Why do we cry? (Part 2)

The crying was associated with a sorrowful facial expression, sobbing body movements, and a voice inflected with sadness. These physical manifestations ended with the termi- nation of stimulation and the patient described feeling sad, but could not express the trigger for the sadness or crying. Results were consistent and reproducible.

I have previously wondered why we cry, from a biological perspective. When I went looking for reasons, I found a paucity of actual evidence. However, in a link from a recent report on sticking electrodes in people I found a study that was able to induce crying. Causing a person to cry by electrically stimulating a part of the brain is about as good as you can get, right? Then you have causal evidence that that region is intimately involved in that behavior.

To recap, when an epileptic patient needs surgery, an electrode will often be stuck in the brain in order to localize the source of the seizures. Scientists are always thrilled about this because it’s next to impossible to get an electrode in a human brain otherwise, and how else are we to study human-specific behavior? So they get into these operations and zap portions of the patient’s brain to see what it does – and what qualitative feelings the patient experiences.

One recent such zapping managed to reliably produce crying in a patient – and not just crying, but crying with a feeling of sadness. This isn’t like what I had reported previously, where crying was the result of very deep areas that may not be directly linked to ’emotion’. The area of the brain they were stimulating was the ‘left posterior orbito-frontal gyrus’, which is a region of orbitofrontal cortex and looks to me like it may overlay the ventromedial (or perhaps ventrolateral) prefrontal cortex? This area has strong connections with amygdala and hypothalamus, as well as other reward-related areas.

So activation of this area of orbitofrontal cortex is sufficient to induce crying and sadness. But is the crying directly caused by this stimulation? Or is it indirectly induced by the feeling of intense sadness? I’ll admit to being pretty interested in what the pathway is here, and then: what is the pathway that causes this area to activate?

Also, three cheers for the surgeon whose job it was to repeatedly and remorselessly cause this patient to cry and feel intense sadness!

References

Burghardt T, Basha MM, Fuerst D, & Mittal S (2013). Crying with sorrow evoked by electrocortical stimulation. Epileptic disorders : international epilepsy journal with videotape, 15 (1), 72-5 PMID: 23531727

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Unrelated to all that, 5/31 edition

frogging in the rain

Dictators are only nightmares, they don’t exist in real life.  How much are the results of dictator games laboratory artifacts?

Also, because it was bad.  Seven reasons why journals reject papers.

The origin of outsight, I’d say!  Book review on foraging with prefrontal cortex.  Not that humans have particularly large frontal lobes anyway.

But look at that author list!  GWAS identifies genetic variants associated with educational attainment, but might it be a bit underpowered?  The variants only explain 2% of variation which is…not a lot.

Australia is surprisingly recognizable.  But then, broad stretches of Norway look like my homeland in the Pacific Northwest.  Geoguessr.

In the “things you should know about” department.  The world’s bloodiest civil war: China, 1850-1864.

Well there go all my passwords.  Why your password sucks.

It’s been a musical week.  Boards of Canada are back, and just as awesome as I had hoped.  Daft Punk and 2001 were made for each other.  And I really can’t get this Daft Punk/Mad Men combo out of my head.

The young and the restless

Elderly chinese men playing chess

It struck me recently that one of the key differences between economists and neuroscientists studying decision-making is their interest in dynamics.  Economists seem more interested in explaining how behavior operates (or should operate) on average whereas neuroscientists would like to explain trial-to-trial variability.  Decisions are rarely made just once in a lifetime, but are instead made repeatedly.  Any behaviorist would instantly tell you that this means that there will be a learning component, something that I hardly see in the economic decision-making literature (feel free to correct me if this is wrong).

In many of these repeated decisions, people are not simply making a decision in a vacuum but are responding to the actions of others.  The decision must then be balanced by their prior beliefs, the results of recent decisions, and their predictions of how other people will act.  All of this can be incorporated into a reinforcement learning (RL) paradigm, where the expected value of any action is a combination of classical RL – where every payoff suggests future payoffs, and every loss suggests future losses – as well as a ‘mentalizing’ component that predicts how the opponent is likely to act, and how the opponent will react.  By fitting the responses of different brain regions to this type of model, one can get a sense of what each region is (kind of) doing.  One region that instantly pops out is the medial prefrontal cortex (mPFC): this region is highly correlated with the prediction of other people’s behavior.

