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Part 2 of presentation Visualizing the alcohol-dependent brain
Presentation: Professor David Nutt, Imperial College, London, UK
Visualizing the alcohol-dependent brain
Professor David Nutt, Imperial College, London, UK
So those are structural measures; now, what about functional measures?
“Whoa! That was a good one. Just poke his brain here!”
In the old days, the way you looked at the function of the brain was to stick a finger into it. This is a famous Larson cartoon. The neurosurgeon is saying ‘Whoa! That was a good one! Just poke his brain there’ and this takes us back to the classic work of Sperry and colleagues in Canada who did open brain surgery and discovered if you probe bits of the brain, things could happen; people would move their arms or their legs.
It’s expensive and difficult and somewhat unethical, so we don’t do that anymore.
Activation of nucleus accumbens during anticipation of reward
What we do is use a technique like fMRI. Here are images, three dimensional reconstructions of the brain of one of our subjects who is doing a task. This task is called the monetary incentive delay task (MID); it’s a very famous task, I have probably 100 papers on this task. It’s a task that was designed to explore the circuits of the brain which are involved in motivated behaviour.
Basically what you do is you stick your volunteer or your patient in the MRI scanner and they have to play a game where when a light comes up on a screen they are told how much they are going to win if they respond within a certain time and you adjust the value of the wins and so when the win is going to be big, they often respond very fast. That’s the ambition, that they respond quickly and earn more money.
Now when you do that task, several reasons light up but the most important one for our discussion and the one for which the task was designed, you see in the ring, in the circle there, the bottom right-hand image and those two highlighted areas there are the two nucleus accumbens or the ventral striatum. So those are part of the dopamine circuit in the brain that are intimately involved in the association of success or reward or pleasure and behaviour.
That part of the brain integrates those two functions and lays down or is part of a circuit of memory laying down which then facilitates subsequent behaviour in that dimension, so this is part of the reward circuit of the brain which we can activate very beautifully.
What this activation means, in physical terms this activation is simply a measure of increased blood volume in that part of the brain. The increase in blood is driven by the increased activity, so it’s a proxy for the increased metabolic activity of that brain. It doesn’t mean there’s more dopamine being released.
Now many people will show you these images and say this shows that dopamine is involved in addition. Well it doesn’t; it just tells you that that part of the brain where dopamine has a role is involved in motivated behaviour.
Activations to emotional images
Another task we do in our patients is to activate emotional circuits. We are very interested in the common clinical phenomenon that stress provokes relapse. It’s one of the major factors that people describe as causing relapse, so we activate the stress system and we do it by using visual images.
We use pictures from the International Affective Disorders profile. There are hundreds of pictures with different levels of emotionality and we show people emotional pictures and we show people neutral pictures. And then we look at the difference in brain activation between the two and you can see here two things. You can see that looking at an emotional picture activates a lot more visual association cortex. You don’t get a lot extra activation of primary visual cortex because that doesn’t have any knowledge of content or the emotional aspect of content but the visual association areas begin to integrate the meaning of those images. This is much more activated when you see an emotional image than when you see a less emotional image and you also see massive activation of the amygdala and the amygdala as you probably know is one of the key brain areas that underpins the behavioural responses to emotion.
When you learn an emotional response to something, when you for instance see a child’s face and you respond to that, your amygdala will be turned on in response to that emotion. When you see something unpleasant and you have a negative emotion, your amygdala is turned on.
So this is a powerful way of activating the brain circuits of emotion in people in a scanner.
Arterial spin labelling (ASL)
The other technique that is coming more and more into use is this technique called arterial spin labelling and it’s a technique which relies on stimulating the blood that’s in the carotid artery, hyperpolarising that by putting a magnetic pulse through the blood and then monitoring what we call the decay or the recovery from that hyperpolarisation in the brain. You can then from that extrapolate the amount of blood which is going into any of the different voxels in the brain that you wish to measure.
This is an important technique because you can use it to look at blood flow in any part of the brain and it’s a much more accurate measure of blood flow than the indirect measure we used to get from the fMRI techniques. Normally we do both together because one controls for the other.
From these kinds of studies in the last ten years or so a picture of brain function has developed which allows us to look at different parts of the brain and how they relate to each other. This technique is often called connectivity analysis or resting state analysis. If you have someone lying in a scanner doing nothing, you can then correlate the activity in every voxel with every other voxel and you can then see whether there are parts of the brain which change in synchrony and parts of the brain which don’t.
Networks of the brain
From that, it turns out that the brain has a whole series of networks that we can image. Now we knew about these networks because we knew about them for hundreds of years because we knew that brain trauma would break some of these networks and that tumours would interrupt these or strokes would interrupt them so we knew there were networks, but for the first time now we can measure them in living human brains without doing anything other than do imaging. We don’t have to do any task; we can just see it there.
These networks, for instance the primary visual network, the secondary visual network I just showed you activated with the emotional task, but this is the one that is particularly interesting in terms of psychiatry and addiction. This is called the default mode network and the default mode network is a network that connects the front of the brain, the anterior cingulate prefrontal cortex region and the posterior cingulate cortex.
In simple terms, in Freudian terms, that’s the ego. Those two parts of the brain define what you are. As you are sitting here, none of you doing it now, but if you weren’t attending to me and you were thinking about what you might do tonight, you would be using the default mode network and that is the part of the brain and the network of the brain that does the thinking about your past, your present, your future, your planning, your analysis, your interpretation.
Because you are looking at me, you are activating this and you are also activating the auditory parts, but as soon as you switch off, the default mode takes over.
One of the compelling ideas about addiction and about other forms of psychiatric disorders as well, such as depression and obsessive compulsive disorder, is that when people get locked into rumination, for instance the alcoholic thinking all the time about alcohol or the depressed person thinking all the time about their negative thoughts, the bad things they’ve done in life, that is accompanied by an increased activity of the default mode network.
One of the new approaches to both depression and to addiction is to try to break away that excessive activity on a single theme like addiction and there are ways of doing that using drugs, there are ways of doing that using other treatments like mindfulness.
Positron emission tomography (PET)
What about looking at the chemical basis of the brain? You are probably aware there are at least 80 different neurotransmitters in the brain, they all work on receptors and the technique of PET allows us to examine receptors in the brain and is beginning to allow us to look at neurotransmitter release.
There is much less published on this than on MRI because it’s very expensive. What this slide shows is that to do a PET scan you have to go from a cyclotron, you have to produce a nuclear reaction, you have to change the chemical atomic structure of an atom into a radioactive atom, so you have to make something like carbon-11 or fluorine-18 in a cyclotron.
You have to then transmute that through a whole series of chemical processes into a drug or a tracer that you can inject and in the case of carbon-11, you have an hour to do that, so you have to go from an atomic carbon to an injected drug in an hour, so it is expensive and complex. It takes a team of about 15 people and then when you do that you get these wonderful images of receptors in the brain.
An MRI scan costs on average about €500, a PET scan costs on average about €10,000, so expensive but when you use them appropriately you can get very interesting data.
Using PET to measure receptors
What can we use it for? We can use it to measure dopamine receptors, you can use it to measure GABA receptors and we can use it to measure opioid receptors and we can use it to measure other receptors as well, but I am focussing on these three because they are central to our current theories of addiction and they are also what we do, so I know a bit about them.