Philosophy of Computational Neuroscience

Just like experimental neuroscience, computational neuroscience can be done well or poorly.

computational models look beautiful (source)

This post was motivated by Janet Stemwedel's recent post in Adventures in Ethics and Science about the philosophy of computational neuroscience. There seem to be three views of the use of computational models in biology and neuroscience:

1. All models are bullshit.
2. Models rely on MATH, so of course they are right.
3. Some models are good and some are bad.

Obviously the first two are extremes and usually posited by people who don't know anything about computational neuroscience, and I am clearly advocating the third view. The only problem is that it is hard to tell if a model is good or bad unless you know a lot about it.

So here are some general principles that can help you divide the good and the bad in computational neuroscience.

1. The authors use the correct level of detail.

devil's in the details (source)

If you are trying to test how brain regions interact with each other, you don't need to model every single cell in each region, but you need to have enough detail to differentiate the brain regions from one another. Similarly, if you are trying to test how molecules diffuse within a dendrite, you don't need to model a whole cell, but you need to have enough detail to differentiate one molecule type from another. If you are trying to test how a cell processes information, you need to have a cell, as you may have learned in how to build a neuron.  Basically a model can be bad simply because it is applied to the wrong question.

2. The authors tune and validate their model using separate data.

When you are making a model you tune it to fit data. For example, in a computational model of a neuron you want to make sure your particular composition of channels produces the right spiking pattern. However, you also want to validate it against data. So how is tuning different from validating? Tuning is when you change the parameters of the model to make it match data. Validating is when you check the tuned model to see if it matches data. Good practice in computational neuroscience is to tune your model to one set of data, but to validate it against a different set of data.
For example, if a cell does X and Y, you can tune your model to effect X, but then check to see that the parameters that make it do X also make it do Y. Sometimes this is not possible. Maybe there is not enough experimental data out there. But if it is not possible, you should at least test the robustness of your model (see point 3).

3. The authors test the robustness of their model.

A robust computational model can be delicious (source)

One problem with computational models is that the specific set of parameters you've found by tuning the model might not be the 'right ones.' In fact they probably aren't the right ones. There are many different sets of parameters that can make a neuron spike slowly, for example.  And the chance that you hit on exactly the correct combination of things is very low. But that doesn't mean the model is not useful. You can still use the model to test effects that are not strongly altered by small changes in these parameters. So you need to test whether the specific effect you are testing is robust to parameter variation. If you are testing effect Q, you can increase the sodium channels by 10%, or the network size by 20% and see if you still get effect Q. In other words is 'effect Q' robust to changes in sodium channels or network size? If it is, then great! Your effect is not some weird fluke due to the exact combination of parameters that you have used.

These are the main things I try to pay attention to, but I am sure there are other important things to keep in mind when making models and reading about them. What are your thoughts?

© TheCellularScale

The Inadvertent Psychological Experiment

Escape from Camp 14 is deeply disturbing, and I highly recommend it.

Escape from Camp 14 by Blaine Harden

Escape from Camp 14 is a chilling tale of Shin Dong-hyuk's escape from a North Korean prison camp. What is so interesting about Shin Dong-hyuk's story as written by Blaine Harden is that he was born inside this North Korean prison camp. Apparently they allow breeding between prisoners as a reward for 'good behavior.'

Escape from Camp 14 reveals the obscene violations of human rights that occur in North Korean prison camps, and was especially poignant because I am a similar age to Shin Dong-hyuk and could directly compare my memories during the specified years to his. For example he escapes on January 2nd, 2005 and I couldn't help but think of the New Years party I was at that year and how absurdly different my life has been from his.

This book struck me in a way that reading about the horrors of the Holocaust never could. Those atrocities happened long before I was born. But the atrocities in North Korea are happening right now. I mean right this minute in a prison camp, a child is likely being beaten, a woman is likely being raped by a guard (later to be killed if she happens to become pregnant), someone may be picking undigested corn kernels from cow dung to ease hir starving belly, and maybe two lucky prisoners are getting to have 'reward breeding' time. Right now. This minute. That is just nuts.

The other thing that struck me about this whole situation is that having children born into a hostile prison environment is an inadvertent psychological experiment. These children are raised without love and without trust. One of the sharpest points in the book is the reveal that Shin Dong-hyuk turned his own mother and brother in to the guards for planning an escape. He watched his mother's execution shortly thereafter and felt nothing but anger at her for planning an escape.

When he finally escaped, it was shocking to him to see people talking and laughing together without guards coming over to (violently) stop it. In Camp 14, gathering of more than 2 people was forbidden. These prison children are being raised on fear of the guards and suspicion of each other. One of the easiest ways to be rewarded is to tattle on another prisoner for something (stealing food, for example), and the children learn this quickly.

If something drastic happens and North Korea dissolves, these children raised in prison camps will have a near impossible time trying to adjust to a life of freedom and will have a difficult time forming attachments and trusting others (as seen in Shin Dong-hyuk and other refugees from North Korea). Their personalities and psychological profiles could be fundamentally different from any other group on earth. These atrocities should be stopped and these people should be studied and rehabilitated.

