I seem to be the last person who hasn't yet blogged about the Nature article advocating a more liberal view of the use of drugs for cognitive enhancement. One reason is that there's so much to say here that I'm not sure where to start. Another, though--this is one of inherent issues with a journalist who does a blog on the side--is that this is the rare issue on which I'm a little leery of preempting what a future in-depth story (and I haven't spoken to the authors yet, something I may well do soon).
With that caveat, though, there are a couple of points that struck me. It seems to me that both people who are optimistic about cognitive enhancement and those who are terrified of it try hard to draw a distinction between the "abuse" of drugs like amphetamines (Adderall or Dexedrine) and the use of these drugs or others like Provigil for "cognitive enhancement." The anti-enhancement folks think that anything that's not prescribed to treat some condition recognized by the DSM-IV is abuse, the pro-enhancement folks think that taking drugs to think better rather than just to get high is not abuse. But both seem to work under the assumption that these uses are less dangerous than, say, taking amphetamines for the fun of it.
The problem, it seems to me, is that the dangers of amphetamines do not manifest themselves from occasionally taking them to get high--the use that everyone seems to think is not okay. They come out precisely in the extended and continuous use of drugs for what people think of as cognitive enhancement. There is no question that dextroamphetamine, the best studied of the smart drugs, can in fact make you think faster and potentially even more creatively ... to a point. There are studies on this; there would be more, except the proposition that amphetamines do offer some kinds of enhancement is not really much more controversial than the proposition that beer gets you drunk.
Unfortunately, there's also a lot of evidence that they will drive you crazy. This is something that folks saw in the 1950s, when Benzedrine (a drug closely related to Adderall) was routinely used by intellectuals and artists for cognitive enhancement, which with some regularity ended up sending them to the mental hospital. From the outside, the distinction between "smarter" and "crazy" looks clear. But from the inside it is emphatically not, and this situation is made worse by the fact that while Adderall or Dexedrine might make you "smarter" they invariably make you think that they've made you smarter, adding still another level of complexity to the cognitive enhancement puzzle. You're particularly likely to think that drugs are making you smarter exactly at the point at which they are in fact making you crazy, and in this situation, unfortunately, it is difficult to consult other people for a disinterested perspective. I'll save for another post why I think that it will be very difficult to find a drug that provides the kind of cognitive enhancement that people look for in amphetamines and other drugs without holding out the same very real risks of psychosis.
1.13.2009
It's Still A Long Road To The Brave New World
How many pitfalls there seem to be on the road to the much discussed future of universal genetic testing! I recently ordered a genetic test from 23andMe.com. The genetic test requires a saliva sample, and apparently the sending and ... uh, collection (you'll see in a second) of this sample has brought the genetic testing companies in conflict with several state authorities. A few weeks after I sent in my sample I got an email that read, in part:
This came in November. By now it's likely that 23andMe has included similar instructions in the initial collection kit (there's really no way to talk about this without some level of grossness). I would've posted this earlier, but, frankly, I wanted to have all of this squared away and actually get my results before posting this.
Option 1: If you spat in the state of New York but are willing to spit again outside the state. Please reply to this email telling us you choose Option 1 and we will ship you a new collection kit. If we ship the new kit to New York we will need your confirmation that you will not spit in the state using the new kit. If you would like us to ship the new kit to you outside of New York, we would be happy to do so.
IF YOU CHOOSE THIS OPTION PLEASE REPLY WITH "OPTION 1" IN THE SUBJECT LINE AND INCLUDE YOUR SHIPPING ADDRESS IN THE BODY OF THE MESSAGE. IF YOU CHOOSE A NEW YORK SHIPPING ADDRESS PLEASE WRITE "I CONFIRM I WILL NOT SPIT IN NEW YORK."
Option 2: If you spat in the state of New York and are unable to spit outside of the state. Please reply to this email telling us you choose Option 2 and we will issue you a full refund. Your current sample will be destroyed.
IF YOU CHOOSE THIS OPTION PLEASE REPLY WITH "OPTION 2" IN THE SUBJECT LINE AND IN THE BODY PLEASE SAY "PLEASE SEND ME MY REFUND AND DESTROY MY SAMPLE."
