"Can a Single Brain Cell Think?"
Discover, June 2005
In the neurosurgery ward of the David Geffen School of Medicine at UCLA, Danny, a stocky 21-year-old college student wearing blue pajamas and sporting a wispy goatee, sits on a bed watching one photo after another flash on a laptop screen. Several macho movie stars appear in rapid succession, including Arnold Schwartzenegger, Steven Seagal, Sylvester Stallone, and Mr. T, the mohawked brawler who plays Stallone’s rival in the boxing film Rocky III. At first glance, one might guess that Danny has volunteered for a Hollywood survey: Who’s your favorite action hero? In fact, Danny is the real hero. The black cables emerging from the white turban wrapped around his skull hint at his role in investigating a truly profound question: How do thoughts form in the human brain?
Danny suffers from epilepsy, and he has had electrodes temporarily implanted into his brain to monitor seizures; ideally, the electrodes will pinpoint the neural defect triggering his seizures so it can be surgically removed. During the week or so that the electrodes remain in Danny’s brain, he has volunteered to participate in experiments aimed at understanding the underpinnings of cognition. Such research is quite rare; for obvious ethical reasons, neuroscientists have few opportunities to gather data from deep inside a living human brain.
This particular experiment touches on one of the most challenging puzzles of neuroscience: How do brain cells recognize items as complicated as a toaster oven, the number nine, a zebra, Bill Clinton, or the film character Rocky? Are single cells like transistors in a computer, or pixels on a television screen, contributing just minute pieces of information that only when combined with the output of thousands or millions of other cells form the complex pattern that means Rocky? Or can a single neuron learn to recognize that face?
Most neuroscientists adhere to the pixel view of neurons, arguing that individual cells can’t possibly be clever enough to make sense of a concept as subtle as Rocky; after all, the world’s fastest supercomputers have difficulty performing that pattern-recognition feat. But Itzhak Fried, the neurosurgeon who implanted the electrodes in Danny’s brain and who leads this UCLA research program, believes he has found "thinking cells" in the brains of subjects like Danny. If he’s right, neuroscientists may be forced to overhaul their view of how the human brain works.
A true thinking cell should be able to recognize a person or fictional character even in many different guises. Danny is a big fan of Hollywood action heroes, especially Rocky; he owns DVDs of all four films in the series and never tires of watching them. So, amid the images that flash on the laptop screen, the research team has included shots that show Rocky running through the streets of Philadelphia, staring longingly at his girlfriend Adrian, or draped in the American flag after defeating his Russian rival. Now and then, to test whether a cell’s recognition cuts across sensory modes, Rocky or some other name is spelled out on the laptop screen or uttered by an eerie synthesized voice.
As Danny peers at the laptop, signals stream from more than 100 ultra-thin electrodes, each sensitive enough to detect the murmuring of a single cell—and into the cables that emerge from his head. The cables ferry the signals across the room to a cabinet crammed with amplifiers. A computer atop the cabinet displays the readouts from Danny’s cells as a series of multi-colored lines unfolding across a screen. Every now and then, a line jerks upward, as one of Danny’s cells sputters in response to an image or name. Rodrigo Quian Quiroga, the Argentinian neuroscientist overseeing this research session, points to one especially energetic squiggle and whispers, "That’s Rocky."
The vast majority of modern brain research involves technologies such as magnetic resonance-imaging, positron emission tomography, and electroencephalography. All measure neural activity from outside the skull. Figuring out how brains work with external scanners is like studying life on a cloud-shrouded planet with satellites. Implanted electrodes, by contrast, are like probes that drop down to the planet’s surface. Electrode studies of monkeys and other animals whose brains resemble ours have yielded valuable insights, but these creatures cannot describe their subjective sensations.
A handful of other hospitals are carrying out electrode research that piggybacks on the clinical treatment of patients with epilepsy, Parkinson’s disease, and other neurological disorders. But no research program approaches UCLA’s in experience, sophistication, or published results, says Christof Koch, a neuroscientist at the California Institute of Technology who has been collaborating with the UCLA group since 1998. "There is no one technique that’s going to give you all the answers" to the riddle of cognition, Koch says. "But this is one that’s very, very good, and we’re getting better at it."