© TheCellularScale


Lee YM, Shin OJ, & Lim MH (2012). The psychological problems of north korean adolescent refugees living in South Korea. Psychiatry investigation, 9 (3), 217-22 PMID: 22993519

It's not you, it's my birth control

So, Valentine's Day, what better time to question the foundations of your relationship?

It's my brain that loves you (source)

Well, part of your relationship may be based on your Major Histocompatibility Complex (MHC) compatibility. The MHC is a cluster of genes that define which antigens get expressed on white blood cells. It is thought to control the ability of the body to recognize pathogens as 'other.' It is also thought that the more varied the genes in your MHC are, the more resistant to pathogens or parasites you are.

So what does the MHC have to do with your love life?
Well the most popular theory goes as such: If you want to have a healthy baby, you want to give it a varied MHC, therefore you want to find a man who has an MHC that is very different from your own.

And... Maybe you can detect whether a man has a MHC that is the same or different from yours through smell (maybe vision too). In 2005, a paper came out explaining that the Major Histocompatibility Complex (MHC) can be detected through smell, and (importantly) that women prefer the smell of men who have an MHC that is different from their own. (However another paper in 2008, did not replicate this preference)

Possible new fragrance? 

Now here's the real kicker: Taking oral contraceptives (birth control pills) might mess this preference up. Roberts et al., 2008 show that in an armpit sweat test (like this one), women on birth control showed more of a preference for the MHC similar men than the women not on birth control. If true, this could have implications for women starting relationships when they are either on or not on birth control. To take this to the greatest sensationalist extreme, you might pick the WRONG GUY because you were on birth control. However, just like I don't believe in destined, fated true love, I don't believe you need to have opposite MHCs to have a good relationship or healthy children.

Roberts et al. 2008 Figure 2C: Odor desirability ratings.

And not only that, I have somewhat of a problem with this graph and their data. As far as I can tell (I found the description to be pretty confusing), the white bars represent 'session 1' in which NO ONE was on the pill and then the gray bars represent 'session 2' when the women labeled 'pill' were actually on the pill, but the women labeled 'non-pill'  were still not on the pill. (following this?)  AND, 0 means that they liked the similar MHC and the dissimilar MHC guys equally, negative means the like the similar guys more and positive means they like the dissimilar guys more... (I told you this was confusing).

So my question is, why are the non-pill and pill users so different to begin with? Unless I am completely misunderstanding this graph, I would think the white bars should be similar, as they represent 'women who are not on birth control.' The huge difference between groups before the 'experimental treatment' should be a red flag: Something is already different between these women.

However, the pill session 1 (white) and pill session 2 (gray) bars are indeed different, and that is their 'main result.' Basically, women on the pill had an overall slight odor preference for MHC similar men, and the same women not on the pill had an odor preference for MHC dissimilar men.

So should you worry this Valentine's Day? Should you break up with your boyfriend because you were on birth control when you met? Should you spend a lot of time smelling your boyfriend's worn shirts analyzing how 'desirable' a scent the give off?

Probably not (unless you really like smelling sweaty shirts). There is more to relationship compatibility than histocompatibility, and making life-changing decisions based on possible olfactory disruptions due to birth control is just not a good idea.

Though if you are worried, you can read more about it at:

Context and Variation "will the pill mess up my ability to detect my one true love?"

and

First Nerve "pill goggles"

© TheCellularScale


Roberts SC, Gosling LM, Carter V, & Petrie M (2008). MHC-correlated odour preferences in humans and the use of oral contraceptives. Proceedings. Biological sciences / The Royal Society, 275 (1652), 2715-22 PMID: 18700206

Intuition or a sense of Smell?

I've long been fascinated by the idea that those feelings often attributed to 'intuition' or 'following your gut' might occur physiologically in the form of odor cues that we don't consciously register.

Intuition or Olfactuation? (source)

An example of this might me when you can just 'tell something is wrong' in a situation and decide to leave, and later found out that something bad happened later that evening. These sorts of stories are often used as evidence that people have psychic powers of some kind, and are equally often dismissed as just a coincidence.

But another possibility is that humans communicate through scents more than we realize. Maybe you could actually 'smell something is wrong' rather than supernaturally 'tell something is wrong' in the above hypothetical situation.

Researchers in the Netherlands tested whether the feelings of 'disgust' and 'fear' could be communicated through smell. They had guys watch scary parts of horror movies or disgusting graphic parts of MTV's Jackass while wearing 'sweat pads' in their armpits.

Who knew this would contribute to SCIENCE?

They then had female volunteers smell the sweat pads and measured their facial motions to see if the expressions they made were more like fear or disgust.

Importantly the protocol was double-blind, so neither the experimenters handing out the sweat pad vials, nor the participants had any idea what 'emotion' was sweated into those pads.