Option 3: If you spat outside the state of New York. Please reply to this email telling us you choose Option 3 and we will continue to process your sample or provide access to your data if it has been processed. We are not asking you to misrepresent where you spat.
IF YOU CHOOSE THIS OPTION PLEASE REPLY WITH "OPTION 3" IN THE SUBJECT LINE AND IN THE BODY WRITE "I CONFIRM I DID NOT SPIT IN THE STATE OF NEW YORK."
This came in November. By now it's likely that 23andMe has included similar instructions in the initial collection kit (there's really no way to talk about this without some level of grossness). I would've posted this earlier, but, frankly, I wanted to have all of this squared away and actually get my results before posting this.
Left And Right On The Mental Map
A while ago a friend sent me this optical illusion of a spinning dancer , who is supposed to turn one way if you're "left-brained" and the other way if you're "right-brained." I'm actually not clear if this is the case. For me, the dancer starts spinning counter-clockwise and then reverses the direction. I took the animated image apart with a graphics editing program, and it seems to me that the dancer would always start off going counter-clockwise, and the left-brain/right-brain distinction has to be in when a viewer sees her changing direction, a switch that depends on an ambiguity in the silhouette about eight frames in.
I spent a lot more time than it was worth on taking apart the image, and ultimately what became interesting to me is why I found myself so resistant to the idea that how you see this image will depend on your handed-ness. Handed-ness is a funny thing because so much of our experience of the world is defined by symmetry. The specialization in brain halves is much more pronounced in humans than in other animals, and it seems awfully hard to understand why it should exist.
On a deeper level, what bothers me about discussions of left vs. right brains is that in general we love to read about the geography of the brain, whether it involves odd stories of brain lesions or those fractal-pretty MRI images, but it's often hard to figure out exactly what to conclude from it. The brain with its fissures and gullies almost looks like a map, and we half expect there to be an "x" somewhere in there marking the treasure. The problem, however, seems to me that without more of a working theory of how the brain stores information, the conclusions that we draw from the maps are very tentative.
One way of thinking about this is to imagine the operations of a computer running Photoshop. You might scan the microprocessor and find that whenever you run Photoshop, some parts of it light up frantically. So you might conclude that those parts have a specific relationship to image processing. But you would turn out to be wrong. From a computer's point of view, photo-editing is a particularly math intensive operation, and the silicon that's working overtime when you manipulate an image is not, as you might think, the part devoted to graphics processing, but the part devoted to math. The same problem of figuring out exactly what's going on applies to the brain. If a lesion on one side of the brain causes a person to confuse words or lose the ability to read, does that mean that side of the brain is specifically given over to speech and reading? Or is there a lower-order way of describing what it does that could ultimately prove more fruitful? I just don't know, but I throw that question out there for anyone who may have a better informed perspective.
I spent a lot more time than it was worth on taking apart the image, and ultimately what became interesting to me is why I found myself so resistant to the idea that how you see this image will depend on your handed-ness. Handed-ness is a funny thing because so much of our experience of the world is defined by symmetry. The specialization in brain halves is much more pronounced in humans than in other animals, and it seems awfully hard to understand why it should exist.
On a deeper level, what bothers me about discussions of left vs. right brains is that in general we love to read about the geography of the brain, whether it involves odd stories of brain lesions or those fractal-pretty MRI images, but it's often hard to figure out exactly what to conclude from it. The brain with its fissures and gullies almost looks like a map, and we half expect there to be an "x" somewhere in there marking the treasure. The problem, however, seems to me that without more of a working theory of how the brain stores information, the conclusions that we draw from the maps are very tentative.
One way of thinking about this is to imagine the operations of a computer running Photoshop. You might scan the microprocessor and find that whenever you run Photoshop, some parts of it light up frantically. So you might conclude that those parts have a specific relationship to image processing. But you would turn out to be wrong. From a computer's point of view, photo-editing is a particularly math intensive operation, and the silicon that's working overtime when you manipulate an image is not, as you might think, the part devoted to graphics processing, but the part devoted to math. The same problem of figuring out exactly what's going on applies to the brain. If a lesion on one side of the brain causes a person to confuse words or lose the ability to read, does that mean that side of the brain is specifically given over to speech and reading? Or is there a lower-order way of describing what it does that could ultimately prove more fruitful? I just don't know, but I throw that question out there for anyone who may have a better informed perspective.
