Review: The Dueling Neurosurgeons (Sam Kean)

If you like this blog, you might like…

I originally intended The Tale of the Dueling Neurosurgeons for epistemic spot checking, but it didn’t end up feeling necessary.  I know just enough neurobiology and psychology to recognize some of its statements as true without looking them up, and more were consistent enough with what I knew and what good science and good science writing looks like; interrogating the book didn’t seem worth the trouble.  I jumped straight to learning from it, and do not regret this choice.  The first thing I actually looked up came 20% of the way into the book, when the author claimed the facial injuries of WWI soldiers inspired the look of the Splicers from BioShock.*

[*This is true. He used the word generic mutant, not the game-specific term Splicer, but I count that under “acceptable simplifications for the masses”.  Also, he is quicker to point out that he is simplifying than any book I can remember.]

At this point it may be obvious why I think fans of this blog will really enjoy this book, beyond the fact that I enjoyed it.  It has a me-like mix of history (historical color, “how we learned this fact”, and “here’s this obviously stupid alternate explanation and why it looked just as plausible if not more so at the time”*), actual science at just the right level of depth, and fun asides like “a lot of data we’ve been talking in this chapter on phantom limbs about comes from the Civil War.  Would you like to know why there were so many lost limbs in the Civil War?  You would?  Well here’s two pages on the physics of rifles and bullets.”**

[*For example, the idea that the brain was at all differentiated was initially dismissed as phrenology 2.0.

**I’m just going to assume you want the answer: before casings were invented, rifles had a trade off between accuracy and ease of use.  Bullets that precisely fit the barrel are very hard to load, bullets smaller than the barrel can’t be aimed with any accuracy.  Some guy resolved this by creating bullets that expanded when shot.  But that required a softer metal, so when the bullet hit it splattered.  This does more damage and is much harder to remove.]

I am more and more convinced that at least through high school, teaching science independent of history of science is actively damaging, because it teaches scientific facts, and treating things as known facts damages the scientific mindset.  “Here is the Correct Thing please regurgitate it” is the opposite of science.  What I would really love to see in science classes is essentially historical reenactments.  For very young kids, give them the facts as we knew them in 18XX, a few competing explanations, and experiments with which to judge them (biased towards practical ones you know will give them informative results), but let them come to their own conclusions.  As they get older, abandon them earlier and earlier in the process; first let them create their own experiments, then their own hypotheses, and eventually their own topics.  Before you know it they’re in grad school.

The Dueling Neurosurgeons would be a terrible textbook for the lab portion of that class because school districts are really touchy about inducing brain damage.  But scientists had a lot of difficulty getting good data on the brain for the exact same reason, and Dueling Neurosurgeons is an excellent representation of that difficulty.  How do we learn when the subject is immensely complex and experiments are straightjacketed?  I also really enjoyed the exploration of  the entanglement between what we know and how we know it.  I walked away from high school science feeling those were separable, but they’re not.

You might like this book if you:

  • like the style of this blog. In particular, entertaining asides that are related to the story but not the point. (These are mostly in footnotes so if you don’t like them you can ignore them).
  • are interested in neurology or neuropsychology at a layman’s level.
  • share my fascination with history of science.
  • appreciate authors who go out of their way to call out simplifications, without drowning the text in technicalities.

You probably won’t like this book if you:

  • need to learn something specific in a hurry.
  • are squeamish about graphic descriptions of traumatic brain damage.
  • are actually hoping to see neurosurgeons duel.  That takes up like half a chapter, and by the standards of scientists arguing it’s not very impressive.

The tail end of the book is either less interesting or more familiar to me, so if you find your interest flagging it’s safe to let go.

This post supported by patreon

Heart Rate Variability

Heart Rate Variability is one of those things that has such an obvious meaning I feel dumb asking follow up questions, but is consistently used in ways that confuse me.  It sounds a lot like arrhythmia, which is bad, but The Willpower Instinct consistently refers to it as good.  Plus it refers to it changing in ways that must be measured instantaneously, but changes in variability have to be measured over time, right?