And they found what they thought they would find: the 'fear muscles' (Medial Frontalis) were most active for the women smelling the sweat of the horror-watching men, and the 'disgust muscles' (Levator Labii) were most active for the women smelling the sweat of the Jackass-watching men. In the authors words (stats taken out for readability):

"Moreover, fear chemosignals generated an expression of fear and not disgust, disgust chemosignals induced a facial configuration of disgust rather than fear, and neither fear, nor disgust, were evoked in the control condition" de Groot et al. (2012)

So at very very close range (like nose in armpit), it seems that emotional signals can be transmitted through scent.

The smell of fear (source)

A quick side note: the scent in this study was created by men and smelled by women. I wonder if this specific gender combination is necessary for the scent-based communication. You would think men smelling men and women smelling women would have the same effect, but they did not investigate other combinations.

If you learn anything from this, let it be to not go see a disgusting movie on a first date, you might end up repulsing each other with your 'disgust sweat' later.

© TheCellularScale


de Groot JH, Smeets MA, Kaldewaij A, Duijndam MJ, & Semin GR (2012). Chemosignals communicate human emotions. Psychological science, 23 (11), 1417-24 PMID: 23019141

SfN Neuroblogging 2012: Implicit and Explicit Gender Bias

Today I am going to talk about just one thing rather than poster highlights from the whole day.
As always, all the SfN Neuroblogging posts can be found here. Other posts on gender and neurosexism can be found here.

Today was the annual "Celebration of Women in Neuroscience Luncheon." This is one of the highlights of SfN for me each year. There is always a fantastic speaker (Phyllis Wise this year) and the lunch is delicious.

Phyllis Wise brought up the 'exact same resume study' in her speech and it got me thinking. The 'exact same resume' study is where researchers construct a fake person and write up their resume, and then submit it in application for various jobs. However, sometimes they put a woman's name at the top and sometimes they put a man's name at the top. 

The study found that the male names received more and higher paying job offers and were judged to be more qualified. And it wasn't just that men thought women less capable. The females who judged the resumes were just as biased as the males who judged resumes. This is pretty depressing. I mean this isn't the middle ages, or even the Victorian era, aren't we past this bias?

But that's exactly the problem. We think we are past this bias. Even though people (both women and men) don't think they have a bias, they actually do. Even you. Just like you probably think you are smarter than average, or a better driver than average, you also probably think that you are less biased than average. That. is. the. problem. People have an implicit bias towards thinking men are smarter, better and more capable even when faced with the exact same description of the person. And they don't acknowledge this bias.

How can you combat or fix a bias that people don't even think they have? A gender blind resume process could be implemented in the initial application process for a jobs. But as soon as the applicant arrives for an interview, the gender bias would rear its ugly head. Should faculty or hiring committees develop an explicit bias towards women in their hiring and salary negotiation process?

I do not know the answer to this question. I can't think of a better way to combat implicit bias than with explicit bias, but it's hard to argue that implementing an explicit bias is 'fair' (It is a bias after all). It would especially seem unfair to those who don't think that they are implicitly biased (which we have established is basically everyone). But is there a fair way to handle this problem?

UPDATE (10/19/12): Thank you to Dario Maestripieri for helping me think about this problem in a new way. Perhaps the best way to start addressing an implicit bias is to make it explicit. When someone makes an idiotic or sexist comment, it should be made public. When someone gets grabby, it should be made public. The whole point of this post is that one of the biggest problems with gender bias in science is that people don't believe it is there. If it is made clear that it is there, people can more easily fight against it.

© TheCellularScale

Moss-Racusin CA, Dovidio JF, Brescoll VL, Graham MJ, & Handelsman J (2012). Science faculty's subtle gender biases favor male students. Proceedings of the National Academy of Sciences of the United States of America, 109 (41), 16474-9 PMID: 22988126

you can't trust your brain: memory

"Flashbulb" memories are those vivid memories of specific salient events.  The 'everyone remembers exactly where they were when...' sort of events.  In the USA, and depending on how old you are, you might remember the assassination of JFK, or Martin Luther King Jr. in this way. In this century, most Americans remember exactly where they were when they heard about the 9/11 attacks on the world trade center and pentagon.

"Never Forget" (source)

It's widely acknowledged these days that the brain is not really a safe place to store information. Memories of events change over time. But for a while the "flashbulb" memory was thought to be immune from the memory-altering properties of time. Think about your own memories of 9/11 or another highly meaningful event. I bet you are pretty certain about the details. I, for example, was in my second year of college and I know exactly who told me that the first tower was hit, exactly where I was standing on the quad, and exactly what class I was going to....

...or do I? 

A study in 2003 tested the consistency of flashbulb memories over time and compared the details to 'control memories' of everyday events. They specifically recorded memories from people during the day after the 9/11 attacks, and then recorded memories of the same events from subsets of those same people 1 week, 6 weeks, and 32 weeks later. They found that the flashbulb memories did have different properties when compared to control memories, but that consistency was not one of them. 

