Hundreds of thousands of patients in the U.S. languish in unconsciousness, cut off from the world by severe brain injuries. But the latest research hints that some of them may still retain reserves of conscious awareness and that there may be ways to reach them — with sleeping pills, antiviral medications, or electric stimulation — and help them to reawaken.
George Melendez was all but dead in January of 1998, when he was pulled from the wreckage of a car that had landed in a small pond on a golf course near Houston, TX. Medics revived him but the combined brain trauma of the accident and near drowning left the then 23-year-old college student in what doctors call a minimally conscious state—awake and occasionally aware of his surroundings but incapable of producing any reliable responses—verbal or otherwise. His mother and stepfather cared for him at home, feeding him by tube, handling his bathing and toileting with the help of a part-time aide. The doctors told them not to expect much, but the parents never lost hope.
It’s these patients, such as Melendez, that scientists are hoping to reach. In 2002, a doctor prescribed the common sleep drug zolpidem (Ambien) to ease his thrashing and moaning at night. That’s when something extraordinary occurred: Melendez woke up.
“Within ten minutes, his face changed totally,” says his mother, Pat Flores. Before, one eye remained open while the other was closed, and Melendez would rub his lip, moaning and shaking. On Ambien, he was composed, opened both eyes and started gazing around the room. “When I said, ‘George,’” Flores recalls, “he said, ‘What?’ And I about fell off the bed!” Flores and her husband stayed up talking to their previously silent son, who, as it turned out, remembered everything about his life except the accident. The next morning, after getting another dose of Ambien, the young man who had been tube-fed for four years ate pancakes for breakfast, using his own fork and wiping his own chin with a napkin.
What happened to Melendez was not a miracle. Though Ambien won’t have the same effect on most patients with impaired consciousness, it can help an estimated one in 15, according to one small-scale trial published in 2009. And a new study by a team led by neurologist Nicholas Schiff at Weill Cornell Medical College in New York City helps to explain why. Perhaps more importantly, the research also identifies a detectable pattern of brain activity that could signal which minimally conscious patients have the potential to awaken further. The study, published in the new journal eLife, is part of a surge of new research that provides insights into what doctors call “disorders of consciousness” and could potentially lead some of those trapped in these states to function more fully on their own.
Although the exact number of patients like Melendez isn’t clear, according to one estimate by experts, nearly 300,000 people in the U.S. hover on the edge of awareness in a minimally conscious state. Most are victims of road accidents, falls, violence, strokes and other events — medical or accidental — that cut off the flow of oxygen to the brain, causing permanent damage to brain cells.
Overall, doctors recognize three categories of consciousness disorders. Coma is a complete loss of consciousness in which the eyes remain closed and there are no sleep-wake cycles. It is generally a temporary condition that can last days or weeks following a major trauma. Patients may recover or progress to another disorder of consciousness. A persistent vegetative state, as its name implies, can last for years, as it did in the famous right-to-die cases of Karen Anne Quinlan and Terri Schiavo. People in a vegetative state have wakeful periods when their eyes are open and appear to gaze around the room, but their responses to touch or sound are mainly reflexive. Still, recent studies using functional magnetic resonance suggest that even a small portion of these patients may retain some conscious awareness. The minimally conscious state has only been recognized since the 1990s. Patients can show purposeful behavior, but not consistently. The prognosis is poor but variable. One famous patient, Terry Wallis of Arkansas, awoke after 19 years and is now able to have halting conversations.
How does that happen? Seeking answers, Schiff examined the brain activity of three minimally conscious patients that responded well to Ambien: Melendez, now 39; a 45 year-old man who suffered a traumatic brain injury in 2009 after falling from a ladder onto a concrete floor; and a 55 year-old woman who suffered a series of strokes in the wake of an aneurysm. All three showed marked improvement when given Ambien, regaining their speech and motor control, though, for the most part, these responses lasted only as long as the drug was in their system.
Although the brain damage and its cause were different in each patient, Schiff and his associates discovered that all three had the same unusual pattern of brain activity when they were monitored by electroencephalogram (EEG): a spike of activity, at a low frequency (7.5 Hz) that was tightly synchronized across both halves of the brain and most prominent over the front of the brain. This abnormal pattern—akin to a motor idling rather than engaging its gears—disappeared when the patients were given Ambien.
In similarly encouraging results, last year a randomized controlled study of 184 patients, published in the New England Journal of Medicine, showed that the drug amantadine, an antiviral medication sometimes used to treat Parkinson’s disease, can speed up the early stages of recovery for patients in minimally conscious or vegetative states. Electrical stimulation into the thalamus can also dramatically awaken some patients, though the effect subsides when the stimulation ends.
How these interventions work and why they help some and not others is a critical question for researchers, says Dr. John Whyte, director of the Moss Rehabilitation Research Institute near Philadelphia, and co-author of the amantadine study, the 2009 trial of Ambien and a forthcoming larger study of Ambien. Minimally conscious patients are an extremely heterogeneous group, and mostly defined by what they cannot do. Key to helping them, says Whyte, is finding some more standard, biological measure of their potential. “We need to segment the population into people who have biologically distinct physiology that is relevant to how the interventions work.”
That is exactly what Schiff was seeking in his small study. He suspects that the unusual EEG idling pattern may be an indicator that crucial parts of the cerebral cortex—the thinking part of the brain—are alive and capable of functioning, but that trauma has disconnected them from key brain circuits that they need in order to fire normally. Particularly important are connections to the striatum and thalamus, structures in the mid-brain that play a key role in consciousness and controlling movement.
“We believe that the switch that Ambien turns on is at the level of the joint connections between these three brain structures,” says Schiff, who is the Jerold B. Katz Professor of Neurology and Neuroscience at Weill Cornell. The drug, he explains, kickstarts the brain by firing up neurons sensitive to the neurotransmitter GABA. Even though Ambien is a sedative, it creates a buzz much like alcohol (also a sedative) and “that buzz is enough to turn on lots and lots of brain circuits,” he says. “It’s like catching a ride on a wave.”
Schiff is now working to find out whether the EEG pattern, is, in fact, an important marker not only for response to Ambien but potentially to other therapies.
Even the fortunate few who have seen wondrous effects from Ambien are hoping for more powerful and durable interventions. Thanks to Ambien, which he takes three times a day, George Melendez can swallow food and respond to his environment, “but initiation of speech comes sporadically,” says Flores. Their last prolonged conversation occurred three years ago. That’s when George asked his mother, ”Why am I like this?” After she described his accident, “he got real sad and pensive,” she says, “and then he said, “It’s good I’m alive.” Flores’ hope is for treatments that will make that kind of lucidity and fluency more lasting for her son and others like him.