UNIVERSITY OF CHICAGO SUMMER 2006 BIOLOGICAL SCIENCES DIVISION

AN ENEMY IN OUR MIDST ⌴␫⌵␦ ⌴␣␶␶⑀r

MIND OVER MATTER: MOVING OBJECTS WITH YOUR MIND HAS LONG BEEN FODDER FOR SCIENCE FICTION STORIES. NOW, RESEARCH IS TURNING IT INTO REALITY. By Kelli Whitlock Burton ⌵icholas Hatsopoulos adjusts university research groups working on the volume on his computer and looks the problem in the United States. around. “Hear that?” he asks. There’s Ten years ago, Hatsopoulos and a steady crackling noise coming from John Donoghue, his former postdoctoral the speakers, like hail on a tin roof. advisor at Brown University, became the Hatsopoulos smiles. The crackling first scientists to teach monkeys how to chorus is as satisfying to his ear as a move a computer cursor with their minds. good guitar riff by Jimi Hendrix, one Two years ago, they taught a person to do of his favorite musicians. it—a quadriplegic who was able to turn What seems like a hail storm actually on a television, check e-mail and wiggle is the sound of firing inside the fingers of an artificial hand, all with the motor cortex, the part of the his thoughts alone. The patient is part responsible for movement—a symphony of an FDA clinical trial of the BrainGate™ that just 15 years ago Hatsopoulos system, the product of a company could only dream of hearing, much Donoghue and Hatsopoulos launched less composing. in 2000. Listening to the brain is no small In a nutshell, the researchers have feat, and if that were the brightest note found a way to turn thought into action— in this little concert, it would be worth without moving a muscle. an ovation. But Hatsopoulos, an assistant professor of organismal biology and WHEN SCIENCE TICKLES anatomy at the University of Chicago, If his dark curly hair, deep brown eyes and can do more than eavesdrop. Along distinctive surname aren’t clue enough to with colleagues at Brown University, his ancestry, the strains of Mediterranean he has developed a way to record signals music coming from his office are a dead sent out by large groups of neurons— giveaway. Hatsopoulos’ parents grew up in commands telling the body how and Athens, Greece, but didn’t meet until the where to move—and to translate the orders into a language a computer understands and acts on. The technology is called a brain- computer interface—BCI for short—and it’s not a new phenomenon. Scientists have tinkered with BCI since the 1970s, but it’s only in the past decade that the technology’s true potential has been realized. The main thrust today is devel- oping BCI systems to aid people who are y r D paralyzed by injury or illness. While these n a D

patients’ limbs may be stilled, studies show y b

o t that the motor cortex is not. Hatsopoulos’ o h team is one of only about half a dozen P Chicago researcher Nicholas Hatsopoulos