Talarico and Rubin 2003, Figure 1a

Talarico and Rubin show that the flashbulb memories and the everyday memories had the same time-dependent decay (that x axis is in days), demonstrating that the flashbulb memory did not have some special property that protected it from corruption. 

However, they did find that the level of confidence in the memory was higher for flashbulb memories than for everyday memories. People thought (incorrectly) that their memories of the 9/11 attacks were more accurate than their other memories. 

So again we learn the lesson that we cannot trust ourselves.

In the authors words:

"The true 'mystery,' then, is not why flashbulb memories are so accurate for so long,... but why people are so confident in the accuracy of their flashbulb memories." Talarico and Rubin (2003)

But I think the most interesting finding in this paper was that the flashbulb memories of 9/11 were more likely to be recalled 'through ones own eyes' than the everyday memories. Everyday memories were seen 'through ones own eyes' at the beginning and a at 1 week, but at 6 and 32 weeks the everyday memories were more likely to be seen 'from an outside observer perspective.' The flashbulb memories, on the other hand, were seen 'through ones own eyes' at all time points. Indeed, when I think of my own 9/11 memory, I still see it through my own eyes.

The authors don't go into why that might be or what it might mean, so we are left to wonder.

© TheCellularScale



Talarico JM, & Rubin DC (2003). Confidence, not consistency, characterizes flashbulb memories. Psychological science, 14 (5), 455-61 PMID: 12930476

Taste cells in weird parts of your body

Everyone knows that taste and smell are intimately related, but what you might not know is that you have actual 'taste' cells in your nose (the nasal epithelium to be exact). 

Don't drink this way (source).

But before you go try to drink through your nose, read on, the story gets weirder.  These 'taste' cells express the T2R receptor which senses 'bitterness'. However, if you sniff some 'bitter' molecules into your nose, you won't feel like you are tasting bitterness because these cells don't go to the official 'taste' part of the brain.  In fact, they do something even cooler.  I'll let a previously-blogged-about author, Dr. Finger, explain:

"Since the SCCs synapse onto polymodal pain fibers in the trigeminal nerve, activation of the SCCs by bitter ligands evokes trigeminally mediated reflex changes in respiration." (Finger and Kinnamon 2011)

The SCCs are the 'solitary chemosensory cells' which are the 'taste' cells in the nose that I was talking about. And basically what Dr. Finger is saying is that when stimulated, these cells cause you pain and change the rate at which you breath. This is probably because it is not evolutionarily healthy to have something bitter up your nose and you might not want to breath it in deeply. Might be poison. 

If taste cells in the nose isn't weird enough, here is a diagram of all the other strange places in your body where 'taste' cells have been found:


Taste cells in the body Figure 2 (Finger and Kinnamon 2011)

So why do you need taste cells in your stomach? Well these cells don't send signals to the taste center of the brain either, but they do release ghrelin, which is an appetite-inducting peptide.  Since the taste receptors in the stomach have T1R receptors which respond to sweetness and amino acids (glutamate), this could be a signal saying 'yum, this is good stuff, keep eating'.

But why would there be taste cells in the bile duct? 
The authors of this review paper don't have that answer either:

"The composition of fluid in the bile ducts is dictated by secretions of the liver, pancreas, and gall bladder, so why is it necessary to diligently monitor the composition of biliary fluids and they move from gall bladder to intestines?" (Finger and Kinnamon 2011)

The moral of the story: Even though cells in weird parts of the body are shaped like taste cells and have taste receptors on them, they don't necessarily make you feel the feeling of taste, but they might serve other important survival functions.

© TheCellularScale


Finger TE, & Kinnamon SC (2011). Taste isn't just for taste buds anymore. F1000 biology reports, 3 PMID: 21941599

The Optimism Bias in Science

"I have always believed that scientific research is another domain where a form of optimism is essential to success: I have yet to meet a successful scientist who lacks the ability to exaggerate the importance of what he or she is doing, and I believe that someone who lacks a delusional sense of significance will wilt in the face of repeated experiences of multiple small failures and rare successes, the fate of most researchers"     -Daniel Kahneman

The Brain: Irrational, Positive, Deceptive

I just finished reading The Optimism Bias by Tali Sharot.  The book explains that most people have an "Optimism Bias," a tendency to over-estimate how smart, good-looking, and capable they are as well as the likelihood that good things will happen to them. 

Sharot points out that in a 1981 study (Swenson O) 93% of participants rated themselves as in the top 50th percentile (i.e. 'above average') for driving ability.  Other studies have shown that this "Better than Average Effect" applies to many aspects of our self-image.  Think about yourself right now... do you think you are smarter than average? better looking than average? nicer than average? etc.  You probably do.  And even though it is logically impossible for 93% of people to be better than the 50% mark, you probably still think that you are actually  better/smarter/nicer. 

So even though you think you are smarter than most people, the reality is that most people think they are smarter than most people.

