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 by on a laptop screen. Several macho movie stars appear in rapid succession, including Arnold Schwarzenegger, 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 that the defect 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.
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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 five films in the series and never tires of watching them. So, amid the images that pop up 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, and draped in the American flag after defeating his Soviet 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 60 ultrathin 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 on top of the cabinet displays the readouts from Danny’s cells as a series of multicolored 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 a name. Rodrigo Quian Quiroga, the Argentine 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 using satellites to study life on a cloud-shrouded planet. 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 Caltech 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 University. 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. This is the first time a reporter has watched Fried’s team at work.
Born and raised in Israel, Fried 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 a dozen tiny 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 who is looking forward to working with the research team as a way to “break the boredom” of his hospital stay. “OK, let’s get down to practical issues,” he continued in his distinctive Israeli accent. At rapid-fire speed, 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 kept 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 registers 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 our episodic memory for places. More than a decade ago microelectrode studies of rats and monkeys revealed place cells that respond when the animals move to a particular spot in a maze. Previous versions of X-Cab, which involves driving a virtual taxi through a cybercity, 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 Indre 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. “If not, to work.”
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A SUPERCHARGED MICROPROCESSOR Each of the 100 billion neurons in the human brain is an elaborate processor powered by neurotransmitters. These electrically charged chemicals accumulate at the receptor nodules of antenna-like dendrites and activate the cell body, which in turn shoots an electric signal down the neuron’s output wire, the axon. At the axon’s end, the signal releases bundled packages of additional neurotransmitters, which burst free and power other neurons. —Susan Kruglinski
Graphic by Bryan Christie DENDRITES A typical cell in the cerebral cortex, the center of cognition, can receive up to 150,000 contacts from other neurons through its dendrites (upper left). Branches are covered in thousands of tiny receptor nodules called synapses. More than 50 varieties of neurotransmitters may make contact by binding to molecules at the synapse, where they become electric. AXON The positively charged cell blasts electricity down the wiry axon (lower left). A bare axon conducts a signal at one to 20 miles per hour, while axons with a fatty insulation called myelin conduct electricity at up to 270 miles per hour, the speed of wind in an F5 tornado. ACTION POTENTIAL When about 0.1 volt kicks in (1/100,000 the strength of a static shock from a rug), negatively charged potassium rushes out of the cell, and positively charged sodium floods in at 100,000,000 ions per second. The cell charge then flips from negative to positive. A neuron can generate action potentials (upper right) at a rate of 300 per second. SYNAPTIC TRANSMISSION Electricity signals the release of neurotransmitters, which exit the axon in packets of about 5,000 molecules (lower right). The chemicals break free en route to the next dendrite synapse. The type of neurotransmitter and the strength of each connection to the synapse affect the functioning of the recipient neuron. |
