strength of Yale’s autism group, he says, isn’t in tools or techniques, or even in the talents of the group’s individual members. What is most important, he says, is the unusual fusion of clinical work and research at the Child Study Center, which keeps the team’s science firmly grounded in the real lives of patients and their families.

“Our very best hypotheses come from our observations of individual children,” Klin says. “We try to match science with disability, one child at a time.” YM