Fried, the driven yet affable commander-in-chief of the program, founded it in 1992 after leaving Yale. Since then more than 100 of his epileptic patients with electrodes implanted in their brains for diagnostic purposes have volunteered as subjects for basic research. From the outset, Fried has been protective of his patients and their privacy; this is the first time he has allowed a reporter to watch him and his team at work.
Fried was born and raised in Israel, and he spends several months a year working at a hospital in Tel Aviv as well as at UCLA. He flew from Israel to Los Angeles on a Sunday, and during a three-hour operation on Monday he drilled ten holes in Danny’s skull and inserted the electrodes into his brain. The following day, wearing a white lab coat over aqua scrubs, Fried strode into a conference room packed with researchers who had gathered to discuss plans for Danny. The team included two undergraduates who flew here from the University of Pennsylvania, a few graduate students from UCLA and Caltech, a couple of postdocs, and two physicians.
Fried briskly provided background on the patient: Danny is a bright, friendly young man, he said, who is looking forward to working with the research team as a way to "break the boredom" of his hospital stay. "Okay, let’s get down to practical issues," he continued in his distinctive Israeli accent. Rapid-fire, he queried the researchers on the status of their "paradigms." He prefers that term to "experiments," which might suggest electrodes had been implanted in Danny’s brain primarily for research rather than diagnostic purposes.
The discussion keeps returning to problems with data storage and analysis. Several researchers asked for upgrades in equipment for storing data—which the microelectrode experiments generate by the terabyte--and Fried said he’d see what he could do. The researchers also received detailed instructions on how to grapple with a major technical challenge: electrodes in patients’ brains often detect pulses from two or more nearby neurons at the same time, which may show up in the computer as one big signal. Quiroga has written a program that mathematically unravels overlapping pulses. The process, called cluster-cutting, makes it possible to extract more information from the data, at least in principle. But some of Quiroga’s colleagues were still trying to familiarize themselves with the fine points of what the team has dubbed "Rodrigo’s code."
The researchers had prepared more than enough studies to keep Danny from becoming bored. One called for him to view computer-generated pictures of celebrities morphing into each other: Mr. T into Will Smith, and Sly into Arnie. The objective: to see if a cell that lights up for Sly fires more slowly as the photo gradually morphs into Arnie, or just abruptly falls silent. In other words, are face-recognition cells like simple on-off switches, or can they act like dimmers?
Another paradigm, called X-Cab, is designed to yield insights into how we navigate. More than a decade ago microelectrode studies of rats and monkeys revealed place cells that light up when the animals move to a particular spot in a maze. Previous versions of X-Cab, which involves driving a virtual taxi through a cyber-city, have confirmed that humans have place cells, too, as well as view cells that respond to specific landmarks, and goal cells that respond to the driver’s ultimate destination.
Arne Ekstrom, a UCLA postdoc, and Indra Viskontas, a graduate student, had made preparations for Danny to test drive a new version of the X-Cab program, which allows the driver to pick up and discharge passengers. Fried asked if they had made the changes he requested in the paradigm. "Almost all of them," Viskontas replied, adding that she and Ekstrom "respectfully" disagreed with some of Fried’s requests and wanted to discuss them with him.
Fried nodded. "Any more questions?" he asked, scanning the room one last time. "If not, to work."
Back in his office, Fried recalled how he ended up overseeing this unusual program. One of his role models was Wilder Penfield, the Canadian surgeon who carried out pioneering operations on epileptics in the 1950’s and 1960’s. After removing the skull-cap of patients, Penfield electrically tickled different spots of their brains with wires and asked them what they felt; because the brain lacks pain receptors, the patients needed no anesthesia. They could report feeling a tingle in their left forefinger, seeing a blue flash, hearing a low-pitched hum.
This procedure not only helped to guide Penfield’s surgical treatment of each patient; it also yielded clues to what different parts of the brain do. "Here was somebody who was really looking at the human mind," Fried said, "but at same time he was helping a human being." Fried’s method is much more refined than Penfield’s. Fried typically drills a dozen holes in the patient’s skull and inserts a dozen hollow macroelectrodes, which can detect large-scale electrical waves emanating from a seizure.