Here is what I have figured out: we (I) think of the heart as beating to A Rhythm, which is your BPM.  The rhythm can speed up or slow down, but it’s still a rhythm.  A deviation from that is an arrhythmia, which is Bad.  We (I) think this because the wikipedia article on sinus rhythm basically says it, and because the article on HRV implies it’s measured in five minute increments over 24 hours, which means it’s basically a measure of range.  But at least some of the time HRV refers to beat-to-beat variation, and it’s being measured in response to an immediate stimulus (although, maddeningly, no one specifies the time period).

HRV_300
four heart beats, separated by .859, .793, and .726 seconds.

Your parasympathetic (relaxed/restorative) nervous system sends signals to your heart to decrease your heart rate.  Your sympathetic (fight/flight/freeze) system sends signals to increase it.  High parasympathetic activity also seems to be associated with high variability, at least to a point.  My personal guess is that high variability indicates both systems are operating and interacting, while low variability indicates one has taken over, and that your body is somewhat biased towards a higher rate, so it takes a bigger push from the parasympathetic to get the rate down.  Having one system dominate is not always bad: when you are running from a tiger, your heart should beat as fast as possible and redirect blood from digestion and immune system to muscles.  And when you are truly safe, the parasympathetic tells your body it can safely pay off it’s technical debt.  But often having both, and being able to switch between the two, is useful.

There’s  a lot of data showing high heart rate variability is increased by known Good Things (meditation, exercise), and low HRV is associated with bad things (alcoholism, PTSD), but I don’t see hard enough data on causality that I’m confident of the direction.

Rehighjacking the dopamine system

One of the contentions of The Willpower Instinct is that a lot of things (hyperpalatable foods, lottery tickets, facebook…) are hijacking the system that incentivizes you to be productive*, making you think feel that if you do this one more thing, you will achieve an important goal (nutrition, money, social connection). You can try to stare it down, but what you are really fighting is not the specific action, but the goal, and everything in you believes that goal is good, so it’s an expensive battle you will ultimately lose.

Recently I’ve been experimenting with hijacking back.  Let’s use food as an example.  I noticed that I would feel a very strong drive to eat candy, but eating it alleviated the urge for less than a second.  There was no amount of candy that would move me to a not-wanting-candy state.  Once I had that perspective, I could use higher brain powers to figure out what would  actually scratch that itch.  Moreover, I could use the urgency generated by the proximity of candy to power making real food with actual nutritional value.   And the dopamine system couldn’t really do anything about it, because it had sold candy to my body as a means to an end.

It works for video games too.  Sometimes I play video games because they are fun.  Sometimes I play them because I need the feeling of Doing a Thing, and doing actual things will involve an unpleasant intermediate steps.  Of course video games can’t actually make me feel productive, but the reward system tells me that means I need to play harder.

onemoreturn

This is a difficult urge to fight.  But if I pull back and notice doing the thing is not making the urge to do the thing lessen, it becomes obvious I need to do the unpleasant intermediate steps in order to get what I want.

*This is identified only as “dopamine”, but dopamine is a neurotransmitter, so she must mean dopamine in a particular part of the brain.  For simplicity I’ll keep referring to it as the dopamine system.

Dopamine: the tension builder

This is Huey.  He has not met you yet, but he loves you, and he wants you to love him too.  Almost all dogs are human-oriented, but Huey takes it to the next level.  He has been known to hyperventilate with happiness when a friend arrives- and that’s after he’s been at home all day with his work-from-home owner, so it’s not loneliness or separation anxiety, he is just that happy to see you.

IMG_20150522_222451
Pictured: a dog that would really like to be told he is good.

Sometimes Huey’s desire for affection puts him at odds with himself.  For example if you tell him to stay and walk away, he wants to do what you said, but he also wants to be near you.  He will literally vibrate with the effort it takes to stay in place.  But once you tell him good puppy, all the strain goes out of him.  He rushes over for his well deserved affection, and then he’s done.  He might even go play with a chew for a bit.

If you’d like a more human example, consider the orgasm.  Most humans on the edge of orgasm will do anything to finish it.  Immediately post orgasm, they will do absolutely nothing.  Even people who have multiple orgasms will usually have a final one after which they really don’t care.

