Ketamine mimics schizophrenia
People with schizophrenia experience a range of symptoms, one being difficulty weighing up different pieces of information in order to make an informed decision. Now, UCL’s Sean Cavanagh has used both a computer model and tests on monkeys to show that low doses of the drug ketamine damps down the activity of NMDA receptors in the synapses connecting nerve cells in the brain to produce the same decision-making deficit seen in patients, as he told Chris Smith…
Sean - The way that we kind of approached this to try to relate the problems at the synapse with the behavioral symptoms, was that we built a computerized neural network, basically a computer simulation made up of nerve cells. It was made up of synapses and these synapses had the NMDA receptors that we were interested in. We then used this neural network to test our ideas. So we said, what happens with this neural network if we interfere with the NMDA receptors? So this gave us specific predictions about how decision-making would change and how neural activity would change. And then we could subsequently test these in an experiment.
Chris - You used the computer to come up with some testable ideas basically, that you could then go to a real brain and ask if we do this, does this happen as the computer suggests?
Sean - Yeah, exactly. That's what we did.
Chris - And so what did you do to actually test it?
Sean - The research subjects that we used for our experiment were monkeys. And the way in which we tested it was by using the drug ketamine, because ketamine is known to block the NMDA receptors. And ketamine is also an excellent experimental model of schizophrenia. As we know when ketamine is given to healthy human volunteers it temporarily reproduces many of the symptoms of schizophrenia, such as the hallucinations, the delusions and the cognitive symptoms.
Chris - What decisions were you asking the monkeys to make?
Sean - The types of decisions that we were interested in were those which involve combining multiple pieces of information. For instance, when we're deciding where to go on holiday, we have to combine lots of different attributes to make that decision. We might be thinking, for instance, of how excited we are about a possible destination, how good the weather will be, what the cost might be, and probably unfortunately at the moment, wherever we'd have to quarantine when we return. So you have to combine all of these different features. Obviously we didn't get the monkeys to decide where to go on holiday, but what we did get them to decide was on a sequence of images, they were showing some different bars. They had to add up the heights of all these different bars, combine lots of pieces of information and decide whether a series of bars on the left or right of a computer screen were higher.
Chris - And your intervention is that you present exactly the same task, but with or without the presence of ketamine. So you can see what role the NMDA receptor, that's going to be hit by the ketamine, is playing in helping them to resolve various stimuli to make a decision.
Sean - Exactly. So what we were trying to achieve was to study how the monkeys make their decisions normally, and then through using the ketamine, because we know it simulates the symptoms of schizophrenia and it blocks NMDA receptors, that's basically giving us a window or an opportunity to what we think might be going on in the brains of people with schizophrenia.
Chris - Before you tell us what happened to the monkeys when you did this, if you ask a person who does and a person who doesn't have schizophrenia to do these sorts of tasks, what different outcomes do you get between the two groups?
Sean - We know from previous studies they have impairments in decision-making. They struggle with combining different pieces of information. They make their decisions off only a small proportion of the information they’re actually shown. And so we come back to the example of deciding about a holiday, we had how excited you were, we had the weather, and we had the quarantine rules. If a person with schizophrenia was making that decision, they may only use the first attribute that they consider. They wouldn't consider any of the other attributes.
Chris - And the monkeys given the ketamine, did they show impairments in doing this simple decision making task based on bringing information together in this way?
Sean - Yeah, they did. So it's important to remember that we used a very small dose of ketamine. So the monkeys were still very engaged. They still were performing a task. They're still enjoying the task, but they just became slightly less accurate in their decision-making. So when they went not administered with ketamine, they were getting it right maybe 85% of the time. When they were administered with ketamine, their accuracy went down to maybe 70%. But it wasn't just they were getting worse at the decisions, it was they got specifically worse in a way that we had predicted with our computer simulation.
Chris - Do you know why that is? And similarly, why a person with schizophrenia would struggle to integrate all these different bits of information together? Is it that they just can't hold all the information in working memory at once and therefore make valid comparisons? Or is there something else going on to explain why their decision-making is falling in this way?
Sean - I think that the NMDA receptor, which is part of the synapse, is important for communicating between different nerve cells. And once this communication breaks down the neurocircuits that they're not able to combine information as well.
Chris - Does this point, Sean, to any ways in which we might present information in a way that is more meaningful for people who have this sort of problem?
Sean - It's important to stress again that we didn't test any people with schizophrenia in this study, although that's something we will be doing in future. But you are correct to say that for using these kind of sophisticated behavioral tests, we've worked out ways in which they may struggle to combine information. So it's also correct that we could also use these behavioral techniques to try to change the way in which these people are able to combine information. So that would be one approach. The other thing that is important to remember is that now we've identified some things which we think may be going wrong in the neurocircuits, the next step can be to work out how we can fix this. So we could think that if we had a therapy or some sort of drug, which could restore the activity of these NMDA receptors, then possibly this may be able to improve the symptoms of patients.