12.08.2008
Prozac For ADHD? One Scientist's View
In the last month I had a couple of conversations with Raul Gainetdinov, a neuroscientist best known for a dopamine transporter theory of ADHD that I've discussed earlier in this blog. I called Gainetdinov, known for his work at Duke and now at the Italian Institute of Technology in Genoa, to try to get to the bottom of how stimulants work in ADHD (and to discuss the strange case of the cocaine-hypersensitive mice I talked about in the earlier entry).
What was most unexpected to me in these conversations was that despite having come up with one of the most compelling theories about why stimulants might work to counter hyperactivity, Gainetdinov's spin on drugs like Adderall and Ritalin was resoundlingly negative. One issue I had with his theory of the paradoxical calming effect of stimulants in young kids is that--for reasons too complicated to get into--it doesn't really work well in explaining why stimulants would work on ADHD in teenagers and adults.
In Raul's view, there's a very good reason for this: he thinks that when it comes to teens and adults, stimulants are a terrible treatment for ADHDs. As he sees it, his theory doesn't need to explain "why stimulants work" for all the conditions they're prescribed for because there's a good chance that they don't. In fact, Raul thought that even kids who do see a benefit from drugs like Adderall are likely to stop seeing it when they get to their teenage years.
Even when it comes to young children, Gainetdinov is extremely leery of how the drugs are used. One thing he pointed out is that even if he can explain how they work in some cases, it doesn't mean they work better than the alternatives. When I asked him if it was possible that SSRIs like Prozac might work just as well, Raul said he not only thought it was possible, but that in actual practice psychiatrists routinely prescribed SSRIs for hyperactivity, with what looked like very good effects. One of the ironies is that years of treating kids with stimulants (an approach based partly on early, shoot from the hip work with kids that no one would even think of doing today) have made it ordinary practice, while prescribing Prozac or Lexapro to kids is "off label" -- the drugs that are thought of as addictive and dangerous in adults are routinely given to kids, while those that in years of practice have proven extremely safe in adults are thought of as dangerous and insufficiently tested for children.
I'm not about to jump on an anti-Ritalin bandwagon here, but this is a basic point worth considering very seriously. In my earlier post I posed the question about stimulants as "how do they work?" But it's very reasonable to add to this "what happens when they don't?" and "what might work better?" These questions are harder to answer than you might think because, as Gainetdinov points out, what ADHD is remains contentious and badly defined. The funny thing about the host of stimulants out there is that we may have more hard data on what they do for air force pilots on all night missions than the effect they have on millions of kids.
PS: After several posts on drugs like Ritalin and Adderall, you may be wondering if I have tried them. The answer is yes (I've tried pretty much every non-prescription "smart drug" and supplement, too). I'll save that for later posts.
What was most unexpected to me in these conversations was that despite having come up with one of the most compelling theories about why stimulants might work to counter hyperactivity, Gainetdinov's spin on drugs like Adderall and Ritalin was resoundlingly negative. One issue I had with his theory of the paradoxical calming effect of stimulants in young kids is that--for reasons too complicated to get into--it doesn't really work well in explaining why stimulants would work on ADHD in teenagers and adults.
In Raul's view, there's a very good reason for this: he thinks that when it comes to teens and adults, stimulants are a terrible treatment for ADHDs. As he sees it, his theory doesn't need to explain "why stimulants work" for all the conditions they're prescribed for because there's a good chance that they don't. In fact, Raul thought that even kids who do see a benefit from drugs like Adderall are likely to stop seeing it when they get to their teenage years.
Even when it comes to young children, Gainetdinov is extremely leery of how the drugs are used. One thing he pointed out is that even if he can explain how they work in some cases, it doesn't mean they work better than the alternatives. When I asked him if it was possible that SSRIs like Prozac might work just as well, Raul said he not only thought it was possible, but that in actual practice psychiatrists routinely prescribed SSRIs for hyperactivity, with what looked like very good effects. One of the ironies is that years of treating kids with stimulants (an approach based partly on early, shoot from the hip work with kids that no one would even think of doing today) have made it ordinary practice, while prescribing Prozac or Lexapro to kids is "off label" -- the drugs that are thought of as addictive and dangerous in adults are routinely given to kids, while those that in years of practice have proven extremely safe in adults are thought of as dangerous and insufficiently tested for children.