19 20 MedicineontheMidway Summer 2006 “As soon as Irecorded“As as soon to becomeaprofessional bouzouki player. idea ofstayinginhisparents’ homeland to amandolin.He even toyed withthe similar with thebouzouki, aninstrument When hewasn’t inclass,hedabbled and computersforayear inGreece. Hatsopoulos decidedtoteachphysics to launchascientificcareer. Instead, after graduation,hewasn’t quiteready Still, whenitcametimetomakeplans to majorinphysicsat Williams College. Mass., justoutsideBoston.He even chose by sciencewhilehegrew upinLincoln, mother, Hatsopoulos wassurrounded dad aswell asamathematicianfor mechanical engineerandphysicistfora MIT andhismotherat Wellesley. With a t early 1950saftereachtraveled separately o Bostontoattendcollege,hisfatherat was hooked.” of aneuron I spiking, m li and the oscilloscope the e st y fir e that’s implanted in the brain’s motor cortex. that’s implantedinthebrain’smotor cortex. ofthebrain-computer interface— The siliconechip—part courtesy of Nicholas Hatsopoulos Nicholas of courtesy ne l e st c ctric d t ell and saw and ell o thec al spikes onal spikes rackle a P program atBrown. By 1992he’d earned he enrolled inthepsychology master’s Harvard mathematicalpsychologist. Soon and tookajobasresearch assistanttoa subconscious, sohereturned toBoston spiking, Iwashooked,”hesaid. oscilloscope andlistenedtothecrackleofa first cellandsawtheelectricalspikeson locust’s brain.“As soonasIrecorded my recording ofaneuron—a singlecellina insects’ . for apostdocwithscientistwhostudied bouz physics, psy Photo courtesy of Nicholas Hatsopoulos But somethingabout sciencetickledhis There, Hatsopoulos madehisfirst hD incognitiv Photo ouki, H chology atsopoulos headedtoCaltech e science.S , cognitionandthe killed in music onabouzouki? together toallow sweet someonetostrum workof neurons inthemotorcortex Hatsopoulos mused.How dothemillions coordinate theirfingersthatway,” work thesemusiciansdoandhow they have alwaysbeenenamored by thefinger do abound whencellswor inter the actionsofonebraincellmaybe that Hatsopoulos enjoys most.Similarly, hear, it’s the combinationoftheirsounds areindividual instruments beautifulto is muchlikehislove ofmusic. While the wnright fascinating. Take thebouzouki, forexample.“I Hatsopoulos’ appreciation forscience esting, butthepossibilitiesthat k togetherar e “What really turns me on in this Things started to come together when All this and the researchers weren’t research is understanding how these large Donoghue met Richard Normann from even sure the device would collect the groups of cells result in motor behavior the University of Utah. Normann had multi-cell data they needed. They trained or thought,” Hatsopoulos said. Studying developed a sensor array—a silicone chip a monkey to move a computer cursor by single cells, as he was doing at Caltech, about the size of a breath mint with 100 maneuvering a joystick with its arm, set would not help him find the answer. tiny electrodes, each capable of recording up their system, and watched. So in 1995, Hatsopoulos returned neuronal impulses. The array not only worked, it func- to Brown for a second postdoc with Donoghue and Hatsopoulos modified tioned better than the scientists had Donoghue. The neuroscientist was bent the array, which had only been used in hoped. In 1996, the team recorded signals on figuring out how to record as many cats and Petri dishes, for their studies from multiple brain cells in a monkey— neurons in the motor cortex as possible. with monkeys. Each electrode on the the first time anyone had collected data Hatsopoulos was more than happy to help. chip, which is implanted on the surface from the monkey using this array. “I of the motor cortex, picks up signals remember that moment as really exciting THE RECORDING from nearby neurons. Those impulses are from more of a scientific point of view,” INDUSTRY carried by gold wires that connect the Hatsopoulos said. “We were looking at Scientists had developed a way to listen chip to a titanium pedestal that protrudes the brain on a more global level, looking in on single brain cells years before about an inch from the monkey’s scalp. at a group of neurons that make up the Donoghue began his studies. Many tech- A cord extends from the top of the neural ensemble that is responsible for niques were employed, but one of the pedestal to a device that amplifies the everything that we do as thinking beings.” most successful was a mechanism created signals. A fiber-optic cable hooks the The next step was to identify patterns by Philip Kennedy, a scientist at Georgia amplifier to an acquisition system, which in neuronal activity related to movement. State University, who launched the first captures the neural impulses and sends Hatsopoulos’ job was to create algorithms human clinical trial of an implanted BCI them to a computer. that translated the chatter between the device. Consisting of glass cones with two microelectrodes designed to pick up neural impulses in the brain, the device was implanted in the motor cortex of a paralyzed patient. The woman was asked to think about moving a computer cursor. The device captured the cell signals and, using a radio transmitter under the scalp, sent them to a computer that decoded them and moved the cursor. s o l

But Kennedy could only record data u o p o

from one or two neurons with his device; s t a H

Donoghue’s sights were set much higher. s a l o h

He wanted to capture signals from dozens, c i N

f perhaps hundreds, of brain cells. Monitor- o

y s e t ing more neurons would provide a clearer r u o c

picture of brain activity, Donoghue believed. o t o h P

A titanium pedestal connects to the implanted chip.

“We were looking at a group of neurons that make up the neural ensemble that is responsible for everything that we do as thinking beings.”

21 neurons in the motor cortex into a A RELUCTANT language the computer could understand ENTREPRENEUR —language that conveys information His father’s dream had been to come to about movement. America and launch his own business. In That required Hatsopoulos to study the 1956, the elder Hatsopoulos did, creating monkey’s brain activity on a monitor that a company to market a device he’d devel- displayed graphs of the neurons in action. oped at MIT that converted heat energy When active, neurons fire between 20 and into electricity with no moving parts. 200 times a second, creating the spikes Entrepreneurship was not a dream on his computer. Hatsopoulos matched Hatsopoulos shared with his father. He neuronal signal patterns with each arm just wanted to be a scientist. But the work movement. A computer program outfitted he’d done with Donoghue changed all with his algorithms could recognize those that. Cyberkinetics was incorporated in patterns and move the cursor before the 2001. The following January, Hatsopoulos monkey moved a muscle. joined the faculty at Chicago and later Eventually, the monkey figured out that that year, the company merged with it didn’t have to move the joystick to make Bionics, a business started by the Utah A computer program the cursor move. These were exciting scientist who’d developed the array developments for the researchers, but outfitted with Hatsopoulos’ group modified for primates. there were annoyances, too. Hatsopoulos In August 2002, the company received Hatsopoulos’ couldn’t ask a monkey questions about its $5 million from a venture capital firm in thoughts or actions. The monkey couldn’t algorithms could Boston and applied for FDA approval to provide any feedback. The researchers’ recognize neuronal conduct a small clinical trial of their BCI excitement soon grew to frustration as technology, which they named BrainGate. they realized they’d taken the technology signal patterns in the “People have always believed this would as far as they could in animals. monkey’s brain activity be possible,” said Tim Surgenor, chief In spring of 2000, Hatsopoulos and executive officer for Cyberkinetics. “We’ve Donoghue discussed their work’s potential and move the cursor been reading about it in comic books to help people. And then, Hatsopoulos before the monkey and science fiction our whole lives and offered an idea that he never thought suddenly, someone comes along and says moved a muscle. would interest him. “What if we form it’s possible.” a company to do this?”

