Most patients take Ambien to sleep, but in some specific cases it seems the insomnia pill can assist brain-injured patients to wake out of minimally conscious states.
After a near-drowning deprived his brain of oxygen, George Melendez remained in a minimally conscious state until his mother, in 2002, gave him Ambien to quiet his moaning and writhing. The next thing she knew, her son was quietly looking at her and trying to talk. He has been using the drug ever since to maintain awareness, but no one could understand why Ambien led to such an awakening.
Now, a team of scientists led by Weill Cornell Medical College has discovered a signature of brain activity in Melendez and two other similarly “awakened” patients they say explains why he and others regain some consciousness after using Ambien or other drugs or treatments. The pattern of activity, reported Nov. 19 in the journal eLife, was identified by analyzing electroencephalography (EEG) tests.
“We found a surprisingly consistent picture of electrical activity in all three patients before they receive the drug. Most interesting is that their specific pattern of activity suggests a particular process occurring in the brain cells of the cerebral cortex and also supports the role of a crucial brain circuit,” says the study’s senior investigator, Dr Nicholas Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience and professor of public health at Weill Cornell, in a release. “These findings may help predict other patients who might similarly harbor reserve capacity, whether they are able to respond to Ambien or other approaches. We are focused on finding ways to identify patients who have a functional reserve of cognitive capacities that can be rescued and how to achieve this result.”
Although each patient’s brain was damaged in different ways, all showed the same unique features of low frequency waves in their EEG readings. These oscillations are most prominent over the frontal cortex, a region strongly dependent for its activity on other brain structures, particularly the central thalamus and the striatum, which together support short-term memory, reward, motivation, attention, alertness, and sleep, among other functions.
In this setting of an idling brain, the investigators propose that Ambien works like any anesthesia drug, in that it briefly triggers a fast wave of excitation in brain cells before producing sleep—a phenomenon known as paradoxical excitation. Instead of going on to produce sedation and sleep, as it does in healthy people who use the drug, zolpidem further activates the brain after it has affected the idling cells, allowing the patients to become more awake than at baseline. “What we think is happening in these patients is that the initial excitation produced by Ambien turns on a specific circuit. The drug creates the opportunity for the brain to effectively catch a ride on this initial wave of excitation, and turn itself back on,” Schiff says.
This proposed “mesocircuit” links the cortical regions of the brain to the central thalamus and striatum. Neurons in the central thalamus are highly connected to other parts of the brain, “so damage in one part of the brain or another will affect the thalamus, which is key to consciousness,” Schiff says. Neurons in the striatum “will only fire if there is a lot of electrical input coming to them quickly,” he says.
“We believe the switch that Ambien turns on is at the level of the joint connections between these three brain structures,” Schiff says. But the circuit turns off again when the effects of the drug diminish. Using the drug regularly at mealtimes, Melendez can speak fluently, and read and write simple phrases. His tremors and spasticity are significantly reduced on Ambien and he can use objects, such as a spoon, and is alert and can communicate. The first patient in the study can reliably move from minimally conscious to “the mid-range of what is called a confusional state—a more alert status, but not full consciousness,” Schiff says. “Use of Ambien offers a step in the right direction, but certainly not a cure.”