Neuroscientists tell Wikinews about empathy and harm aversion observed in lab rats

Thursday, April 30, 2020

In findings published last month in the journal Current Biology, neuroscientists from the Netherlands Institute for Neuroscience examined harm aversion in laboratory rats for conspecifics — rats not wanting to hurt other members of the same species — and reported which region of the brain was crucial for it. Wikinews caught up with Dr Christian Keysers and Dr Valeria Gazzola, two of the authors who contributed to the paper.

Portrait of Dr Christian Keysers (Image: Valeria Gazzola)
Portrait of Dr Valeria Gazzola (Image: Christian Keysers)

For the experiment, the rats were put in a container with two levers. The rats were trained to develop a preference for one of the two levers: each delivering one pellet of sucrose. One of the two levers was harder to press.

After developing a preference, the preferred lever was wired to deliver a shock to another rat in a neighbouring compartment, while delivering a single pellet of sucrose. The study showed the actor rat, which pressed the lever tend to switch the lever to avoid shocking the other rat. The rat receiving the shock was called a victim rat.

Aversion of harm to fellow rats was reported to be equal in both male and female rats. If the actor rats were previously exposed to the shocks, their degree of harm aversion for others was heightened, the study revealed.

The investigation reported the rats avoided pressing the preferred lever to shock another rat, even if that lever delivered two sucrose pellets and the no-harm lever delivered only one. However, this was not the case when the rats were given three pellets by the shock lever. Most of the actor rats did not switch when they received three pellets pressing the lever, which also delivered an electric shock. Dr Gazzola called it a "tipping point" and said it was a "cost-benefit" function.

The study also revealed the importance of the anterior cingulate cortex (ACC) region of the rat's brain for harm aversion. The scientists tested harm aversion for conspecifics in the rodents after deactivating the ACC using muscimol. Muscimol was injected in the rats belonging to the test group, while saline water was injected to rats in the control group. The observations showed without the active ACC due to muscimol, the active rats in the test group were no longer averse to harming the victim rats, but degree of harm aversion did not drop in the control group rats.

Interview with Dr Keysers and Dr Gazzola

 

Thank you for agreeing for this discussion, by the way.

 ((Christian Keysers )) Um, hmm. Our pleasure.

 ((WN )) So, I would like to discuss about the study, the observations you've made and what lies ahead to be discovered in this field.

 
Brain scan of a human being. (Image: Dwayne Reed)

 ((WN )) So, what prompted you, and your interest in studying about this harm aversion?

 ((Valeria Gazzola )) So half of the lab works on human research. And half on animal research, right? So, the main topic of the lab is really to try to discover the brain mechanism that allow us to be empathic, basically. That's the main theme. So in particular, from the human research what we are interested is really trying to see whether embodiment: so these processes that these brain regions have become reactivated when we see somebody else in pain, for instance. You know, the regions normally involve[d] in [making] pain also reactivated when you observe somebody else [in pain]. Whether these, the activity of these regions is essential to motivate us for instance not to hurt other people.

 
Front view cross-section of a brain. Highlighted are the areas that were activated during pain. (Image: Dr. Arne May)

 ((Valeria Gazzola )) And one of the biggest limitation[s] in particular of the human research is that you can go so far in understanding the brain mechanism. Because we cannot, we don't have tools with the correct resolution in terms of, for instance, understanding what a single cell does, in these processes. And that's why, for many years, we developed, we tried to develop a model in animals where all these techniques are more available that would allow us to investigate similar processes to those in humans. So processes basically that are involved in perceiving the other['s] distress also in animals. And, that's basically the main reasons why we move towards this research and then we started from coming up with the experiment in which we simply measure the distress of an animal in reaction to the distress of another. Which what we call emotional contagion, for instance. And we made it more and more complex in order to reach slowly a degree of complexity that can be comparable to processes in humans. Emotional contagions: you can compare it, for instance, that the level of humans when you are in a crowd, or when you are baby, that as a crowd you are contaged by the emotions are around. And, but then, we wanted to go a little bit of a step forward: okay now I am contaged, what does it mean to be contaged? Can I use this information to, for instance, avoid hurting other people. And that's how we came about, more or less, so.

 ((Christian Keysers )) I mean, one other motivation we have is that in the past we've also been interested in people that seemed to lack the aversion to harming others. I mean, with that psychopath, sometimes they're called sociopath as well. And so, a couple of years ago, we made this study in which we identified psychopathic criminals in high-security institutions. We brought them to the lab, and we scanned their brains while they witnessed the pain of other individuals. And what we saw was that if they don't have any particular reason to empathise with others, they really have reduced activity in their own pain regions while they witness the pain of others. So, of course, that's interesting and it may suggest that perhaps, the reason why if they can make some money, for instance, they don't mind to harm other people is because they don't activate their own pain much while they witness the pain of others. The problem like Valeria was saying, is that in humans we can see that the brain region is active while you see the pain of others, but you can't easily change the activity in the brain region to see whether that would change the way that the psychopathic criminal would act. I mean, ideally, what we'd like to do is increase the activity of these pain regions in psychopaths and see that now suddenly they would really care to not harm others anymore.