I once took a behavioral economics class in which the professor pointed out that deviations from rational behavior are only important if they translate to something in aggregate.  In other words, who cares if just a few people have abnormal mPFC function.  In a large population you won’t notice them.  But in fact there is a very large group of people with degraded mPFC: the elderly.  13 percent of the US is over the age of 65, and this group is known to have significant loss of volume in mPFC.  The prediction, then, would be that older individuals would be less inclined to take into account the behavior of other individuals when making decisions.

To test how they will act, we can take the experimental game the “Patent Race”.  In this game, two players are selected from a pool to compete for a prize.  They are each given either a large five credit or a small four credit endowment, and are asked to “invest” some portion of that.  They then get to keep whatever is left over, and the person who “invested” the most wins ten extra credits.

Cumulative distribution plots of how influential other individual's behavior is in determining one's own behavior.  Blue represents young adults and purple-dashed represents the elderly.

Cumulative distribution plots of how influential other individual’s behavior is in determining one’s own behavior. Blue represents young adults and purple-dashed represents the elderly.

There does exist a Nash equilibria to this game, and young adults will play the Nash equilibria exactly.  Old adults, on the other hand, play a significantly different strategy.  What is more interesting, though, is half of elderly adults behave as if they did not care at all about the strategy of the other player.  In other words, they are making decisions using a pure reinforcement learning strategy where they only cared about payoffs, not about how the other player was going to act.  In contrast, no young adults played like this: they all took into account the strategy that the other player would use.

References

Hampton, A., Bossaerts, P., & O’Doherty, J. (2008). Neural correlates of mentalizing-related computations during strategic interactions in humans Proceedings of the National Academy of Sciences, 105 (18), 6741-6746 DOI: 10.1073/pnas.0711099105

Zhu, L., Walsh, D., & Hsu, M. (2012). Neuroeconomic Measures of Social Decision-Making Across the Lifespan Frontiers in Neuroscience, 6 DOI: 10.3389/fnins.2012.00128

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A mechanics of depression

There are many reactions that can be taken in response to the world going crazy on you, and depression is one of these.  Even though it is (rightly) seen as perhaps not the greatest illness to have, there is a case to be made that depression is an energetically-efficient response to overwhelming stress; it can be better to shrink back and conserve your energy than fight it.  Think about it like this: you probably know some people who are super laid back, who take things as they come and don’t seem to stress out.  And you also probably know some people who freak out at stress, work really hard, and just seem to be stressed out all the time.  These are two different strategies for dealing with stress and one seems more likely to lead into depression.  At the same time that same strategy seems like the person is fighting harder to get out of the stressful situation.  How does the brain do something like that?

It is thanks to tools from the lab of Karl Deisseroth that we are finally able to begin to really, mechanistically, understand what is going on in the brain.  And fortunately, Deisseroth is both a research scientist and a psychiatrist who is interested in helping people with mental diseases.  There are three (!) papers published in Nature over the last month with his name on them, and they shed a lot of light on the mechanisms that are at work.

No one is really sure what it is about the brain that causes depression, although we have some hints: antidepressant drugs tend to work by modifying the release of the neuromodulators serotonin and dopamine (and norepinephrin).  We also know that an area called the prefrontal cortex (PFC) is highly linked to all sorts of psychiatric disorders; the PFC is an area that receives inputs from all over the place and then sends outputs right back out.  He’s the boss, the one that hears everything people have to say and then directs other areas in order to coordinate the brain to accomplish internal goals.  You can imagine what might happen if you have a bad boss: your brain is out of sync, things don’t get coordinated properly and then BAM, schizophrenia and depression.

As you might imagine, these things are all interconnected in the brain: the PFC talks to the serotonin and dopamine areas, and the serotonin and dopamine areas talk to the PFC.  And these connections are particularly important.  Take the connection between the PFC and an area that releases serotonin, the dorsal raphe nucleus (DRN).  This connection is required to motivate an animal to avoid escapable stress.  A mouse that is in a position to escape from stress will clearly do so.  However, if you inactivate the PFC the mouse will not escape from stress and its release of serotonin will look the same as if it were in a stressful situation it can’t escape from.  If you disable the PFC in a stressful situation that it can’t escape from?  No change: the PFC seems to control motivated behavior from escapable situations only, and without it you can’t.

