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The first report of a zolpidem awakening came from South Africa, in 1999. A patient named Louis Viljoen, who, three years before, was declared vegetative after he was hit by a truck, had taken to clawing at his mattress during the night. Thinking he was suffering from insomnia, his family doctor suggested zolpidem to help him sleep. But 20 minutes after his mother ground the tablet up and fed it to him through a straw, Viljoen began to stir. His eyes, which normally wandered the room, vacant and unfocused, flickered with the light of consciousness. And then he began to talk (his first words were “Hello, Mummy”), and move (he could control his limbs and facial muscles). A few hours later he became unresponsive. But the next day, and for many days after that, zolpidem revived him, a few hours at a time.

Here was a case worthy of Hollywood: three years was well past the point at which doctors would expect any sort of spontaneous recovery. Viljoen awoke with the ability to speak in complete sentences. Not only did he recognize his mother, but he also recognized the voices of people who had spoken to him only when he was apparently vegetative. He remembered nothing of the mysterious realm he kept receding back into. When doctors asked him what it was like to slip away, he said he felt no changes at all. But he could recall conversations from the previous day’s awakening, along with bits and pieces of his former life: his favorite rugby team, specific matches he attended, players that he rooted for and against. As time passed, his cognition improved. He could laugh at jokes, and his awakenings stretched from a few hours to entire days. Eventually, he no longer needed zolpidem.

Photo

Chris in 2008, shortly before his coma. Credit Todd Baker
In the years that followed, a steady trickle of similar reports emerged — some from doctors who tried zolpidem after hearing about the Viljoen case, others from those who discovered its benefits accidentally, as Viljoen’s doctor had. The drug did not work for everyone, and even when it did, its effects typically wore off after an hour or two. But for a lucky few, those effects were profound. People who seemed vegetative for years were waking up.

There are roughly 200,000 patients in the United States trapped in

the borderlands between consciousness and oblivion.

Until recently, most doctors believed that recovering from this

condition was not possible.

Vegetative states were considered permanent after three months if the injury was caused by oxygen deprivation, or one year if it was caused by blunt trauma. And since minimally conscious patients did not fare much better than those who were vegetative, most doctors did not bother to draw the distinction.

But in the past decade, a series of developments have coalesced into a far more complicated picture than previously imagined. In 2003, an Arkansas man named Terry Wallis emerged, after 19 years, from a minimally conscious state. Neuroimaging suggested that his brain had essentially reconfigured itself — surviving neurons bypassed dead ones and forged new connections to one another. In a 2007 Nature paper, Nicholas Schiff, a neurologist from Weill Cornell Medical College, and his colleagues showed that deep brain stimulation — surgically implanting a “brain pacemaker” that sends electrical impulses to specific regions of the brain — can help some severely injured patients recover the ability to speak and eat, years after the injury. And just this month, Adrian Owen, a British neuroscientist, reported in the journal The Lancet that the brains of some patients who seemed vegetative responded to basic commands: their bodies didn’t move, but distinct patterns of neuronal firing were detected on EEG scans when these patients were told to make a fist (which triggered one region of the premotor cortex) or wiggle their toes (which triggered another).

This year, scientists at Moss Rehabilitation Research Institute and at the University of Pennsylvania, both in the Philadelphia area, began the first large-scale clinical study of zolpidem as a treatment for disorders of consciousness. (Amantadine, a drug used to treat Parkinson’s disease, and the anti-anxiety medication Ativan also show promise in increasing awareness in minimally conscious patients.) So far, the evidence suggests that less than 10 percent of brain-injured patients will experience the drug’s paradoxical effects, and that among those, only a few will respond as profoundly as Viljoen did. For families like the Coxes, such odds provide a tortured kind of hope. For doctors, they bring questions. Why does a sleeping pill induce awareness in some patients but not others? And what can these bizarre awakenings tell us about the brain’s ability to heal?

Two weeks after Chris first emerged from the coma, he began tracking objects with his eyes. At one month, he could follow simple commands. “His friends would come in the room, and there’d be two or three on each side of the bed,” Judy recalled. “And eventually, when they’d say, ‘Look at Jim,’ or ‘Look at Bob,’ he’d fix his eyes on the right guy.” Wayne and Judy asked for a follow-up M.R.I., but their neurologist said it would be pointless. Chris’s behaviors were entirely reflexive, he said; they were produced by his brainstem, which regulates basic functions like breathing and body temperature, not by his cortex, the region responsible for higher-order thinking. That Chris’s friends and family saw him following commands was proof of their denial, not of Chris’s recovery.

“Every couple days, the doc would stop in the doorway and shout Chris’s name to see if Chris responded,” Judy said. “But he wouldn’t come in the room and look at Chris up close. So one day, I practically grabbed his arm and dragged him into the room, over to Chris’s bed.” She told Chris to blink his eyes. He did. Then she made the doctor walk across the room and told Chris to keep his eyes on the doctor. He did. Finally, with the doctor standing across the room, eyes fixed on Chris, she asked Chris to give her a thumbs up. When he wiggled his thumb, just the tiniest bit, the doctor’s jaw dropped. Chris was not in a vegetative state after all. He was minimally conscious.