 ((Valeria Gazzola )) Although it's not yet, it's also not yet very clear that we need activity of these regions to avoid the harm, right? At that point, that's how we came about to run the experiment, because the first question was: is it really necessary. The activity of these regions. So, you start with okay, you want to manipulate these regions to reduce psychopathy. But the field could not even prove that this activity was necessary to reduce harm.

 ((Christian Keysers )) And so, that was really one of the strong motivation behind the rodent-experiment, because rats have a very similar cingulate cortex to what humans have. It is really a core part of the brain that is involved in feeling your own pain. So, if you don't have a cingulate cortex and you hurt yourself, you still feel that you've cut yourself, but you don't mind. And so you are not going to do a lot to avoid being cut again. So this region exists also in the rats and it is a relatively deep brain region. So therefore, we turn to the rats, and figure that in the rat, we can change the activity in the brain region and see whether that would then change how much the rat would be aversed to harming other rats or not.

 
The experiments were conducted on Sprague-Dawley rats.
Image: Jean-Etienne Minh-Duy Poirrier.

 ((WN )) Could you briefly explain this study and its findings?

 ((Christian Keysers )) Ah. So very briefly, what we do is we give a rat a choice between two levers that the rat can press. Both of these levers will provide the rat with one little pellet of sugar which they really like. So, they are happy to press these levers to get the reward. In the main experiment, what we do is that one of the two levers is a little bit more difficult to press than the other one. So most of the rats start to prefer the easy lever to press.

Now, as soon as they have developed the preference for the easy lever, what we do is that now, still both levers give one pellet of sucrose. But now the preferred, the easy lever, also gives a shock to a rat that's in the compartment next door. And so then, the rat that presses the lever not suddenly hears someone next door, kind of, in the protesting with the pain-squeak about the shock that he just got. And what we see is that the, about a little bit less than half of the rats will now stop to use their preferred lever because it gives a shock to the other one, and they would start to press the harder lever to avoid to shock to the other rat.

 
Setup of the experiment

Now after we found that, we could do is go to the cingulate cortex, which is the region that we saw was less active in the psychopathic criminal, and is normally active when you feel the pain of other people. And what we saw was that when we deactivate this region with muscimol, which is a bit like a local anesthetic, which you can inject the part of the brain, now suddenly, the rats that continued to use their favourite lever even when it harms another rat. So now, what we see in there mainly are kind of two big findings. One is it shows us that humans are not the only animals that don't like to harm other animals. Rat also do that. And second is the fact that they use the same brain region, which is the cingulate cortex that humans use while they witness the pain of other people, as a necessary part of this harm aversion.

 
Chemical structure of muscimol (Image: Edgar181)

And the fact that it's the same brain region that we see to be active in humans tells us that in a way, it's not just the case that rats and humans have independently developed harm aversion. It suggests that there is kind of a common ancestor that already had this ability, and that was then given to both the rats and the humans. Which means that kind of harm aversion and not wanting to harm other people is at least 100 million years old, because that's more-or-less when our race separated from rodents like rats and mice.

 ((Valeria Gazzola )) And that also what we see is that there is variability in the responses of the observers, of the rats that make the choice between the levers. And these variabilities also present in humans: when you do tasks that are rather similar, you see that not everyone acts socially, preferring the social lever. But you also have individuals that would go for the reward more often. So this is also another similarity between the animal world and the human world. And on top of that, I think that the other things we've learned from that experiment is that, the decision is a cost-benefit function, basically. Because, we have a condition for instance where we increase the reward for the animal, for the observer. And when you increase the reward, they are less willing to switch to the other lever. So that also another similarity with human world and shows that maybe that it is a bit of complex, a tipping point, and it is like a function that really weighs the cost and the benefit of that particular context.

 ((Christian Keysers )) Because when Valeria says that we increase the reward, we increase the difference between the two levers. So in the main experiment, the only difference is that one is harder to press than the other, but they both give one pellet. Then in two other experiments, what we did was that now that two levers are equally hard to press; but one of them gives you two pellets, the other one just one pellet. And then rats are still willing to switch away from the two-pellet to the one-pellet to save the other one from pain. But when we made it three pellets versus one pellet, then, none of the rats were willing to give up the three pellets to prevent the shock to the other person.