That’s exactly what one of the recent Deisseroth papers examined.  They were able to directly activate only the PFC neurons that send information to the DRN and by doing so they found a way to escape from a learned kind of helplessness.  Rats that are stuck in a cup of water will struggle for a while, attempting to escape.  After a while they learn that struggling isn’t getting them anywhere and they just kind of give up.  But if you activate the PFC connections to the DRN?  The rats launch back into the struggle again!  But this doesn’t happen if you just activate all the neurons of the PFC or all the neurons of the DRN: there is a specific pathway through both of these brain regions that motivates an escape from helplessness.

Release of dopamine can help motivate escape from a helpless condition as well, although it is released from a different part of the brain.  The ventral tegmental area (VTA) is one of the main release sites of dopamine in the brain and is the signal of ‘pleasure’ in the brain, although it is perhaps more accurate to say that it is the primary signal of motivation.  And if you stimulate the neurons in the VTA you get an increase in motivation to escape a depressing circumstance, just as you’d expect from that area.  And specifically, this is because of a release of dopamine from the VTA to another area of the brain, the nucleus accumbens (NAcc).  What is likely to be happening is that the VTA is sending a motivating signal to an action and learning center of the brain (the NAcc), and that center of the brain helps decide what to do next, and what to do next is to get the heck out of there.  Something exciting happens here: if you now go and record the neurons in the NAcc after additional dopamine is released from the VTA, they now respond to different things.  The whole way that an action is represented in the brain changes, and in a way that emphasizes escape.

But this ability to learn escape can have a negative side.  Take the example of another method of stressing out mice, chronic social defeat.  What you do here is force mice to get defeated in battle again and again.  Yes, this is actually a commonly studied behavior; these poor guys are basically given PTSD.  But it turns out that some mice are resilient to this stress, they can withstand it and not get depressed.  If you look at the neurons in the VTA, the susceptible animals show an increased amount of bursts of activity (technically: phasic firing) during stress while the resilient animals just hummed along with no change of activity in the VTA at all!  This natural increase in firing can be simulated in the resilient animals by artificially increasing VTA firing.  Then, when you test whether they have acquired PTSD?  Well, it turns out that they have.  This makes a certain kind of sense: dopamine reinforces behavior, so susceptible animals are seeing more dopamine and hence more reinforcing of defeat than are the resilient animals.  Again, though, different internal pathways have different effects in the brain: if you activate the neurons that send information to the ‘pleasure center’, the nucleus accumbens then you are more vulnerable to stress.  And if you inhibit the activity of neurons that send information to the PFC, then you also become more vulnerable to stress.

The same sets of neurons that can help you escape stress (the VTA to NAcc connection) are the ones that will cause you to be more depressed in the future.  This suggests that there might be a tradeoff in life: you can be stressed out but really motivated to escape stress, or you can put up with a whole bunch of stress and be laid back about it in the future.  But it seems like it might be hard to be both.  There are of course in-betweens: the PFC, the boss, has specific circuits dedicated to telling the VTA and the DRN what to do, and can tell them to do opposite things.  And of course, the more you try to escape stress and fail, the more you learn it is futile to escape stress, triggering a terrible feedback cycle.  But if you want to be learning, you better be trying.

References

Chaudhury, D., Walsh, J., Friedman, A., Juarez, B., Ku, S., Koo, J., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D., Nectow, A., Ekstrand, M., Domingos, A., Mazei-Robison, M., Mouzon, E., Lobo, M., Neve, R., Friedman, J., Russo, S., Deisseroth, K., Nestler, E., & Han, M. (2012). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons Nature, 493 (7433), 532-536 DOI: 10.1038/nature11713
Tye, K., Mirzabekov, J., Warden, M., Ferenczi, E., Tsai, H., Finkelstein, J., Kim, S., Adhikari, A., Thompson, K., Andalman, A., Gunaydin, L., Witten, I., & Deisseroth, K. (2012). Dopamine neurons modulate neural encoding and expression of depression-related behaviour Nature, 493 (7433), 537-541 DOI: 10.1038/nature11740
Warden, M., Selimbeyoglu, A., Mirzabekov, J., Lo, M., Thompson, K., Kim, S., Adhikari, A., Tye, K., Frank, L., & Deisseroth, K. (2012). A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge Nature DOI: 10.1038/nature11617
Amat, J., Baratta, M., Paul, E., Bland, S., Watkins, L., & Maier, S. (2005). Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus Nature Neuroscience, 8 (3), 365-371 DOI: 10.1038/nn1399

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