ZOLPIDEM PARADOX

Researchers are gaining insights into why some minimally conscious patients with a severe brain injury appear to "awaken" after taking the sleep medication zolpidem (Ambien, Sanofi-Aventis).

The answer may lie in a pool of recruitable and functional brain cells that are activated in response to zolpidem treatment, Nicholas Schiff, Jerold B. Katz Professor of Neurology and Neuroscience, and professor, public health, Weill Cornell Medical College, New York, New York, told Medscape Medical News.

"What's new here is that we have insights as to the mechanisms," explaining the well-documented paradoxical awakening in brain-injured patients given zolpidem, said Dr. Schiff.

The new research was published online November 19 in the open-access journal eLife.

Additional Insights

The observation that zolpidem can have a paradoxical arousal effect on patients with a severe brain injury dates back about 6 years and has been reported by many different groups. For example, Dr. Schiff and his colleagues previously described the case of a 48-year-old woman who had been in a minimally conscious state for 2 years following a suicide attempt. She couldn't move, feed herself, or speak. When given zolpidem to treat insomnia, she could communicate, eat, and move unassisted within 20 minutes.

At the time, researchers noted from imaging studies that regions of the woman's brain, including the frontal cortex and the thalamus, were highly active when she was receiving zolpidem and very inactive when she wasn't.

Brain damage can result in loss of a pathway consisting of excitatory projections from the cortex to the striatum, which in turn sends inhibitory projections to the globus pallidus, Dr. Schiff said. The net effect can be inhibition of the thalamus, which, along with the striatum, supports alertness and sleep as well as short-term memory, reward, motivation, and attention.

In this report, Dr. Schiff and colleagues present additional insights from observations of 3 patients with severe brain injury patients: One had sustained head trauma from a fall, another was oxygen deprived after nearly drowning, and the third had had multiple strokes from vasospasm after a subarachnoid hemorrhage. All 3 patients had shown strong arousal responses to zolpidem.

Using electroencephalography (EEG) while the patients were both on and off the drug, the researchers observed that despite having very different types of brain trauma, the patients had similar patterns of brain activity. The researchers found this "very surprising and very compelling," said Dr. Schiff.

"They were so similar that they almost looked like different measurements of the same person."

Off the drug, that pattern was a low-frequency rhythm or oscillation — about 7.5 cycles per second — in all parts of the brain, but more so in the front than in the back and on both sides, said Dr. Schiff. "This rhythm was about the same rate and was highly synchronized within each half of the brain and across the 2 halves of the brain."

When patients were receiving the drug, there was an increase in the average frequencies of brain waves, which correlated with improvement in alertness of the patients.

Dr. Schiff compared the initial arousal effect from zolpidem to the paradoxical excitation that sometimes occurs when low doses of an anesthetic induce excitation rather than sedation, or the initial "buzz" after consuming alcohol.

Zolpidem, which is selective for a subtype of gamma-aminobutyric acid (GABA) receptors, could block the inhibitory inputs from the globus pallidus to the thalamus, "thus allowing the thalamus to excite the cortex and help restore cognitive and motor functions," Dr. Schiff and his colleagues write.

Predictive Model

The researchers believe that the initial excitation produced by zolpidem allows the brain to ride on this "buzz." "It's like catching a wave and as those cells get recruited, they turn on and as they start to actually function and do things, then they wake the brain up even more," said Dr. Schiff. "That whole process can hold on until the drug wears off."

The new findings should help identify residual capacity or untapped capacity in other people with severe structural brain injury, he said. "We discovered there is this marker for this potentially vast pool of usable cells."

This model could also help explain past success with treatments for severe brain injury, including central thalamic brain stimulation and amantadine, said Dr. Schiff.