 ((Valeria Gazzola )) Yeah, and then, the last, I think, result I kind of like in a way is that, as in many human studies, also in the animal world we did not find significant difference between sex. So both, the female and the males acts in a similar way. And in this type of paradigms, is also often the case in humans.

 ((Christian Keysers )) That's true.

 ((Valeria Gazzola )) So that's also interesting.

 ((WN )) What is the most fascinating aspect of this finding?

 ((Valeria Gazzola )) Well, in a way, I would say, to really show — I mean, I always believed it that animal performed these choices too. And that they do it to a certain extent to at least care or at least perceive what goes on in the other, right. It can't maybe specifically speaking of voluntarily care about others, but at least they perceive what goes on and I think this is something that the study shows pretty well that they do perceive, and that based on these perception[s], they make a decision. And I think it is a complex — I mean, to me it was in a way trivial, because I always believed that, you know, if you are a "social animal", whether you are a rat, or a person, we are still animals, right? They must develop behaviours that take advantage, or that they adapt to the fact that it's a social environment that involves more individuals. But [...] the field keeps discussing, right? Whether animals also have emotions, whether animals also can take this sort of decision. And to see, slowly that evidence accumulates in favour of processes similar to what we call prosocial emotion or decision-making. You know, similar: not exactly the same, but similar processes also are present in animals, to me is sort of reassuring also. And I think it allows us to learn from how evolution evolved as well. Maybe apart from knowing exactly how it works, but we start having some models where we can think, oh, evolutionary: maybe this process was already there, and then it developed further, more complex for the humans, but still is there to a certain extent.

 ((Christian Keysers )) Yeah, and I think the fact that it's really the same brain region as well that seems to be involved kind of gives us some confidence that prosociality in caring about others is really deeply ingrained in our biology.

 ((WN )) What technologies were used to conduct this study?

 ((Christian Keysers )) Yeah so in many ways it's a relatively simple study. So we didn't need to use anything very high-tech in this case. Because to alter brain activity, we use the injection of muscimol, which is a GABAA blocker. It is a very simple pharmacological agent. So it's really technologically a very simple study. Nothing fancy.

 ((WN )) How did you get involved in this study?

 ((Valeria Gazzola )) Oh, we brainstormed about it. We started, as I said, we did a lot of research on, since our early ages, let's say in all our scientific career is based on embodiment, and activities in these areas and slowly we kept wondering more and more, on the role of these areas. And then, the way it goes, we normally speak about a topic and include other people and keep brainstorming, and I think, that's how it goes. At least for us. And in humans, we are also developing similar paradigms, so it just came one plus one equal to two. [laughs]

 
Julen Hernandez-Lallement was one of the authors of the study. (Image: Academia.edu)

 ((WN )) What were the roles of other people involved in this study?

 ((Christian Keysers )) So, Julen Hernandez-Lallement, the first author of the study, was the one that basically made the vast majority of the experiments. And he was helped by the other two: [Augustine Triumph] Attah: who did part of the other animal groups, and then Cindy [Pinhal] and Efe [Soyman] helped to analyse the data. And basically Valeria and me have been kind of help designed this study initially and helped to analyse the data and wind up the study. So we kind of lead the lab, but it's the other people that really manipulate the rats and do all the hard work.

 ((WN )) What was the timeline of this study?

 ((Valeria Gazzola )) Well, it was long.

 ((Christian Keysers )) Yeah, I would say, four years?

 ((WN )) (Wow!)

 ((Valeria Gazzola )) Yeah, because the behavioural part is the longest one. Because you need to understand the best way to teach the animal, first to manipulate the lever, then to manipulate two levers, and then, before the lever, there is also another action that they need to do; and everything needs to be done within a certain time. So you need to let the animal the time to learn and for you that you run the experiment, you need to learn what's the best way, what's the best way to teach them to do the task?

Yeah, behavioural experiments of animals: they normally take quite some time to develop, specially more complex ones.

 ((WN )) Which activity took the most time and attention?

 ((Christian Keysers )) Yeah, I think that Valeria just said what's really important in these studies is to understand what kind of situation you can create for the rats that they are really understand and which they can in a way, show you what they're capable of. So, kind of fine-tuning all the elements of the task, kind of how long do you let the rats develop the preference for one lever. Because if you give them too much time to get too used to one lever, they are not so willing to switch anymore. So the, most of the time is really involved in trying different versions of the paradigm, understanding what the rats really understand, and then analysing all the behaviour.

Explanation of the experiment

 ((WN )) What were the conditions did you test the hypothesis on?

 ((Christian Keysers )) Yeah exactly; so the three kind of conditions we looked at was the hard vs the easy lever, and then seeing whether they switch to the harder lever when, to prevent the shock to the other one. And we tried the two pellets versus one pellet and, then the three pellets versus one pellet. And then finally, to test really whether the cingulate is necessary for that, we compare the condition in which we inhibit the activity in the cingulate using muscimol against the condition where we just inject salt water into the same brain region which doesn't have any effect.