According to The Willpower Instinct, dopamine release corresponds to the vibrating-with-effort phase, not the good puppy phase.  Dopamine doesn’t mark pleasure, because pleasure doesn’t need to be marked.  Dopamine tells you pleasure is just around the corner, so keep trying.  Note that this is slightly different than Peter Redgrave’s timestamp hypothesis I talked about before, but either would account for a lot of available data.  For example, people with ADHD (who are energetic and yet somehow unable to get themselves to do the thing to get the results they want) are on average low in dopamine, and almost all ADHD treatments increase dopamine availability*.  Dopamine levels rise copiously during sex until orgasm, at which point they plummet.  Dopamine is also heavily involved in addiction.

When asked for comment on his dopamine levels during training, Huey rolled over and requested tummy rubs.
When asked about his dopamine levels, Huey asked which answer would make me love him the most.

This makes slightly more sense to me than the timestamp hypothesis, but is less interesting.  Normally interesting is a bad sign for a hypothesis (almost anything is more interesting than chance, and chance explains a lot), but I’m not sure that applies in this case.  The timestamp hypothesis is a lot more specific and thus testable, the priming hypothesis seems sort of vague in comparison.  And of course both could be true- dopamine simultaneously says “reward coming soon” and “reward is because of this”.    Those actually make sense to go together, as opposed to some things our body has combined.

I’m never going to be able to conclusively prove one or the other sitting at my computer, but let’s talk about how they differ.  Timestamp hypothesis suggests people with low dopamine will be attracted to things that make it is easy to distinguish what caused a reward, like video games and obsessive facebooking.  Based on my friends and reddit, those are heavily associated with both depression and ADHD.  My literature search turns up some support for this**, but nothing with a design I consider rigorous.

Timestamp covers the H in ADHD better (a low baseline makes a small increase more distracting than it should be), but priming seems more apt for ADHD- inattentive type (ADHD minus H) and depression, where nothing is attractive enough to pull the person out of their focal activity.

So the answer is “some of both plus probably some other stuff”.  But variations in which of these dominate might explain why a given person reacts to low dopamine the way they do.

*In addition to changing other neurotransmitters and hormones.  The brain is complicated and no one understands it.

**Most interestingly the effect of bupropion in treating video game addiction.

Bupropion finds its real family

When it comes to anti-depressants, there’s SSRIs, tricyclics, MAOIs, and… bupropion*.  I always wondered why it was that every other anti-depressant** came in a variety of forms, but there was only one bupropion.

Bupropion is metabolized into several different compounds in your body, the most important being hydroxybupropion, which is a norepinephrine-selective reuptake inhibitor***, meaning it causes the neurotransmitter norepiniephrine  to hang around longer so your nerves experience more of it.  “Selective” means it doesn’t affect all receptors equally, but is otherwise spectacularly uninformative.  Bupropion itself and several lesser metabolites also increase dopamine availability, but it’s not clear if that happens to any measurable degree in humans in the doses we take.  So we assume the effects on norepinephrine is the major reason bupropion works, but no one really has idea what it is going on in the brain so we can’t be sure.

Turns out there is another NSRI available, and it is actually quite well marketed. Just not for depression.  Atomoxetine is better known as Strattera, one of very few non-stimulant treatments for ADHD.  Its effects are not identical to bupropion, but they’re pretty similar, and there are studies showing atomoxetine is useful for treating depression.  Why then does no one market atomoexetine as an antidepressant, or bupropion as an anti-ADHD treatment (even though it’s shown promise)?  I don’t want to jump to the worst possible explanation, but the FDA requires new trials for every usage of a drug, and crazymeds.us is not wrong when it notes there is more money in treating ADHD and competing with very heavily controlled drugs that work very differently than there is in treating depression and competing with many off-patent drugs, one of which works in a very similar way.  And now that’s its been approved for something, any doctor who wants can still prescribe it for depression.  Meanwhile bupropion went off patent before ADHD was really a thing, so no one has any incentive to pay for additional testing now.

There are a number of other NRIs and NSRIs, few of which made it to the US.  But I hope bupropion takes comfort in knowing it does have a family, even if they spell their name differently.

*Brand name Wellbutrin when marketed as an anti-depressant, Zyban when marketed as an anti-smoking aid.

**Until you get to the really weird stuff they use for treatment-resistant depression.  Every atypical antipsychotic is its own little snowflake.

