Nicholas Schiff, Weill Cornell Medical College, New York
The sedating medication "zolpidem" has the paradoxical effect of waking up some patients with severe brain injuries...
Nicholas - We had the good fortune of finding three subjects, all of whom came to us with the history that they would respond paradoxically and improve their behaviour with zolpidem. And, what we did was we brought them in, carried out behavioural assessments, allowed them to take their medications as they were doing and collected continuous electrophysiology data, behavioural data, and cerebral-metabolic data before and after they received the medication zolpidem, to look at brain activity across different times of the day and to make comparisons within and across the patients as to what might be happening.
Chris - Tell us what these patients were like before you gave them any zolpidem, what was the baseline situation?
Nicholas - Each patient was different. One patient was in what’s called the minimally conscious state, he showed very clear responses to his environment to indicate that he had some level of consciousness ,but he could not reliably follow commands to do things. He did not speak, he did not answer questions, and he could not organise movements to show basic goal-directed behaviours. On the drug, he reliably and consistently could speak in sentences, he could answer basic questions about himself, historical information about his life, he was able to demonstrate easily the use of common objects, he could also write, and he could ambulate, and he could carry out a wide range of relatively high level cognitive operations. And he would maintain this level of function on the drug for about two and a half hours and then it would start to fade.
Chris - And if you asked him to recall what it was like being off the drug next time he was on the drug, could he recollect that at all?
Nicholas - No. He was not oriented to his situation and he did not show a continuity of memory of his state when he was not on the drug.
Chris - So, we’re in this bizarre situation where you’ve got patients like this and you give them what’s otherwise, a sleeping medication, and they wake up. Why do you think this is happening?
Nicholas - Well, the most interesting thing was that when we looked at these very different patients, their brain injuries were very different. But, yet when we look at their electrical activity, we found that remarkably they had very similar frequencies of oscillations, at around 7.5 cycles per second, mostly over the front part of their brain. And we realised that the number of the oscillations, the 7.5 cycles per second might actually point to a very specific hypothesis which was that these oscillations could be generated by what’s called intrinsic activity of the cell membranes, that the cells just oscillate on their own like a crystal. When they have a little bit of input but not enough to generate the typical kind of firing the nerve cells generate by getting lots and lots of inputs from other nerve cells, integrating them and then deciding to fire an informative signal.
Chris - So, why would giving zolpidem remedy that?
Nicholas - What we believe is that it would have a direct excitation effect at the cortical cells, but also a suppression of the cells in the globus pallidus, which is the structure in the centre of the brain that can inhibit the thalamus, and the thalamus is the critical structure for arousing or turning on activity across the cerebral cortex. So, the old model, which we call the the MISO circuit model, suggests that after structural injury, in general, the front half of the brain is much more down than the rest of the brain. And that the critical node here is the central thalamus, which plays a role in activating all these structures. And that zolpidem allowed the restoration this thalamic activity and that’s why these cells which are just sitting in an idling position, start firing the way they normally would by responding to inputs selectively, and playing a role in the exchange of information and computations at the level of the cerebral cortex.
Chris - And do you think that by bringing people back to life almost in this way, that this might enable you to tap into more plasticity and therefore, their brain can recover better when they’re in an on-state like this on the drug?
Nicholas - Well in fact, of the three subjects, there’s a little bit of a hint that something like that may be the case. The second subject, unlike the first two, regularly took the drug for 5 years, 3 times a day, every day, and over that 5-year period, the patient changed from being in minimally conscious state when off the drug, to recovering to a level above minimally conscious state, even at base line. So that suggests that there is an increase in background activity and some element of plasticity arising through the continued use of the drug. So, I think that is likely to be true.