 ((WN )) So, you mentioned the study took four years. So you started back in 2016?

 ((Christian Keysers )) Correct. Yeah.

 ((Valeria Gazzola )) Yeah, more or less. I don't know the date.

 ((WN )) What was the most difficult part of this study in these four years?

 ((Valeria Gazzola )) I think it was really again the establishing the behaviour. And in particular because we, at first — so the paradigm itself, we took it from a previous study, that was run years ago, do you remember?

 ((Christian Keysers )) Yeah, in '69, so that's kind of 50 years ago.

 ((Valeria Gazzola )) Fifty years years ago, so the idea of the two levers. And so and at that time, the articles' level of detail were not so many. The articles were not giving as much information as we now have to write down. And so we had to guess some parameters over there. And, the fact that the rats would prefer the easy lever was also not so straightforward. So we thought "oh, they are gonna prefer the easy lever, and that's it." But at the end, you know, some rats, some animals develop a preference on the side; like they prefer their right lever, or the left lever, or others, they prefer the heavy lever. Right? And that was also a bit puzzling at first. We said, okay, so what do we do? We find that a couple of rats prefer the hard lever, is that meaningful or not? So we have to discuss a lot, how to adapt the paradigm to make it work, and this is also why we came about in using this switching index, because for our purposes, at the end, as long as the rat is able to switch a preference, right, whatever preference is developed is irrelevant, right? And before the beginning of this study, we were more thinking: oh, they have to develop the preference for the easy lever. And that's what is bringing us a bit out of the main purpose. And we realised: okay, but, what preference they develop at the end, it doesn't matter as long as we have a preference that we can show they can change because of the shock. So, I think this was one of the longest part[s], I would say.

 ((WN )) Were you anticipating this outcome?

 ((Christian Keysers )) Yes.

 ((Valeria Gazzola )) Yeah, I would say yes.

 ((Christian Keysers )) For once.

 ((Valeria Gazzola )) [laughs] Yeah, for once, yeah. I mean, there was some evidence around and previous work was already bringing us towards that direction. And, yeah, I mean we could not anticipate the proportion of animals that they would switch. But, we surely were expecting the rats to switch.

 ((Christian Keysers )) We were hoping for the cingulate to be necessary, so.

 ((WN )) So what was your first reaction after confirming the hypothesis was true?

 ((Christian Keysers )) Jubilation.

 ((Valeria Gazzola )) We were happy.

 ((Christian Keysers )) Yeah.

 ((WN )) How many rats were used, roughly speaking, for this study?

 ((Christian Keysers )) I think it's written in the paper, but my guess would be something like, I'd say, 70.

 ((WN )) How distantly were the rats related to each other?

 ((Christian Keysers )) Yeah, so that's interesting, in this study we really find that there is a lot of variability between the rats. So like I was mentioning, we have about 40% that were ready to switch when they witnessed other one getting shocked. And about 60% that do not switch, so as a group, we really see that they do switch. But then only a proportion of individuals really show that sensitivity, and others do not.

 ((Valeria Gazzola )) Or did you mean how close they were in terms of familiarity?

 ((WN )) I meant in kinship. How genetically close they were?

 ((Christian Keysers )) So they're not genetically related. They're not brothers or sisters. And what we have is we have, we made one of the experiments with rats that didn't meet each other before, and it [the experiment] works. And we had other cases in which they were living in the same home cage, and so they [would know] each other very well. And the effect was not stronger. So, amongst our rats, we really noticed that they care even about the fate of a stranger.

 ((WN )) So, if it fair to say there was no change in the degree of harm aversion when the actor and the victim were mates?

 ((Christian Keysers )) Correct. Well, mates as in cage mates. Yeah, there was no sign of a difference. We did look at it and it was not the perfect comparison because the two groups were slightly different in the paradigm as well. But, it didn't look like there was a big difference.

 ((WN )) So, do you think the degree of harm aversion would have been greater if the actor-victim shared some sort of kinship?

 ((Christian Keysers )) So we're actually going to test that very soon. And it is up for grabs. But in the past we've looked at whether a rat shows more freezing when it sees another one get a shock. Which is a form of emotional contagion. And there we compare a kind of rats from different strain,s even. So one of the albino rats against a black and white rat, versus, that had never seen each other before, or ever seen a member of that strain, the one end. And on the other end, really the rats have spent five weeks together and knew each other very well. And we didn't see any difference there. So I think the most robust findings is really that they care even about what happens to a stranger.

 ((Valeria Gazzola )) Yeah, we are testing it again now, in the future.