Still, there was little that the community hospital could do for him. It had neither the resources nor the expertise to tease out a prognosis or chart a course of therapy. The same was true of local nursing homes, which is where many patients like Chris end up.

Photo

Credit Stephanie Sinclair/VII, for The New York Times
So Wayne and Judy took over their son’s care, bringing him first to a premier brain-injury center in Atlanta (where Chris had a device implanted in his spine, which releases drugs to help with spasticity) and then to a clinic in Destin, Fla. (where he tried an experimental treatment known as hyperbaric oxygen therapy). They had just made their way back home to Tennessee when a friend told them about the Ambien paradox and the clinical trial in Philadelphia.

One hallmark of the minimally conscious state is a rapid fluctuation between levels of awareness. Spend 10 or 20 minutes with Chris Cox, and you might conclude that there is nothing going on upstairs. But spend a full hour, and at some point you’ll see his puppy-dog eyes come into focus. They will appear to search for one of his parents, or to settle quizzically on the new person in the room. Ask him to say something, and he’ll smack his lips frantically before leaning forward and tapping his feet in apparent frustration. You’ll swear that he is there with you and that only his physical infirmities (he cannot quite swallow or control his jaw) prevent him from describing the netherworld from which he has just emerged.

And then, a few minutes later, he’ll slip away again.

This fluidity makes diagnosis a challenge. “If a patient follows every command you give them, you know that,” says Dr. John Whyte, director of the Moss Institute and lead investigator on the zolpidem trial. “If a patient has never, ever followed a command, you know that too. But if you tell a patient to wiggle their finger, and they do it occasionally — which is the case for most of these folks — how do you figure out if that ‘occasionally’ means something or not?”

Whyte has spent his entire career trying to answer this question. His first job after his residency was at a facility with a large number of vegetative patients. While working there, he was struck by the amount of contention over diagnoses. For all their experience with this population, clinicians could not seem to agree on whether any given patient was actually conscious. Family members also argued, with one another and with staff, over the meaning of every wince, twitch and eye flutter.

It turned out that a lot of people — staff members included — were drawing their conclusions from pure coincidence. Whyte told me about one mother who insisted that her son would point down toward his feeding tube to indicate that fluid was leaking onto his stomach, causing irritation. “He did it while I was there,” Whyte says. “And she lifted his shirt and said: ‘See, doctor, there’s the liquid. He’s communicating with us.’ And I said: ‘How often do you look under there when he isn’t pointing like this? Never? Not even once?’ ” It was possible that the pointing corresponded to the leak, Whyte explained. But it was also possible that the leaking was constant and the pointing was random. There were countless other examples. “Behaviors would be exceptions if they happened at the wrong time, and evidence if they happened at the right time,” Whyte says.

To help eliminate this bias, Whyte developed what he calls the single-subject assessment, in which doctors design a set of tests specific to each patient’s idiosyncrasies to determine whether the patient is vegetative or minimally conscious. It is painstaking work, but the information it yields is significant. “Patients who achieve minimal consciousness early tend to have a better prognosis,” Whyte says. “And you can at least try to build a communication system with them, because you have a foundation to work from.”

With a reliable assessment method in place, he began searching for ways to build on that foundation. Then the curious Ambien awakenings caught his attention.

Photo

Credit Stephanie Sinclair/VII, for The New York Times
It’s not entirely surprising that Ambien would arouse instead of sedate. The pill has long been linked to reports of bizarre sleepwalking behavior (not to mention sleepeating, sleeptalking, even sleepdriving). Some scientists call this phenomenon “paradoxical excitation.” So far, none of the accepted determinants of prognosis — age, overall health, the nature of the initial injury or the extent of brain damage as determined by an M.R.I. — have proved useful in predicting which brain-injured patients will experience it and which won’t. To begin answering that question, Whyte says, you need to study both responders and nonresponders in an unmedicated state.

One morning this past March, I met Chris, Wayne and Judy at the University of Pennsylvania’s main hospital, where they had been flown in from Tennessee, at the study’s expense, so that Chris could be tested in an unmedicated state. From the corner of a small hospital room, we watched as Whyte’s research assistant, Andras Szeles, attached dozens of tiny electrodes to Chris’s face and scalp, then fitted him with a large headset. The electrodes would measure Chris’s brain activity as Szeles administered a series of cognitive tests.

For one test, Szeles placed a rubber glove on Chris’s right hand. A voice coming through the headset told Chris to either “squeeze glove” or “squeeze bare,” several times over. Chris did not seem to be responding at all, but Szeles explained that the electrodes would measure what the naked eye could not. “We’re not so interested in whether or not Chris can squeeze,” he said. “We just want to know if he’s trying to squeeze.” Different neurons fire when you move your left hand versus your right hand. They also fire if you imagine moving it, prepare to move it or start to move it but stop, all of which the electrodes would detect.

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