22 Cyberkinetics is trying The plan, Hatsopoulos said, wasn’t enroll up to five paraplegics for a one-year to develop a system just to create something that allowed trial, implant the device, and teach them paraplegics to control electrical devices to move a computer cursor with their that takes the brain’s with their minds. To set themselves apart minds, a small step toward giving those own movement from similar entrepreneurial efforts in the without the power to move the ability to BCI field, they needed another “killer app.” turn thought into motion. commands to the “We eventually came up with an idea “This technology is a whole new way outside world. that is implicitly the mission of our of dealing with neural repair,” Donoghue company: We want to provide the basic said. “Instead of finding a substitute signal operating system by which any brain- for movement—like using the eyes to move computer interface system can work,” he a cursor instead of a hand—Cyberkinetics said. “We want to be the Microsoft of is trying to develop a system that takes the communications between the brain and brain’s own movement commands to the the outside world.” outside world.” With a basic operating platform, tech- nology could be developed to help people ON TRIAL THE BRAINS BEHIND BRAINGATE with paralysis answer a phone, type a Cyberkinetics received its first volunteer letter, turn off a coffee maker—all at the for the trial in June 2004: Matthew Nagle, 1 The person thinks about moving the computer cursor. Electrodes on a silicone speed of thought. And scientists could a 25-year-old from Weymouth, Mass., chip implanted into the person’s brain build on Cyberkinetics’ operating system detect neural activity from an array whose spine had been severed at the neck of neural impulses in the brain’s to develop therapeutic devices for neuro- motor cortex. in a knife attack five years earlier. logical disorders: For example, a chip Nagle underwent a five-hour surgery, in 2 The impulses transfer from the chip to a pedestal protruding from the scalp implanted in the brain of an epileptic which physicians made an 8-inch incision through connection wires. that senses when a seizure is likely and in the scalp and bone, exposing the motor 3 The pedestal filters out unwanted signals emits an electric jolt to stop it. or noise, then transfers the signal to an cortex. They placed the silicone chip on the amplifier. It took a year and five cases of supportive brain surface with the electrodes penetrating 4 The signal is captured by an acquisition documents to prepare the FDA application, the cortex about 1 millimeter down. The system and is sent through a fiber-optic but by the middle of 2004, Cyberkinetics cable to a computer. The computer then pedestal was positioned and the scalp translates the signal into action, causing received the go-ahead. The plan was to closed around it, leaving about 1 inch the cursor to move. protruding from the top of Nagle’s head. Three times a week, Nagle was visited PEDESTAL by Maryam Saleh, a technician who used to work with Cyberkinetics and now is a SILICONE CHIP doctoral student in Hatsopoulos’ lab. Saleh’s first task was to teach Nagle to think about moving. Before he was paralyzed, if Nagle wanted to move a computer cursor,

COMPUTER SYSTEM he reached out his arm, grabbed a mouse, and moved it. Without use of his

AMPLIFIER limbs, however, he must rely on his mind. But how do you teach someone to “think” about moving? n a m l l U a n i t s i r h C y b n o i t a r t s ACQUISITION SYSTEM u l l I FIBER-OPTIC CABLE 23 “Training patients to move things “What’s so intriguing about this is NORMAL NEURAL ACTIVITY with their minds is difficult and different that we’re really listening in on what CELL BODY OF MOTOR NEURON with each patient,” Saleh said. She had neurons are doing,” Penn said. “This is Signals sent through Nagle visualize himself moving the cursor, the strangest, most interesting surgery dendrites cause chemical changes that result in an a simple-sounding command that took I’ve ever done in that sense. Not the electrical signal in the cell body. him months to master. Then, during one technical stuff, but the data that we get of their all-day sessions, Nagle did it. from the neurons firing in different DENDRITES He thought about moving the cursor— patterns when you’re thinking in different and it moved. ways. And seeing it is only the beginning.” “He was so excited, he told everybody,” Researchers presented findings from AXONS Nerve impulses said Saleh, who now is working with a Nagle’s trial, which ended in 2005, at the are carried through axons patient in Chicago who enrolled in the Society for annual meeting away from MUSCLE trial last year. “Most people involved in later that year. Although the results are the neuron’s FIBERS cell body. the study think of themselves as pioneers. preliminary, they suggest the BrainGate n a m l l Even though they’re told that this is system works. U