 ((Christian Keysers )) Exactly, specifically whether a mother would do more for her own kids than for...

 ((Valeria Gazzola )) Kids of somebody else.

 ((Christian Keysers )) Yeah.

 ((WN )) Well, that would go on to support Richard Dawkins' The Selfish Gene.

 ((Christian Keysers )) Correct. Right.

 ((Valeria Gazzola )) Yeah.

 
The highlighted region of the rat brain is essential for harm aversion.

 ((WN )) How was the functioning of the anterior cingulate cortex (ACC) deactivated in the rats?

 ((Christian Keysers )) Yeah, what you do is you place a cannula. So you put the animal in a stereotact which is a system where you can go to a very specific position in the brain. We place a cannula, which is like an injection needle just where we know the cingulate to be. Then you let the animal recover with the cannula cemented in place. Then, on the day of the experiment, you basically inject a little bit of muscimol, which is an agent that blocks neurotransmission. Then by doing that, you can reduce the activity of the cingulate for about one hour. And during that hour, you can make the experiment. And then the control group is the same thing, but instead of injecting the muscimol, you inject some salt water.

 
Highlighted region is the anterior cingulate cortex in a human. (Image: Geoff B Hall)

 ((WN )) What are the affects of muscimol on the rat's body other than deactivating the cingulate?

 ((Christian Keysers )) Nothing really. Because you inject a very small quantity, that should only spread about 1 mm in the brain. So it really just affects the region that you — and you don't see any change in behaviour. So we also tested, for instance, whether they move more or less, whether they press the levers quicker or slower, and there was no difference. The only difference is that they didn't learn to not press the one [lever] that shocks the other.

 ((Valeria Gazzola )) And for instance, when you inject with muscimol, in case you see doing a normal fear conditioning paradigm. So whether you are still shocked to the sound, and then you present the sound. In that case, the rat behaves normally. And it still freezes. So, it does suggest that the muscimol effect is not impairing the normal behaviour, but specifically impairs the social behaviour of feeling...

 ((Christian Keysers )) ...of feeling for others.

 ((Valeria Gazzola )) Exactly. That was also the interesting part of the ACC that we believe to contribute really, to including the other [animal] into your decision-making. Because for a normal fear conditioning paradigm, you don't need to go through the ACC. They are made to be self-sufficient. But, if you do a fear conditioning basically that involves another individual instead of sound, like of pain, then you do need to go to the contribution of the ACC. So there seems to be two slightly complementary pathway for fear-detection.

 ((WN )) After the effect of deactivating the ACC wore off, was the degree of harm aversion of the actors back to the previously observed level?

 ((Christian Keysers )) Yeah, that we didn't measure. So, in that study, the muscimol animals were only in the behaviour with the ACC deactivated and the other ones were only with their ACC intact. So, but this is something that we plan to test in the future as well. To really see whether the ACC is necessary to acquire the aversion versus to maintain it.

 ((WN )) Okay. So it is not a permanent loss of empathy. Right?

 ((Christian Keysers )) We don't know, but I think there is no reason to assume that when the muscimol wears off, they would not become normal again, right? So that's most likely. What we don't know is whether if we had for instance, because there's three days of experiment, right, where we develop the aversion. And what we didn't try is for instance, give muscimol on Day 1 and Day 2 and then stop it on Day 3, and see whether on Day 3, they would then suddenly stop using the lever that gives shocks on the other days. So that we don't know whether it's necessary for learning or for recall; we just know that if you don't have it at all, you don't learn at all.

 
Figure 4c of the study.

 ((WN )) Did any of the actor rats choose to switch when they were on muscimol, and their ACC was deactivated? Did any one of them switch?

 ((Christian Keysers )) It's a good question. I would need to look in the paper. If you have the paper there, perhaps you can see it. But I can have a quick look to see if I have the paper somewhere. Yeah, so if you look at the Figure 4c, you can see the behaviour of each individual animal. And what you will notice is that there are some animals like some of the red animals which are the muscimol group that did switch, but the majority didn't switch. So I see there is one and only one animal in the muscimol group that really did switch. But what happens is that when you make those experiments, you never know for sure that when you inject the muscimol, that it has the desired effect. Because of course you have a cannula that's in the brain, and the cannula could become clogged also. So it can be that that one animal switched because the muscimol wasn't effective for some reason.

 
A model of the Ecstacy drug, which is reported to increase empathic feelings in humans.
Image: Jynto.

 ((WN )) Did the team test the change in the degree of harm aversion when the actor rats were given psychoactive drugs?

 ((Christian Keysers )) No.

 ((Valeria Gazzola )) No. Could be nice, but we didn't.