Similarly people under-estimate the likelihood that bad things will happen in their life and over estimate the likelihood that good things will happen. Ask any newly engaged couple what they think their chances of divorce are, and if not too offended by such a rude question, they will probably rate the chance of divorce as very low or even zero.  However reality says that they actually have a 41-50% chance of divorce. 

divorce cake (source)

But as Sharot claims, this optimistic skew to reality is actually beneficial. Which newly engaged couple would actually get married if they fully realized and believed that their chances of staying married were no better than the chance of flipping heads or tails on a coin? The irrational belief that we are somehow exceptional is motivating. Sharot even suggests that the optimism bias is so prevalent in our species and culture that people who realistically evaluate their situation are not the norm, and may even be clinically depressed. 

While The Optimism Bias has a great premise and recounts some exciting research, I thought the book in general was way too long.  Some very simple concepts (like that people have an optimism bias) were repeated over and over and over, and some (interesting) concepts were introduced that had pretty much nothing to do with optimism (like that memories are unreliable). 

The book didn't really teach me much about how the brain works, but it did set me thinking about how a strong optimism bias is an essential trait in academia.  As the Kahneman quote above states, most scientists face critique after critique and failure after failure.  Successes are few and far between and the same sense of realism that would prevent many a marriage, would also prevent a potential scientist from entering a Ph.D. program. Who would even apply to graduate school if they fully understood and believed the dismal statistics about finishing Ph.D. programs and the subsequent tenure-track job search. 

We have to believe that we are special, that our work is crucial, and that our contributions are significant.  No scientist will succeed if they get their peer-reviewed paper back from a journal and immediately think: 'yep, the third reviewer is correct, this work is flawed and has little impact, I should quit and become a cab driver.' A near-delusional sense of significance and an "it's not me, it's them" attitude is required to stand by your ideas and abilities in the face of these kinds of criticisms. 


© TheCellularScale



Sharot T (2011). The optimism bias. Current biology : CB, 21 (23) PMID: 22153158

LMAYQ: Can Odor be recorded?

Let Me Answer Your Questions: part 2, in which I answer your very important questions via google search terms. Part 1 and all subsequent LMAYQ posts will be archived in the LMAYQ index.

by Likarious

So let's get to it, what fascinating questions are you asking google?


1. "Can odor be recorded?"  

This likely brought someone to my post "You can't trust your receptors:smell" in which I discuss the EOG (electrolfactogram) where you can record the electrical activity of a smell receptor while certain smells are presented.  But it does not answer the question of whether a smell itself can be recorded.

So I looked into it a little bit and surprisingly, the answer is yes!

Nakamoto and others have created an "odor recorder"

Nakamoto 2005 figure 1

Unlike visual recording, which only need red, green, and blue to make essentially all the colors, odor recording requires a few more components. For example, the authors created an apple smell using 8 components.

I would love to say that this odor recorder is going to appear in every living room and plug into the TV so that restaurant and perfume marketing can be truly effective, I just don't see the demand being strong enough to make it worth mass producing. Though, I think it would be pretty amazing. 

I also had doubts as to whether the odor recorder could accurately transmit the scent of a really nice perfume which is not static, but develops over time. But The 2005 Nakamoto paper shows that they can actually record the changes of an odor over time!

While there is always the fact that a perfume reacts differently with every one's skin, the odor recorder actually seems like a promising device and might find a market in die hard perfume fans.

or..."odor recorder prevents murder"

The quest to permanently record the scent of a woman drives a man to murder in the mediocre movie "Perfume: the Story of a Murderer."  If only he was in possession of an odor recorder.

© TheCellularScale

Nakamoto T (2005). Study of odor recorder for dynamical change of odor. Chemical senses, 30 Suppl 1 PMID: 15738143

A Pain in the Hippocampus

Neuropathic Pain (source)

Pain is usually a helpful sign that something is wrong with a part of your body. Heat-pain will cause you to pull your hand back from something hot before it burns you. The pain of a cut will draw your attention to it, so you can clean it.

However damage to the central or peripheral nervous system can result in chronic neuropathic pain, which is not helpful form of pain. Neuropathic pain is basically some mis-firing or mis-connected pain neurons sending meaningless, but persistant pain signals to the brain. And as bad as that sounds, chronic pain can also apparantly wreak havoc on your brain.

A recent study by Mutso et al., (2012) shows that in both humans and experimental animals, the brain is actually re-organized in response to chronic pain.  Specifically, they look at pain-related changes in the hippocampus, the part of the brain most strongly implicated in memory encoding. 

They compared human patients with chronic back pain, complex regional pain syndrome, and osteoarthritis to people with no pain-related condition, and found that the people with both chronic back pain and with complex regional pain syndrome both had reduced hippocampal volume when compared with the normal control group. The osteoarthritis patients showed a trend toward reduced hippocampal volume, but the result was not statistically significant. 

Hippocampus (source)

So what does this mean? If you have chronic pain you have a smaller hippocampus? We've covered this kind of study before, basketball players had larger striatums that non-basketball players, but it is never really clear what the volume of a brain region tells us. 

Does the volume of a brain structure mean more neurons, more blood flow to that region, more glia cells, or differently shaped neurons?