I'm not about to jump on an anti-Ritalin bandwagon here, but this is a basic point worth considering very seriously. In my earlier post I posed the question about stimulants as "how do they work?" But it's very reasonable to add to this "what happens when they don't?" and "what might work better?" These questions are harder to answer than you might think because, as Gainetdinov points out, what ADHD is remains contentious and badly defined. The funny thing about the host of stimulants out there is that we may have more hard data on what they do for air force pilots on all night missions than the effect they have on millions of kids.
PS: After several posts on drugs like Ritalin and Adderall, you may be wondering if I have tried them. The answer is yes (I've tried pretty much every non-prescription "smart drug" and supplement, too). I'll save that for later posts.
10.31.2008
That Old Unconscious, Lyin' Again
Away from Nervewracker for a little while, and looking for a chance to rev up and return when nothing less than a New York Times op-ed arrives to fortuitously bonk me over the head with a subject. In this column Nicholas Kristol, a writer I like, turns to a couple of researchers who looked at reactions to the Obama candidacy based on a test of "implicit associations." And it turns out, according to the researchers that college students are less likely to see a black candidate as "American." Subconsciously, that is.
You can take the kind of implicit association test this is based on here. I've taken it before, and just took it again now. And in my experience, the results are plain nonsense. And the problem here is that it is insidious nonsense, because as a test of unconscious biases any objection can be answered with, "Oh, but you're just in denial," or some more technical sounding version of that. Better to just say nothing, because if the test shows you have an unconscious bias that you don't think you have, you're a two time loser, a bigot who just can't accept it.
Well, let me tell you my results over several tests. When I first tried a series of these tests a couple of years ago, I showed an unconscious association of blacks with guns and violence (the assumption of the test, by the way, seemed to be that guns have negative associations--though frankly, for me I'm not really sure they do). I also, according to more tests, believe that women are better at math and science than men. Have no preference for thin people over fat people. And, according to the test I took now, have a slight preference for gay people over straight ones. All this basically makes me say, "Huh?" Really? Well, okay, maybe I'm an unconscious bigot. And ... gosh ... could I be gay and not know it? But what am I supposed to make of the idea that I think women are better at math and science? No amount of introspection lets me make sense of this. I really have no idea either way, though when I was younger I knew a number of folks with a truly spectacular talent for math--all, as it happens, men.
The dumbest part here, though, is the test of attitudes about people who are overweight. Because here I think I'm pretty in touch with my automatic impulses, and (unfortunately) they're not what the test shows at all. My ex-wife once told me that when she wanted me to dislike someone, she took care to drop in that he was fat. This is a stupid prejudice, that I'm not proud of. But it's one that I have trouble shaking. And this test utterly misses it. The bottom line is that I see no more reason to beat myself up over a supposed fear of blacks than I do to pat myself on the back about my inclusive attitudes about women in science or my comfort with different body types. I have no doubt that prejudices exist. But as a journalist I can tell you that it's easy enough to make them come out just by asking.
What I find distasteful about the test is that it is ultimately a bizarre inversion of the great Freudian project of self-understanding. For all the problems with Freudian analysis, the basic principle that our inner thoughts are something worth bringing out and examining is a worthwhile one. At its root, the Freudian project assumed that we have thoughts that we don't want to admit, and this accords with all of our experience. The premise of the implicit association test, on the other hand, is that our thinking is just not subject to introspection or examination, and can be brought out only by measuring the speed with which we press a sequence of keys. This would be a depressing idea if it could be proved true. It is an insidious and scary one when presented in a way designed to make sure that it can't even be proved false.
You can take the kind of implicit association test this is based on here. I've taken it before, and just took it again now. And in my experience, the results are plain nonsense. And the problem here is that it is insidious nonsense, because as a test of unconscious biases any objection can be answered with, "Oh, but you're just in denial," or some more technical sounding version of that. Better to just say nothing, because if the test shows you have an unconscious bias that you don't think you have, you're a two time loser, a bigot who just can't accept it.