 ((Christian Keysers )) Exactly. Yeah, and in particular, there is a drug called Ecstacy that you may have heard of. So, some people reported that Ecstasy for instance, increases the feeling of empathy amongst humans. And I think that there is somewhere a study suggesting that if you give that to animal, there is also an increase in the sensitivity to what happens in another animal. So we didn't test that.

 ((WN )) Did you also conduct the test with only one lever delivering the food also the electric shocks: how far the rats were willing to starve before they chose the victim should suffer?

 ((Christian Keysers )) Yeah, no so we didn't do that. That is a very old experiment from [Russell] Church. I think in the 50s, he did that experiment kind of with rats and with monkeys. And he sees that the rats will use the lever less. So even if you just have one lever, they'll use it less if it causes pain to others. But in monkeys, that was a very strong affect. Some of the monkeys really would rather not eat anything than to shock another monkey. So it's an interesting experiment, but we haven't done it.

 ((WN )) In that diagram, we can clearly see the difference between contingent harm of males is lesser as compared to the females. Even though it is somewhat similar.

 ((Christian Keysers )) Yeah, what you see here is the two lines: the dark green and the light green that represents the males and the females. For harm aversion, for that you should look at how much it changes from the baseline through the three shock sessions. And the change is exactly the same in males and females. But the difference between the two curves that you see is the fact that the females started off with the higher preference than the males did. But the reduction in preference is same across groups.

 ((WN )) Tell us more about the observed differences between these rats.

 ((Christian Keysers )) Between which rats? Rats, you mean, in general in the experiment?

 
Figure 3b of the study.

 ((WN )) In general, like the rats, which were on the extremes, how extreme were they on the case-by-case basis?

 ((Christian Keysers )) Well, that you can see, if you look at Figure 3b in particular, you can see that some examples on the top of 3b of rats that had started off with a very strong preference for that were around 100 on the baseline session. And it stayed at 100. So they absolutely didn't care at all. And in the other case, if you look at the bottom panel, you have some animals that initially had a preference around kind of 80%. And by Day 3, they really go down to 0% of the shock lever used. So it's really a very substantial difference; some changes much as they possibly could and some don't change at all.

 ((WN )) What could be the possible reason for this?

 ((Christian Keysers )) Yeah, it's a good — if we knew that, we would be very happy. I think the things that we did look at and didn't play major difference is actually the reaction of the demonstrator. So the first thing we figured perhaps you have demonstrators that really squeak a lot, and others, that don't give a lot of pain signals, and that could could explain the difference. Then we quantified the reaction of the demonstrators, we saw there were no major differences there. Where we did see really, big differences is in the reaction of the observer. So we saw that there is some observers for instance, when they realised that they had shocked the other one, they really stopped to do anything for a while, and took longer to go get their food and ate the food very quickly. So they really showed that they were disturbed by these shocks. And those were the ones that switched. And then were other rats that didn't seem to mind at all, they just kept eating their food as if nothing had happened. And those ones were the ones that didn't switch. So we feel that there's really just a striking difference in how much attention as well the agent paid to the harm signals of the other person.

 ((Valeria Gazzola )) But the causes are not known. The causes of these are not: could be different brain activity, it could be the relationship between the distress that the observer perceives from the other that stops them to do anything, or actually motivates the other. I mean, there are a lot of factors that could play a role. And we are trying to think of it: how to test and untangle this aspect apart. But it is not easy, but it is definitely a topic we are interested in.

 ((WN )) How much do we know about the evolution of harm aversion?

 ((Christian Keysers )) Yeah, well we don't know that much. So from a kind of biological point of view, kind of it's only over the past, I would say, 10-20 years, that evolutionary biology is really paying a lot of attention to kind of altruism and mutualism. Because if you read kind of traditional and evolutionary kind of books, they underline the selfishness of individuals. So the idea that you mainly need to survive yourself, and that other animals are really competitors. And then more slowly, people started to say, "well of course, you care about your kids, because they have a lot of your genes and therefore, that makes sense". And it's only quite recently that people start to really see that even if you are not really related to another animal, but kind of you help each other, your whole kind of herd or group ends up better-off. And the individual ends up being better-off. Because often, rats actually, or animals have a sense of mutualism. So if someone was kind to you at some point, you're more likely to be helped by that person in the future. So that helping others is a way to facilitate being helped by them in the future. And so, it still is a relatively young field of research that really acknowledges the fact that kind of in social animals, that live in groups. And individuals will really do things for others kind of and that this is beneficial for evolution. So it's really only starting to be explored.

 
Anterior cingulate gyrus of left cerebral hemisphere, shown in red (Image: Anatomography)

 ((WN )) Is the ACC responsible for harm aversion in other vertebrates too?