It is very difficult to draw any conclusions about the effect of pain on the hippocampus simply by learning that the hippocampi of people with chronic pain are smaller than the hippocampi of normal people. 

Luckily the study did not end there. Mutso et al. also investigated the effects of chronic pain on the cellular level. 

Hippocampal Neurons (source)

They found that in mice with chronic pain, the hippocampus has fewer 'new' cells. By staining for two specific markers DCX and BrdU, you can tell which neurons are new.  The hippocampi of control (normal) mice had around 40 new cells, while the chronic pain mice had only 14.  This is an indication that neurogenesis is much reduced in response to chronic pain, and suggests that the reduction in hippocampal volume could be related to fewer new neurons being generated (though it does not show this conclusively).

Unfortunately, chronic pain is bad for your hippocampus, and a cure for both the pain and the collateral brain re-organization are still illusive. 

© TheCellularScale


Mutso AA, Radzicki D, Baliki MN, Huang L, Banisadr G, Centeno MV, Radulovic J, Martina M, Miller RJ, & Apkarian AV (2012). Abnormalities in hippocampal functioning with persistent pain. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (17), 5747-56 PMID: 22539837

Neuroscientists should study Zombie Ants

Zombie ant controlled by fungus (source)

The fungus-controlled zombie ant is one of nature's greatest wonders. A fungus (e.g. O. Unilateralis) is inhaled by an ant (e.g. Camponotus Leonardi), and begins to grow inside its body.  Eventually the fungus infests the brain of the ant, causing it to drunkenly wander, periodically convulse, climb up a leaf and clamp down on its ridge. Once the ant is securely in place, the fungus devours the brain and innards of the ant and grows out the back of its head often (but not always) releasing its spores onto the ground below. Un-freaking-believable, right?

As if this wasn't amazing enough, it's not like it is only one fungus species that infects only one ant species. There are many of these fungi and they infect many different kinds of insect, but somehow maintain a species specificity. In other words, fungus#1 can infect SpeciesX, but not SpeciesY, and Fungus#2 infects SpeciesY, but not SpeciesQ, and so forth. 


So WHY does this happen? and HOW has no one looked at the brain cells of these ants? 

Though no one has looked at the brains of these ants, Last year a paper painstakingly characterized their behavior under 'fungi control'. The most interesting characteristics are:

1. The ants display a 'drunkard's walk' (the author's words)
2. The ants periodically spasm and fall down (if they are above ground level)
3. The ants clamp down on the underside main vein of a leaf (never the side of the leaf, never the top) Interestingly they all bite down on the leaf around solar noon.

Figure 1, Hughes et al., 2011

This figure shows the behavior of several ants.  Each ant was observed during the time of the horizontal blue bar.  The black vertical lines and 'spasms' which caused the ants to fall down (gray stars), and the red triangles are when the ant bit down on the leaf ridge. 

Because we have no idea how the fungus is manipulating the ant, let's wildly speculate.

1. The Drunken Walk:
Why: The reason for this is not clear.  The ant doesn't go far, so the non-directional walking could be to keep it close to more ants.
How: The mechanism is also not clear, but usually an ants directional walking could be following a pheromone trail. The fungus could presumably cause random walking by confusing the ants ability to sense pheromones. It could possibly even cause 'hallucinatory' pheromone sensing.

2. The Periodic Spasms:
Why: The authors speculate that the purpose of these spasms is to keep the ant near the ground.  The infect ants spend much more time on the ground level than the uninfected ants, and the spasms are often followed by a fall.
How:A fungus could essentially cause a seizure in the ants brain by manipulating potassium or calcium channels. On the other hand, I suppose the fungus could be acting directly on the muscles, causing them to twitch in an uncontrolled way. 

3. The Clamping:
Why: This has an obvious function, to root the ant for ultimate fungal growth and dispersion. 
How: First of all, biting and even walking on leaves is not something these ants normally do. So the fungus isn't just hijacking a behavior that the ant already has, it's basically creating a new one.  The correlation with solar noon indicates that a light or heat signal could contribute to the trigger, but basically nothing else is known about it. Interestingly, the clamping does not always have to be one single event either.  A few of the ants clamped down on the leaf vein more than once. The authors of this paper spend time discussing fungi's direct effect on the mandible muscles of the ant.

Figure 3 Hughes et al., 2011

They show that the mandible muscles of the normal ant are fat and healthy (B), but the muscles of the infected ant are separated and reduced in size (C). Though this image is of an ant at the moment of biting, the authors suggests that the deterioration of the mandible muscle might be to prevent re-opening of the clamp. They do not speculate on how the clamp is initiated in the first place, or why it occurs at noon.

So please, fellow neuroscientists, somebody stain these brains! It's just too fascinating to resist exploration. What proteins are altered? What is the receptor composition of behaviorally-specific neurons? Are the dendrites differently shaped?
And who knows what sort of great advances might be hidden in these brain-controlling fungi. The magic of optogenetics comes from lowly light-sensitive bacteria, just think of the possibilities hidden in brain-controlling fungus. 