Well, let me tell you my results over several tests. When I first tried a series of these tests a couple of years ago, I showed an unconscious association of blacks with guns and violence (the assumption of the test, by the way, seemed to be that guns have negative associations--though frankly, for me I'm not really sure they do). I also, according to more tests, believe that women are better at math and science than men. Have no preference for thin people over fat people. And, according to the test I took now, have a slight preference for gay people over straight ones. All this basically makes me say, "Huh?" Really? Well, okay, maybe I'm an unconscious bigot. And ... gosh ... could I be gay and not know it? But what am I supposed to make of the idea that I think women are better at math and science? No amount of introspection lets me make sense of this. I really have no idea either way, though when I was younger I knew a number of folks with a truly spectacular talent for math--all, as it happens, men.
The dumbest part here, though, is the test of attitudes about people who are overweight. Because here I think I'm pretty in touch with my automatic impulses, and (unfortunately) they're not what the test shows at all. My ex-wife once told me that when she wanted me to dislike someone, she took care to drop in that he was fat. This is a stupid prejudice, that I'm not proud of. But it's one that I have trouble shaking. And this test utterly misses it. The bottom line is that I see no more reason to beat myself up over a supposed fear of blacks than I do to pat myself on the back about my inclusive attitudes about women in science or my comfort with different body types. I have no doubt that prejudices exist. But as a journalist I can tell you that it's easy enough to make them come out just by asking.
What I find distasteful about the test is that it is ultimately a bizarre inversion of the great Freudian project of self-understanding. For all the problems with Freudian analysis, the basic principle that our inner thoughts are something worth bringing out and examining is a worthwhile one. At its root, the Freudian project assumed that we have thoughts that we don't want to admit, and this accords with all of our experience. The premise of the implicit association test, on the other hand, is that our thinking is just not subject to introspection or examination, and can be brought out only by measuring the speed with which we press a sequence of keys. This would be a depressing idea if it could be proved true. It is an insidious and scary one when presented in a way designed to make sure that it can't even be proved false.
10.13.2008
The High Price Of Remembrance
Some readers might recall a small wave of publicity about a study by UC-Irvine researchers led by Elizabeth S. Parker of a woman identified as "AJ" with an uncanny memory for everything that had happened over a period of years. I read the study, A Case of Unusual Autobiographical Remembering this weekend, and it's blow-away fascinating.
AJ had spectacular recall of dates and events both in her life, and was able to bring back news events, her schedule, and even details such as how her house smelled for years back. What the news reports didn't make clear was what a big cognitive cost this memory seems to come with. The authors propose that AJ's memory could be called a disorder, and when you look at the details you see why. AJ has preternatural autobiographical recall, but that does not translate to a memory for, say, numbers or patterns.
More strikingly, she has serious impairments in tests of concept formation and executive function--way below average (the study gives some fairly technical statistical results, but they translate to numbers in the bottom 5 percent of normal scores on these tests). AJ--whose kindness in cooperating with the researchers was really great, so it's a little painful to say this--just doesn't think very clearly.
The paper doesn't really settle on a biological hypothesis for what's going on in AJ's brain. Understandably so, since one person just isn't going to give you a set of definitive answers. I won't try to formulate one here, or bore you with technical details. But for the biologically inclined, you might consider looking into some of the studies of scopolamine (once thought of as "truth serum"--maybe more on that in a future post) and apomorphine. Apomorphine clearly clobbers executive function and working memory, with much less certain effects on "episodic memory." Scopolamine, on the other hand, has hugely negative effects on memory formation while leaving most other functions intact and, interestingly, increasing verbal fluency--a profile that's pretty close to the opposite of AJ's.
The paper doesn't really settle on a biological hypothesis for what's going on in AJ's brain. Understandably so, since one person just isn't going to give you a set of definitive answers. I won't try to formulate one here, or bore you with technical details. But for the biologically inclined, you might consider looking into some of the studies of scopolamine (once thought of as "truth serum"--maybe more on that in a future post) and apomorphine. Apomorphine clearly clobbers executive function and working memory, with much less certain effects on "episodic memory." Scopolamine, on the other hand, has hugely negative effects on memory formation while leaving most other functions intact and, interestingly, increasing verbal fluency--a profile that's pretty close to the opposite of AJ's.