 ((Christian Keysers )) Yeah, so what we know is that for instance, in monkeys, the cingulate seems to be necessary as well to, for instance, decide to work, to give juice to someone else. So, in the primates they have some paradigms where you see a symbol on the screen that means that if you now do something, there can be juice for yourself. And a different symbol if you work will give juice to another monkey, and a third symbol if you work that one, there'll be juice that's delivered in an empty glass. And what you see is that monkeys that really work hard for themselves, but they're also willing to work a little bit to give juice to another monkey. And that's more than they are willing to work if the juice is just gonna get wasted in as glass. And there as well, the ACC seems to be important to motivate the monkey to work for another monkey and that's the other example that we know. In mice, there is some evidence that if you disrupt the cingulate, then the mouse will no longer freeze when it see[s] another one getting shocked. But that's it. As far as I know, there's no other animal that has been explored.

 ((WN )) Are there any ethical considerations around conducting this study?

 ((Christian Keysers )) Yes, of course! So, we ourselves, of course do not particularly like to have to give shocks to one animal. So the only reason we really do these experiments is that we feel that harm aversion is such an important phenomenon. Because in human society, when people lack harm aversion, they really cause a lot of damage to society. Both because they harm people, and they end up in prison and that has a huge cost; but as well for the fact that these individuals really erode trust and they harm in a way the interaction that all of us have with each other. Because we are always afraid that the person we have in front of us might be someone that will take advantage of you and harm you. So I think, in understanding how that works in the brain is really really important. And because of that, we feel that it's important to really understand how it works. And currently, working with animals is the only way that we can really modify brain activity and see if it changes behaviour.

 ((WN )) In future, might you test this hypothesis with different species?

 ((Christian Keysers )) Yes, we might do it in mice. So, of course, for other people, rats and mice are pretty much the same thing, but kind of there is a difference between them. And ultimately, we hope we can do this in humans. But for that, we need techniques in which we can modify brain activity in deeper brain regions.

 
The insular lobe is highlighted in red. (Image: John A Beal)

 ((Valeria Gazzola )) You can do it once in a while in patients that already suffer from epilepsy and normally the surgeons inserts electrodes to measure, to find out the source of epilepsy, and you can at times stimulate to see whether the region is essential in some of the normal behaviour. So at times, you can have access to these patients and ask them to participate in our task and we have a couple of collaborations, that we hope that will help us to tell something more about the role of the ACC and the insula in these type of tasks. And we are also currently trying to develop methods that are human-friendly, in the sense that they are not invasive, and to be used in active participants to try to disrupt the activity of these regions as well. Nowadays it's not easy to do because the TMS that [is] normally used to simulate the brain in humans, the Transcranial Magnetic Stimulation, is not very well suited to reach deeper structure. Like the ACC goes really inside and it's a bit curved as well. You can reach with TMS, but it's not the cleanest way. So we are also trying to see whether we can use, for instance, ultrasound stimulation to do it and test it directly in humans. Of course, it will also make use of data that comes from patients that show damages in the ACC. And it was a study from Ralph Adolphs in the past that did confirm that some of these regions like insula for instance, are important and essential for discriminating emotions for instance, so, you can also test in these patients: use our tasks and test these patients. So there are bit, some ways, to do it in humans, but it's quite small so we are investing, but the results take longer. And of course, when you use patients, you always have the problem of reorganisation of the brain structure that you are looking at, possibly, so.

 ((WN )) Is there a way to increase the degree of harm aversion in anti-social beings?

 ((Valeria Gazzola )) Yeah, that's the question we are really interested in, and we don't know. And that's why we are interested in finding out whether a particular region like the ACC is necessary for the development, or for the behaviour to occur. Because once we know, we can confirm that in humans as well, what you could think are several ways. You can manipulate plasticity in that region, so, ask the participants to go do certain tasks where they learn something. And while you are modifying for instance, the {w|neuroplasticity|plasticity}} of the brain with current or magnetic simulation. Or you can think of targeted therapies, for instance like neurofeedback, when you project the activities of the areas where the participants doing a task and the participants can directly modify through visual feedback the activity of these areas coming up. So that if I now project on the screen the activity, real-time, the activity of the particular regions, I can tell you "okay, try find a way to modify that region". So you would come up with thinking of something, you know, it's just a random process, but you could come up with a task saying like, "Okay, if I think of how my friend is feeling now, I see that manipulated region". And then you can practice and practice to the point that it becomes automatic kind of things and that activity of that region now is modified based on your exercise and your activity.