***The more common name for these is selective norepinephrine reuptake inhibitor, but that has the same acronym as serotonin norepinephrine reuptake inhibitor, a different kind of drug, so I use NSRI to avoid confusion.

Pain, ADHD, and happiness

I jokingly referred to pain-induced ADD on Monday, but I’m becoming more and more convinced that is actually what was happening.  After prior surgeries I was too exhausted to notice anything, but this time I was energetic enough to experience the pain.  I mean, unless I tried to go outside or something.  That led to a really entertaining systems crash in the supermarket.  But if I stayed inside I was able to do things like get food and put away dishes without strain.  Contrast with when my pain meds sabotaged my cortisol production.  Intellectually I was there and able to do things like read and blog, but physically it was a struggle to make myself a smoothie.

After surgery I could not read or write or even enjoy a movie.  It was more than pain making everything 70% less fun, it was that everything was annoying and frustrating and no fun at all.  I couldn’t enter a state of flow or concentration or even relaxing for any length of time.  Except when I played video games or the piano.  Neither were fun, exactly, and I was still in pain, but they were at least distracting and rewarding.  Looking back, this explains a lot of my behavior when I was in constant pain last year, it just took being out of pain and then very sharply in a lot of pain to make the pattern obvious.

At first I thought this was  Harrison Bergeron type thing, where pain was sending out interrupts too often for me to get into a groove on anything.  But then I read this blog post (blogs were just about in my power) by Sara Constantin on dopamine, explaining Peter Redgrave’s hypothesis that the spike (phasic increase) of dopamine is not itself a reward (which is how pop journalism usually describes it) but a timestamp that lets you know what actions should get credit for the actual reward chemicals you are about to receive.  That would explain why humans and animals with broken dopamine systems do feel pleasure when eating but will nonetheless starve to death unless you put the food directly in their mouth.

Many of the drugs used to treat ADHD inhibit dopamine reuptake, which raises your tonic (baseline) dopamine levels.  Constantin hypothesizes that if the baseline is too low than stimuli that should be ignored suddenly are interpreted as important, leading to a lot of SQUIRREL.

[ I was going to make this a gif but putting unpausable moving pictures in a post on ADHD just seemed cruel]

If this is correct, it offers an explanation for why ADHDers are so drawn to things like videogames and sex:  the time gap between doing the correct thing and getting the chemical reward is so short they can still determine causality, even against the a background of SQUIRRELs.  This needn’t be purely about hedonism- if it was, something consistently pleasant would work.  I think it’s about having an internal locus of control and self-efficancy.  Humans are happiest they feel like they have the power to change their own circumstances and have an impact on the world.  It’s hard to feel those things if your attention is constantly being torn away from what you choose and you can’t (on a neural level) determine what made you feel the emotion you are currently feeling.  This is one reason the toll of ADHD shouldn’t be measured in lost productivity alone; even people with very successful coping mechanisms are being denied that internal locus of control, and that’s miserable.

Here’s my contribution: my description of being in pain sounds a lot like other people’s description of ADHD, right down to video games being rewarding without strictly being fun.  And as it turns out the basal ganglion, the area Redgrave believes is using dopamine to timestamp causes so they can be matched with effects, also releases dopamine in response to pain.  It seems entirely possible to me that high baseline levels of dopamine could diminish the effect of a spike.  Instead of everything being timestamped “good job”, nothing is, with similar results

But let’s make it even more interesting.  Several anti-depressants are also useful in treating chronic pain, and NSAIDS (usually mild pain killers) treat depression.  I had previously put this down to “pain is depressing”, “depression appears to be connected to inflammation in ways we don’t understand” and plain old “brains are squishy and they don’t make sense”, but if there was a causal link?  The symptoms of depression include fatigue, feelings of helplessness and lost of interest or enjoyment of previously liked activities, which sure sounds related.  Quick googling found a very tiny study showing a connection between low dopamine and suicide, and this fascinating study suggesting that inflammation reduced the basal ganglia’s production of dopamine, which would tie all of this up in a very pretty bow.  Something causes pain and/or inflammation (the two often go together), which long term causes inflammation in the basal ganglia, which causes depression and reduces your body’s natural analgesics.