An Easy Way To Misunderstand Addiction
I keep running into studies that that promote "likeability" as a measure of how likely psychotropic drugs are to be abused, studies that are loved by makers of drugs like Strattera and Provigil that score low on this measure. The idea is that if they don't get you high in a pleasant and immediate way, they will not create what we think of as addiction. This is a weird conclusion to draw, for a couple of reasons. One is that and the problem with, say, methamphetamine is not that it is likable. It's that it will eventually cause mania, delirium and basically drive you crazy in a bunch of ways. Likeability tells you nothing about this.
Worse, however, is that likeability tells virtually nothing about dependence, because much of what we've learned about addiction is that addiction and likeability are two very separate things. Addiction involves repetitive, stereotyped, compulsive behavior. The pattern absolutely doesn't have to involve something that's likeable--think of some young women's compulsive self cutting. In fact, the general direction of work on drugs like cocaine and amphetamines from both human and animal studies points to the repetitive behaviors increasing with higher doses or extended use even as the high ("likeability") decreases or disappears. I'm not willing to do the experiment myself, but my bet is that anybody who stays up for three nights popping Provigil is going to be just as just as anxious and agitated as any speed addict--and will be looking around for the next dose.
Worse, however, is that likeability tells virtually nothing about dependence, because much of what we've learned about addiction is that addiction and likeability are two very separate things. Addiction involves repetitive, stereotyped, compulsive behavior. The pattern absolutely doesn't have to involve something that's likeable--think of some young women's compulsive self cutting. In fact, the general direction of work on drugs like cocaine and amphetamines from both human and animal studies points to the repetitive behaviors increasing with higher doses or extended use even as the high ("likeability") decreases or disappears. I'm not willing to do the experiment myself, but my bet is that anybody who stays up for three nights popping Provigil is going to be just as just as anxious and agitated as any speed addict--and will be looking around for the next dose.
10.09.2008
Anxiety, Attention, And The Value Of Dark Glasses
Everybody knows that you'll never make a free throw in basketball if you let anxiety take over. But what's less obvious is why you can't make one by just shutting that anxiety down—say, pop a Xanax? It'll certainly make you less anxious. And it'll pretty much guarantee you'll miss.
In the last post I wrote about the neurotransmitter norepinephrine, and the range of disparate effects it seems to produce. In the brain, anxiety and attention are linked in a way that is not obvious when you're experiencing them. Norepinephrine raises some signals and the brain and dampens others; the effect it produces depends on what else is going on. And while it is clearly associated with anxiety, it's linked to concentration, too. An experienced therapist I know (quite well, actually—she happens to be my mother) points out that changing the word “anxiety” to “worry” brings out the natural—and perhaps evolutionary—link. To be worried is to be anxious, but it's also to be attentive to your surroundings.
One example of this relationship comes from studies of the eye in decision making. The release of norepinephrine makes the pupils dilate—it's why someone can be “wide eyed” with surprise. The dilation that marks surprise or shock also, as this study from Caltech shows , marks key moments of concentration and decision making. You can't just shut down the rush of norepinephrine—it has to be there in the right moment. Though sometimes in competition it pays to hide it, which is why, as the authors of the study have pointed out, poker players wear dark glasses (why they wear bolo ties is beyond the scope of any scientific investigation).
In the last post I wrote about the neurotransmitter norepinephrine, and the range of disparate effects it seems to produce. In the brain, anxiety and attention are linked in a way that is not obvious when you're experiencing them. Norepinephrine raises some signals and the brain and dampens others; the effect it produces depends on what else is going on. And while it is clearly associated with anxiety, it's linked to concentration, too. An experienced therapist I know (quite well, actually—she happens to be my mother) points out that changing the word “anxiety” to “worry” brings out the natural—and perhaps evolutionary—link. To be worried is to be anxious, but it's also to be attentive to your surroundings.
One example of this relationship comes from studies of the eye in decision making. The release of norepinephrine makes the pupils dilate—it's why someone can be “wide eyed” with surprise. The dilation that marks surprise or shock also, as this study from Caltech shows , marks key moments of concentration and decision making. You can't just shut down the rush of norepinephrine—it has to be there in the right moment. Though sometimes in competition it pays to hide it, which is why, as the authors of the study have pointed out, poker players wear dark glasses (why they wear bolo ties is beyond the scope of any scientific investigation).