Protruding from the end of each macroelectrode are as many as ten flexible microelectrodes that can detect the pulses of individual neurons. The patient’s clinical status dictates the placement of the macroelectrodes. In Danny’s case, tests suggest that his seizures originate in his frontal lobes, so Fried inserted most of the macroelectrodes in that region. He embedded one macroelectrode in Danny’s hippocampus, a minute region that underpins memory and is often implicated in epileptic seizures.
The patient’s clinical health and comfort, Fried emphasized, take precedence over research objectives. Even the most carefully planned paradigm must be set aside if the patient becomes bored, tired, frustrated, gets a headache, or just wants to be left alone. Fried carefully screens prospective colleagues to ensure that they treat his patients like human beings rather than laboratory animals. "The person who will not do well," he said, "is a compulsive-obsessive animal physiologist who, if he doesn’t control all the variables, falls apart." But Fried also said he believes that "there is a responsibility" to take advantage of these rare chances to learn more about the behavior of individual neurons, which he calls the building blocks of cognition.
Following Penfield’s example, Fried occasionally does studies that involve stimulating brain cells with minute electrical jolts. In 1998, he and three colleagues discovered that a female patient burst into laughter every time they stimulated a spot at the top of her brain called the supplementary motor area. Her hilarity was not just physiological; the woman felt subjective sensations of "merriment or mirth." She displaying a syndrome known as confabulation—she invented reasons for her hilarity, telling the researchers at one point, "You guys are just so funny... standing around."
But most of Fried’s findings, which he has described in more than a dozen papers in such leading journals as Nature, Neuron, and Proceedings of the National Academy of Sciences, involve not electrically stimulating neurons but passively listening to their chatter as a patient performs various tasks. In one set of experiments, Fried, Koch, and Gabriel Krieman, a Caltech grad student, found cells that light up both when a subject looks at an image—of a baseball, say, or a woman’s face--and when he closes his eyes and recalls the image in his minds’ eye. The results provide the most convincing evidence yet that human perception and imagination share neural circuitry.
The experiments that have attracted the most attention are those supporting the existence of "thinking cells." The possibility of such cells has been debated at least since the 1950s, when researchers found single neurons in the visual cortex of cats and other animals that respond to simple stimuli, such as lines oriented at a certain angle or moving in a specific direction or light of a particular wavelength. Some theorists wondered whether single neurons might also respond to much more complicated stimuli, such as specific people.
Once known as gnostic cells, after the Greek word for knowledge, they were dubbed grandmother cells in the late 1960s by neuroscientist Jerry Lettvin of the Massachusetts Institute of Technology. Lettvin meant to make fun of—if not to dismiss--speculation that single cells could be dedicated to recognition of family members or other individuals who loom large in an individual’s mental universe. In one paper, he joked that mother-smothered neurotics such as Portnoy, the hero of Phillip Roth’s novel Portnoy’s Complaint, could be cured of their Oedipal disorders by having all the mother cells purged from their brains.
Many neuroscientists found it hard to believe that a single cell could recognize an inanimate object, let alone a human being. Even objects as simple as chairs, trees, or buildings come in an almost infinite variety of forms, and the same object looks different from different perspectives or in different contexts. Neuroscientists were therefore startled in the early 1970s when experiments on monkeys by Charles Gross of Princeton turned up cells that respond selectively to hands and faces--not specific faces but faces in general.
No one had really followed up on Gross’s findings, however, until the late 1990s, when Fried and his colleagues started reporting how epileptic patients reacted to various images. Some neurons were apparently smart enough to comprehend the highly abstract concept "non-human animal." Their neurons fired when the patient was shown a picture of a tiger, eagle, antelope, and rabbit, but not when shown pictures of humans or inanimate objects. Other cells favored images only of food, or of buildings, or of human faces. Some cells responded to all faces, but others were picky, firing for male faces but not female ones, or scowling faces but not smiling ones—or, finally, faces of specific individuals.
One of the first neurons of this type was the so-called Bill Clinton cell, which was buried deep in the amygdala of a female patient. The cell responded to three very different images of the former President: a line drawing of Clinton laughing; a formal painting of him; and a photograph of him mingling with other dignitaries. The cell remained mute when the patient viewed images of other people, including male politicians and celebrities. Fried’s group found cells in other volunteers that responded in this same highly selective way to actors, including Jennifer Anniston, Brad Pitt, and Halle Berry.
