eLife Episode 7: Sedatives, Maths and Evolution

The sedating medication "zolpidem" has the paradoxical effect of waking up somepatients 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.

Can mathematics model the evolution of altruistic microbes that make molecules benefiting other bugs? Some microorganismssecrete factors that benefit, not just themselves, but their neighbours too. And mathematician, Benjamin Allen has been developing a way to model how this comes about...

Benjamin - So, we've been looking at cooperation in microbes, and this happens a lot in nature. One of the main ways that microbes cooperate is by releasing chemicals that are useful to others. In a colony of cells, one cell or more has to produce some useful chemical and then that benefit is shared by other cells. So, one example of this is yeast cells, when they are out of their preferred nutrient, glucose. They can produce an enzyme that breaks down more complex sugars into glucose. These digested sugars then, they don't go the cell that makes the enzyme, but they're shared kind of throughout the colony.

Chris - So in other words, that one cell that makes, I think it's called invitase isn't it, the enzyme. That goes into the media that all the cells are growing in. So, it's sort of, one cell pays to make that molecular machine, all of the cells benefit from the fact that it's chopping up other sugars to make things available for everybody.

Benjamin - Yes, that's exactly right.

Chris - So, what's the big unknown then?

Benjamin - Well, so this is a form of costly cooperation and the question is how does this behaviour evolve? So, if we think of survival of the fittest, you would think that the cell that produces this enzyme is at a disadvantage because it is doing all the work to produce this and then other cells get to reap the benefit.

Chris - Doesn't that sort of assume that the other cells are going to cheat on the equation in the sense that if the cell is producing some invitase secreted into the local environment, won't its neighbours do the same?

Benjamin - You have to think that behaviour evolved somehow, so at some point there must have been competition between cells that produce this enzyme and cells that don't. And somehow, this production behaviour survived through evolution. So the question is what gives this production behaviour an evolutionary advantage over the cheating behaviour? There's two answers to that. One is that the cell actually does get to keep some of the benefits from its own production of whatever useful resource it makes. The other thing is that if the cells are arranged in some spatial configuration and they reproduce locally, so that they're daughter cells remain near the parent, then they're sharing this benefit with other cells who are also likely to be producers of this public bit.

Chris - Simple to say, I suspect rather tricky to model mathematically.

Benjamin - Right, it is. Our test was to simplify nature enough to be able to do exact mathematics on it, but not so much that we'll lose the essential features of what's going on. For example, in colonies of microbes, cells can be arranged in all kinds of chaotic, interesting ways, but there's a certain regularity to it.E. colifor example, are long, thin cells. So, when they're arranged in a colony, there's some chaos, but there's also spaces where the cells are kind of arranged in a predictable end to end fashion. And so, we took that regularity and said, well let's assume that all the cells are arranged in some very predictable, regular fashion. And so then we can say, well, what if one of these cells produces this chemical, how does that become shared with the various neighbours?

Chris - And what do you find if you do that?

Benjamin - We find that the cooperation behaviour has an evolutionary advantage if the benefits are high enough and if they're shared locally enough. We call this a diffusible of public good, because some of it is kept by their producer, some of it is kept by the neighbours, some of it is kept by the neighbours of neighbours, and that rate of sharing has to be small enough so that most of it really goes to the cell and its immediate neighbours.

Chris - What about the concept of things cheating because it could be that an external organism comes in and steals, it takes away but doesn't pay back into the pot? And equally, it could be that the organism itself evolves to do that and becomes parasitic on its parents, if you'd like, rather like modern day teenagers.

Benjamin - Right. So, that's then the evolutionary question. If you have a colony that's already cooperating, and then a cheater arises in that colony, you have to ask, well, what are the odds that that cheating behaviour will spread throughout the colony? What we find here in our model is that even though this cheating behaviour might initially have an advantage, it doesn't have enough of an advantage to take over because say, the cheater does well initially and produces some offspring, some daughter cells then - those daughter cells - will also be cheaters. And so, the cheater will then be surrounded by other cheaters and thus, in the long term, it won't be actually getting any of the useful public goods that it needs.