So there are ways that we hope we may be able to use in the future to see whether we can use, can maybe improve or help these people to care more about. But again we need to identify not just the region that is involved, but also at what point of the decision-making is happening. So is it the motivation that is lacking, is just the attention, or is the general level of activity of that area, I mean, we don't know yet. What is the reason why harm is done or you don't care to the other. And if you consider that these decisions are always or in most of the cases this balance between a cost and a benefit, what you need to do is we need to readjust the cost-benefit balance which complicates the thing a little bit more. But that's the way we want to go but it's the future. So you also have this ethical aspect like, so it depends what — if somebody, like, with psychopathy, is just in the tail of the normal distribution right, so it is not just the specific dysfunction, but it's just a normal variability that went to the extreme, right, then where would you put the line and say, "Okay, now I intervene to change these and when I don't". Because we know that certain traits or certain aspects of psychopathy can be useful in society as well. So, then it becomes an ethical problem of when do we actually intervene? And do we want to intervene early in kids that already manifest aggressive behaviour, or do we need to let them experience it and then act later on.

So there are a lot of considerations before doing interventions on these topics.

 ((WN )) Are there any future plans to explore more on the harm aversion and its evolution?

 
Representation of a neuron (Image: BruceBlaus)

 ((Valeria Gazzola )) Ah, yes there are a lot of plans and, roads, let's say. One of the plans we have is to really understand a little bit even more in details what is happening in the brain, at the cellular level and which are the inputs of these neurons are involved, what type of neurons are involved and all these aspect[s], we are also interested in trying [to] understand the developmental curve, what is happening, for instance, if you are exposed to a very stressful life when you're young, what kind of consequence it has on harm aversion later in life. And we are interested in seeing how it is also transmitted through generations, like if you have these variabilities between individuals, with some individuals having higher propensity to be prosocial, or whether, you know, you select individuals that are mostly prosocial, would this selection be brought forward in the next generation. So we also want also to see how much is learned and how much is more genetically encoded. So all these aspects, we are trying to tackle with different experiment. And let's hope we — of course the other aspects are very early at this stage.

 ((WN )) What are the other research you are currently working on?

 ((Valeria Gazzola )) [laughs] You want them all? No, okay, so as I mentioned from the animal's point-of-view, we are doing, we want to do electrophysiology on the, a bit more of the physiology, and up the genetic to discover the role of the ACC and each single cell of the ACC, as I mentioning before. So, is it for instance, let's say, what type of cells is involved in mapping the other pain into my own pain. And where the information comes from, so what is the circuit that is involved, and how the other things change the information: this is one aspect of one of the experiments we're gonna run.

In humans, for instance, we are also, we've been implementing a lot of learning paradigms, similar to the one in this paper where people are faced with two symbols: they have to understand what are the consequences of choosing one versus the other and one symbol most often brings you higher reward, monetary reward, but also you would also see the other be more in pain, and the other symbol is the opposite. And we again want to understand whether the circuit that is involved is the same as we see in the animal and vice-versa. And again, whether we would like to simulate some of the areas we find, to see how the causality between this particular brain activity and the behaviour. And we are also curious to see whether it matters, whether you see the other person being in pain in front of you, for instance, compared to simply receiving a message that the other person is in pain. Because we believe that the embodiment component mainly comes into play when you see the other person. You can also recall some embodiment processes through text. But whether there is a difference between the two, we don't know. So we are also interested in that aspect, and also interested in differentiating whether when you encounter such a type of conflict, whether there is a negative consequence like pain vs money as a reward; whether you value the pain of the other similarly to how much you value the pain for yourself.

And this is just a glimpse on all the things we are are doing. I would say, on this aspect. We also are interested in experiments that are trying to see how [we] ourselves encode emotions, do we have cells that code for happiness and cells that code for pain, painfulness or sadness or the cells simply encode the negative and positive aspect towards how strong it is. Independently of a specific emotion. So these are also other questions we have. Unless you want to mention more, but I think it is plenty.

 ((Christian Keysers )) Yeah.

 ((Valeria Gazzola )) Yeah.

 ((WN )) What is your role at the Netherlands Institute for Neuroscience?

 ((Christian Keysers )) Yeah, so we basically are both of us department heads, so that means that we each have a a group of people we basically manage. And of course we really work very very closely together. So our two groups kind of together form what we call the Social Brain Lab which is basically investigating how our brain processes the emotions of others and reacts to them.

 ((WN )) Well, that were all the questions we had for you both.

 ((Christian Keysers )) Okay. Very good.

 ((WN )) Is there something you would like to add?

 ((Christian Keysers )) No.

 ((Valeria Gazzola )) No, I think it was quite thorough. Yeah.

 ((WN )) Thank you very much for agreeing for this [interview]. It was great pleasure discussing this with you.

 ((Christian Keysers )) You are welcome.

 ((Valeria Gazzola )) Thank you.

 ((Christian Keysers )) Thank you. B-bye. Have a good day.

 ((WN )) Thank you.

 ((Valeria Gazzola )) Bye.

 ((WN )) Bye.

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