To be fair, some neuroscience has been done on parasitic brain control, but it is very limited.  In fact it is limited to basically one histological study about parasitic worms who infest crickets and cause them to drown themselves (the subject of a future blog post). However, suicide-crickets are no zombie-ants and the exact mechanisms of the interaction is not likely the same.

© TheCellularScale

Hughes DP, Andersen SB, Hywel-Jones NL, Himaman W, Billen J, & Boomsma JJ (2011). Behavioral mechanisms and morphological symptoms of zombie ants dying from fungal infection. BMC ecology, 11 (1) PMID: 21554670

Real or Not Real: NeuroTorture

I am not going to lie, I recently got caught up in Hunger Games fever, tearing through all three books at a breakneck pace and staying up way too late doing so. While these books raise interesting questions on some of my favorite topics (like 'how much is too much to sacrifice for victory?'), one particular neuroethics issue jumped out and stung me.

Without divulging any plot points or spoilers, I will explain:

In the last book, Mockingjay, a good guy is taken hostage by the bad guys.  Although you never see any actual scenes, it is clear that this person is being tortured for information. One particular form of torment used on this character is called Hijacking.

Injected with the hallucinogenic venom of the mutated wasp (the tracker jacker), this person is forced to recall memories and watch videos of people s/he loves.  This disoriented and unquestionably negative emotional state then alters this person's memories such that when s/he finally sees the familiar faces, s/he distrusts them, hates them, and wants to kill them. 

This portrayal of neurotorture (yes, you can put neuro in front of any word) brings up several questions:

1. Could this really work?
2. Has any one every tried it?
3. Is it wrong?

Let's take a deeper look:

1. Could this really work?
There is no such thing as a Tracker Jacker, but in principle, could a mood or perception altering drug be used on a person to change their memories?

A drug that depleted a person of dopamine or serotonin, or in contrast flooded them with dynorphin, could depress someones mood and possibly make them paranoid or distrustful. Could re-opening a memory during a suspicious, paranoid mood cause someone to re-encode that memory with doubt, distrust, misery, or hate? Or could the addition of a powerful hallucinogen, result in the person not being able to tell which memories were real and which were not?
Kindt et al., in 2009 showed the opposite was true, that application of a beta-blocker (an anti-anxiety drug) during the recall of a fearful memory could dampen the fear response associated with that memory, while the drug alone (without the re-opening of the memory) had no effect.

So my answer: yes, to some extent.  If you can open a memory and extinguish the fear, why couldn't you open a memory and instill the fear?

Could this method sow doubt and confusion in a prisoner's mind? yes.
But, could it make some one ready to kill their old allies? not too likely. I think it would take some seriously extensive and targeted hijacking to even come close to something like that.

In my opinion, the most likely outcome to any hijacking attempt with current known neurological targets would be to drive the prisoner into despair and madness. I doubt you could 'reprogram' a person to kill a specific target.


2. Has anyone tried this?

This is a pretty tough question. If a government has tried this, it is likely a secret, and all the sources I can find online explaining how governments weaponize LSD or whatnot appear about as reliable at The Men Who Stare at Goats. (so I am not adding links to them here, google it if you want some serious theorizing)

Answer: I really don't know, but I want to know.

3. Is it wrong?

In one sense, the answer seems an obvious yes, so I will re-phrase this question into a slightly more complex one: Is neurotorture worse than physical torture?
Is it a greater violation of human rights to take away their identity, their loyalty, and their ability to make rational decisions rather than hurting their physical body? 

In a sense it seems much worse.  It was certainly much more heart wrenching to read about hijacking and its repercussions than to read about physical torture.  But why?

It could be argued that the whole point of the physical torture is to break a person's mind and take away their ability to make rational decisions. And if you have a physically non-painful neurochemical shortcut to do so, why shouldn't you use it? Maybe it would save every one's time, get that critical information soon enough to stop the terrorist attack, and even protect the prisoner's body from pain. 

So why does it seem so distasteful? Is it important to give the person a chance to resist physical torture? Is that more fair?

My answer to is neurotorture wrong? yes, but not more wrong than physical torture. 

Readers, I am sure you have opinions and I am curious to hear them.  please express your opinion here or in the comments section.

neurotorture:

To make things even more complex, what if instead of neurotorture, the opposite tactic was used. what if a prisoner was given extensive repetitive doses of oxytocin to try to hijack their trust? Is it ok to purposefully induce a form of stockholm syndrome in your prisoners? This would be a physically or psychologically non-painful way to get a prisoner on your side.
Would it work? possibly.
Has it been tried? no idea.
Is it wrong? good question.

© TheCellularScale



Kindt M, Soeter M, & Vervliet B (2009). Beyond extinction: erasing human fear responses and preventing the return of fear. Nature neuroscience, 12 (3), 256-8 PMID: 19219038

If you give a mouse a placebo...

...It might ask for some cocaine.  Or it might feel the effects of cocaine anyway. 