One reason celebrities have played a prominent role in Fried’s experiments is that their photographs are often easier to come by than images of a patient’s own relatives. But as part of her dissertation project on biographical memory, the UCLA graduate student Viskontas has for several years been showing patients photographs of family members. Viskontas is reluctant to reveal details about her results, which have not been published yet. But she confirms that she has found neurons that respond to a particular relative: father, mother, brother, sister, grandfather, and, yes, grandmother. The experiments have also found cells that light up when a patient sees an image of himself. Call them narcissism cells.
Viskontas is wary of over-interpreting these results or others emerging from the UCLA program. She does not believe, for example, that they support the most extreme version of the grandmother-cell hypothesis, in which cells are exclusively and permanently assigned to one person, place, or thing. The past few decades, she adds, have revealed that brain cells are versatile, or "plastic," changing their roles in response to new experiences. The UCLA experiments may not be detecting long-term memory but so-called working-memory, in which cells are temporarily assigned to the job of representing Grandma, Jennifer, Aniston, or Rocky only as a result of the stimulation provided by the experiment.
Koch isn’t so sure. It would make sense, he argues, for our brains to dedicate some cells to people or other things frequently in our thoughts. The larger significance of the UCLA experiments, he says, is that neuroscientists may have to change their view of neurons as simple switches, transistors, or pixels. Each neuron may be more like a sophisticated computer, running customized software. After all, individual neurons can receive input from hundreds of thousands of other cells, some of which inhibit rather than encourage the neuron’s firing. The neuron may in turn encourage or suppress firing by some of those same cells in complex positive or negative feedback loops.
What excites Koch most about the thinking-cell results is the possibility that they may illuminate a fundamental component of cognition. Our comprehension of the world, he says, requires that we ignore much of the data flooding in through our senses. When we turn on a TV or reminisce about a movie, our brains somehow instantly compress raw sensory data into meaningful concepts and categories. This feat may be accomplished at least in part, Koch says, by cells that represent not just this or that particular image of Rocky but "the platonic ideal of Rocky."
Quiroga notes that a short story by a fellow Argentinian, Jorge Luis Borges, spelled out what would happen to us if we lacked this capacity for compression. Funes the Memorious tells the tale of a youth who, after falling from a horse and striking his head, becomes gifted, or cursed, with photographic recall of every minute experience. He is so overwhelmed by the infinitude of his perceptions that he retreats into a darkened room. "To think is to forget a difference, to generalize, to abstract," Borges writes. "In the overly replete world of Funes there were nothing but details." Unlike Danny, Funes had lost the capacity to perceive the platonic ideal of Rocky.
In Danny’s hospital room, weighty philosophical issues yield to more practical concerns, like getting a tray on rollers properly positioned over his lap. "I’m not an engineer, just a scientist," Quiroga says apologetically as he struggles with the balky tray. He eventually succeeds with the help of Emily Ho, who is an engineer, and the team’s chief troubleshooter.
As other researchers come and go, Ho remains in Danny’s room, manning the amplifiers, computers, and other equipment. When the readouts from Danny’s microwires go haywire, Ho starts checking lights and other appliances that might be causing electrical interference. Within minutes she traces the problem to the remote-controller that Danny uses to make his bed go up and down. After she unplugs it, the readouts return to normal.
The atmosphere in the room is surprisingly cheery. One reason is the frequent presence of Danny’s father, Bill, owner of a carpeting business. Although silence reigns during experiments, so that Danny doesn’t get distracted, between sessions Bill teases both the researchers and his son. At one point, Ho, watching signals from Danny’s neurons scroll across a computer screen, tells him that he’s got "great brain cells."
"Are you kidding?" Bill exclaims. "He’s got lousy brain cells!"
Danny grins, even more so later after his father fumbles a styrofoam container of Chinese food, sending chicken chunks skidding across the floor. "Who’s got the lousy cells?" Danny chortles.
Bill turns serious when asked why he and his wife agreed to let their son participate in these studies. "It’s a duty," Bill says. Danny, Bill points out, has benefited because many other patients before him have volunteered to be subjects for research. In the future, people suffering from epilepsy or other brain disorders may benefit from what the UCLA team learns from Danny.
For his part, Danny says he enjoys hanging out with the scientists and doing the experiments--"as long as there’s no math."
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