a n i NEUROMUSCULAR JUNCTION t specifically geared toward controlling a So far, four volunteers have joined the s i

r The signal is passed by neuro- h

C computer cursor, they see the prospects for trial: two with spinal cord injuries, one

transmitters from synaptic bulbs on y b

the neuron to muscle fibers. The

n future applications. That’s why they do it.” with amyotrophic lateral sclerosis (ALS, o

i muscle fibers then react to the signal. t a r t Indeed, study participants are told at also called Lou Gehrig’s disease) and a s u l l I the outset that the trial’s goal is to help stroke patient. scientists learn how to improve the “Depending on their specific situation BrainGate system and how to train future and their specific interest, [people with patients to use it. The system won’t disabilities] may be interested in computers operate without a technician’s assistance turning text into speech, dialing telephones, and when the yearlong trial is over, the playing games, controlling their environ- entire apparatus—pedestal, chip and all— ment, moving their wheelchairs and is removed. moving their arms,” Surgenor said. “For “This isn’t being done for the patient’s each of these four participants, I think benefit; it’s being done for mankind’s each one is interested in something benefit,” said Richard Penn, professor of different. We have to develop something neurosurgery at Chicago who operated on that’s flexible enough to work with a another study participant with whom number of different devices.” Saleh now works. SET IT AND FORGET IT! An unabashed fan of infomercials, 6 Study participants are told at the outset that the 0

0 Hatsopoulos draws his philosophy about 2

r

e trial’s goal is to help scientists learn how to improve this project from a jingle he heard on a m

m promotion for a rotisserie oven. Baking a

u the BrainGate system and how to train future S

chicken or roast in a conventional oven is

y patients to use it. hard, messy work that requires constant a

w oversight, the infomercial host proclaimed. d i M e h t n o e n i c i d e M

24 Just what is the brain-computer interface going Finally, the researchers need to focus to interface with? A robotic arm? A computer? on the end target: Just what is the brain- computer interface going to interface A wheelchair? with? A robotic arm? A computer? A wheelchair? That may be the most difficult question of all—and one that But with the rotisserie, you can “set it From a physiological standpoint, the scientists must answer if they are and forget it!” researchers need to find out just how to prove that BrainGate is better than “That’s exactly my philosophy on long the chip can remain in the brain what’s already out there. electrophysiology. You put the device and continue to function. Some of the “The kind of control that can be in and you forget it,” he said. “That’s monkeys they’ve studied received implants obtained, I believe, will surpass these different than the way we used to do three years ago that still function with no other current methods,” Hatsopoulos said. recordings, with a single electrode that changes in brain physiology. But it’s yet “We’re just scratching the surface now.” you had to move around and spend to be seen how a long-term hours collecting data. Here, you just will affect a human. ‘set it and forget it!’” At least, that’s the hope. BrainGate SILICONE CHIP has a long way to go before it functions The chip is implanted in the well without oversight. For example, brain’s motor cortex. the cables and components patients use now are fairly onerous and impractical. 1 MM Hatsopoulos and Donoghue want to PEDESTAL make the system wireless. There’s also work to be done on the 4 MM array’s ability to capture neuronal impulses.

Now, the quality and number of signals Actual size recorded are inconsistent, and Hatsopoulos doesn’t know why. The team also wants to improve the decoding software that translates the brain’s electrical chatter into movement commands a machine MOTOR CORTEX This neuron-rich area of the brain can follow. That requires faster and initiates body movement. more accurate algorithms, a task assigned to Hatsopoulos’ group.

CHIP SENSOR PROCESS Sensors, or electrodes, on the silicone chip detect signals sensor on from surrounding neurons motor cortex silicone chip in the brain’s motor surface cortex. This area is highly saturated with neurons, but each sensor only signals needs to detect signals from 10 to 50 neurons n a

m to trigger the BrainGate l l

U system to move the

a n

i computer cursor. The t s i

r sensors act as facilitators

h neurons

C for the message, which is release y

b carried out by the computer. signals n o i t a r t s u l l I