Look body, if you were worried about us getting high off of pain, maybe you could have releases fewer happy chemicals in response to pain, instead of making it just as fun but also cause depression some time later.

This would also explain why ADHD medicines are promising in treating depression (source, source, and a large showing among my friends), and why ADHD and depression so often go together.*

I cannot stress enough how unqualified I am to make this hypothesis.  Lots of people know lots more on all of these things than me.  But it comes together to be an extremely plausible explanation for both the literature I’ve read and my personal experiences.

*There’s a lot of evidence that depressed parents correlate with ADHD kids, but it’s probably environmental.

Anticholinergic agents and dementia

A new study came out this week suggesting use of a particular class of drug after age 65 was associated with dementia.  Here’s what you need to know.*

The study is retrospective, meaning it took people who developed the disease of interest and then looked backwards at their medications.  Retrospective studies are prone to a number of problems, the biggest one being that even young people with healthy memories are crap at giving you their drug history over the past 10 years, and this is a study of people with dementia.  The researchers dodged this by using an HMO database of the subjects complete medical history, which is a neat trick.  The second problem is that retrospective studies can easily end up being painting the bulls-eye after they’ve fired the arrow.  Mere chance dictates that if you track enough traits, any random subset of a population is likely to have something more in common with each other than with the rest of the population.  If you use the traditional bar of statistical significance (5% chance of results arising by chance), checking 20 traits gives you an expected value of 1 false positive.  To be fair, this study has a much higher significance level, and the effect was dose dependent, which is a very good sign that it’s legit.  The authors heavily imply they deliberately studied anticholinergics rather than shotguning it, but without preregistration there’s no way to be sure.

Anticholinergics come in two forms: antimuscarinics, and antinicotinic.  Short version: these work on different types of neuroreceptors, which live in different parts of the body and do different things . Every example drug they give is an antimuscarinic and of the classes of drugs they list, many have no antinicotinic members.  Even if they technically included antinicotinics in the analysis, they would be such a small portion of the sample that their effect could be overwhelmed.  So I don’t think you can apply this study to drugs like bupropion, which is an antinicotinic.

I don’t like the way they calculated total exposure at all.  Essentially they counted the normally recommended dose of any medication as One Standardized Daily Dose.  But those dosages vary wildly (even the examples they give span an order of magnitude), as do the particular drugs’ ability to cross the blood-brain barrier.  The drugs are prescribed for a huge variety of causes, and what’s sufficient to stop incontinence has nothing to do with what’s sufficient to slow Parkinson’s.  This oversight may cancel out with the fact that they created buckets of dosages rather than do a proper linear regression, in the sense that low-def pictures cancels out bad skin.

The obvious question is “but maybe the same thing that drove people to need anticholinergics increases the likelihood of dementia?”  This study has a much better retort for that than most, which is that anticholinergics were prescribed for a variety of causes, and it’s unlikely they all correlate with dementia.  I find that explanation extremely satisfying, except that they only evaluated the drugs as a single unit.  Antidepressants make of over 60% of the total SDDs taken.  The next most common is antihistamines at 17%.  But since more than 60% of the population took at least one SDD, it seems likely that those were taken intermittently, as opposed to the constant drip of antidepressants.  This leaves open the possibility that the entirety of the effect they attributed to anticholinergics was in fact caused by tricyclic antidepressants alone- and that the real culprit was depression.  The obvious controls were to evaluate the anticholinergics separately, and to compare rates of dementia among TCA treated patients with those treated with other antidepressants.

The subtler version of this question is “what if anticholinergics prolong life, giving you more time to develop dementia?”  I don’t see anything where they checked for that either way.  They did ask for people’s perception of their own health, and that was negative correlated with TSDD, but if TSDD is correlated with depression it’s hard to know how to interpret that.

For all those criticisms, this is an amazingly strong result for a medical study**.   No one study can prove anything (even if i think they had the data to do more than they did).  It definitely merits further investigation (ideally some with animal models, so we can do the causality experiments that would be super unethical in humans), and maybe even behavior change in the meantime, although a lot of the drugs studied are already obsolete or second line.  Plus it another piece of data that will help us figure out how to fight dementia, and that makes me really hopeful.

*Read: here’s what I learned.

**Yes, this should worry you.