Just say no, Rat (source)

The "Placebo Effect" occurs when someone takes a functionally ineffectual drug, but feels the effects anyway. There are many examples of this: Someone in pain takes a sugar pill, but is told that it is a painkiller might report 'feeling much less pain'.  A Parkinson's patient takes a sugar pill having been told it was their 'L-dopa' medication and can suddenly move more fluidly. The "Placebo Effect" is so strong that most experiments testing the effectiveness of a drug in healing anything use a placebo control.  The researchers want to make sure that the drug has an actual effect that is greater than the placebo effect.  (It has been proposed that homeopathic remedies are entirely due to the placebo effect)

One problem with deeply understanding the physical mechanisms which underlie the placebo effect is that all the experiments must be on humans.  You can't simply tell a mouse it's getting a 'cure' and give it a fake pill.  However, scientists at the National Institute on Drug Abuse (NIDA) have conducted an ingenious experiment that involves giving a mouse what is essentially a placebo.  Better still, they published it in PLoS One, so everyone can read the paper for free!

Before we dive into the placebo aspect of this paper, we need to back up and learn a little about as the addiction and reward system works in the brain.

In 1954, James Olds and Peter Milner published a paper showing that a rat would press a lever to receive an electrical stimulation in certain areas of its brain.

Olds and Milner, 1954 Figure 2, Xray of rat

This was a huge discovery showing that 'reward' could be activated directly. 

Later studies found that when this electrode stimulates the dopamine system of a rat, the rat will press and press and press this lever, even forgoing food when it is famished.  Incidentally, a mouse/rat will also compulsively press a lever to get injections of cocaine (which acts by stimulating the dopamine system).  You can do all sorts of experiments on drug addiction using this cocaine self-injection system. You can test how long it takes the mouse to become addicted, you can test the effect of drug concentration, you can test how other drugs interact with self-injection of cocaine, and you can even test aspects of withdrawal and relapse.

Which brings up back to our placebo.  Wise et al., (2008) investigated the mechanisms underlying this self-administration.  What was happening in the mouse brain when they got a dose of cocaine? They found that when the mouse pressed the lever and got the cocaine there was a surge of dopamine almost immediately after.  There is a center in the brain called the VTA that contains neurons which release dopamine. When these neurons are active, other areas of the brain are flushed with dopamine and the person/rat/mouse 'feels reward'.  But what makes these neurons active?

This brings up a problem we discussed a while ago, about the never ending cycle of neuronal firing.  The dopamine neurons fire, but why? what neurons are firing onto them to make them fire, and then, what neurons are making those neurons fire and which ones are firing before that...so forth into forever. 
To go one step up in this firing-chain, Wise et al. cleverly looked at 'brain juice' in the VTA and found that when the cocaine is administered, the mouse gets a surge of glutamate there.  (Glutamate activates cells, so this would cause the dopamine neurons of the VTA to fire and release dopamine onto other cells). 

So what does all this mean, and how does it get us to a placebo for a rat?

Here's the thing: the surge of glutamate that stimulates the VTA only shows up in mice that have already learned that a lever press gives them cocaine.  (That is, this glutamate surge doesn't occur the very first time the mouse gets cocaine)

Wise et al., 2008 (figure1B)

 Here is the figure showing this glutamate surge in the VTA.  The vertical dotted gray line is when the mouse presses the lever for the cocaine.  The red and yellow traces are the condition where the mouse actually gets cocaine in response to the lever press.  the blue and green traces are the condition where the mouse gets saline instead (a control), and the gray trace is the first time the rat gets cocaine in response to the lever press.

 Another peculiar aspect of this glutamate surge is that it is probably too fast a response to be a result of the cocaine acting in the brain.  So how is the injection of cocaine causing a glutamate surge if it is not even acting on the brain yet?  This is quite the puzzle.  Wise et al., wanted to make sure that this glutamate surge was absolutely not due to the cocaine reaching the brain, so they invented the rat placebo! They altered the cocaine molecule, so it was mostly the same shape as normal cocaine, except it couldn't cross the blood brain barrier.  That is, when it is injected into the mouse, it can be detected in the blood and in the peripheral body, but it won't be detected in the brain, and the cocaine will not be able to act directly on the neurons.

When they run the test with this molecule injected instead of cocaine, the figure looks like this:

Wise et al., 2008 (figure1E)

Pretty similar! This cocaine molecule can't reach the brain, but it causes the same glutamate surge as the real stuff! This shows that glutamate surge is somehow due to the cocaine being felt by the body, but not being felt by the brain.  Although they don't call it a placebo in the paper, that is essentially what it is.  It is tricking the brain into thinking it has just received cocaine. (In a stronger way than context can, as evidenced by the lack of response to saline.) 

 So there you have it, a way to trick a rat into thinking it has just received a 'real drug' when it has actually received an ineffectual drug. I think this technique could be adapted to actually study the physiological mechanisms governing the placebo effect. 

© TheCellularScale

Wise RA, Wang B, & You ZB (2008). Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release. PloS one, 3 (8) PMID: 18682722