Back To Those Knockout Mice
I can write about knockout mice—that means mice genetically engineered to lack individual genes, I mentioned them a few days ago days ago in a post about ADHD—pretty much endlessly I'll try to keep this from turning into the Knockout Mouse Blog, but I chanced on a study by researchers at Vanderbilt University that has some more counter-intuitive results that are worth recounting.
Norepinephrine, is a hormone and neurotransmitter that is associated with anxiety and anger—and also with attention, and protection from depression. In the Vanderbilt study, mice were bred to lack the norepinephrine transporter, meaning they had a persistently high level of the hormone in their brain and nervous system.
This had two very different, and essentially opposite, effects. On the one hand, when placed in a stressful environment, the mice had lower heart rate and blood pressure than ordinary mice. They functioned well under stress—to a point. But they also had an extreme reaction to shock, with their heart rate shooting up dramatically, the equivalent of panic in humans. This makes a lot of sense. The operation of norepinephrine is complex. One thing that it does is vary the frequency and amplitude of signals in the brain, making some signals stronger and others weaker—you can imagine it as working a little like the dials on a higher end stereo.
What I find especially compelling here is how useful this kind of study is in modeling human behavior. Just as a malfunction in the dopamine transporter may be associated with hyperactivity and attention problems, so we can see patterns in the norepinephrine transporter deficient mice eerily reminiscent of those that we see in humans—surprisingly complicated patterns. Sometimes the very same people who seem to do well in real world stressful environments will have mysterious panic attacks, or choke under pressure. What looks like a confusing and hard to explain set behaviors can get traced back to a change in a single gene that affects levels of a single molecule in the body.
Norepinephrine, is a hormone and neurotransmitter that is associated with anxiety and anger—and also with attention, and protection from depression. In the Vanderbilt study, mice were bred to lack the norepinephrine transporter, meaning they had a persistently high level of the hormone in their brain and nervous system.
This had two very different, and essentially opposite, effects. On the one hand, when placed in a stressful environment, the mice had lower heart rate and blood pressure than ordinary mice. They functioned well under stress—to a point. But they also had an extreme reaction to shock, with their heart rate shooting up dramatically, the equivalent of panic in humans. This makes a lot of sense. The operation of norepinephrine is complex. One thing that it does is vary the frequency and amplitude of signals in the brain, making some signals stronger and others weaker—you can imagine it as working a little like the dials on a higher end stereo.
What I find especially compelling here is how useful this kind of study is in modeling human behavior. Just as a malfunction in the dopamine transporter may be associated with hyperactivity and attention problems, so we can see patterns in the norepinephrine transporter deficient mice eerily reminiscent of those that we see in humans—surprisingly complicated patterns. Sometimes the very same people who seem to do well in real world stressful environments will have mysterious panic attacks, or choke under pressure. What looks like a confusing and hard to explain set behaviors can get traced back to a change in a single gene that affects levels of a single molecule in the body.
10.06.2008
A Depressing Debate About Antidepressants
A much publicized study released earlier this year purported to show, based largely on the results of the drug makers' own research, that anti-depressants such as Prozac and Paxil don't work much better than a placebo at ameliorating depression. I don't like the study very much, in part because even the authors' own engineering of the numbers actually shows that the serotonin reuptake inhibiting drugs are in fact effective in cases of major depression. That's something you may not have caught if you saw articles about the study by writers who didn't get past the press release.
One question that studies like this raise for me is whether say more about the drugs or about the criteria for the illness the drugs are supposed to address. Folks who read that antidepressants are not more effective than a placebo pill come away with the idea that these drugs don't do anything. But this is obviously untrue. Anybody who has taken antidepressants knows that they have dramatic effects. They certainly are not always the effects that you might want—they can be bad effects—but that they do something is very clear.
The gap between the results of studies that show little effect from drugs and the experience of people (some of whom swear by antidepressants, some of who detest them) who have used them underlines a more profound split between drugs and the criteria againt which they are tested. The expectation that a drug will have effects that neatly line up with the definitions of the DSM-IV yields the preposterous conclusion that the drugs have little effect when the problem of something like “depression” is so badly defined that it may well be made better or worse by the very same drugs in different people—or in the same people at different times.
Oddly, this situation benefits both critics of drugs such as antidepressants and their developers. Critics can point to studies that show unclear or unpromising results. Drug companies, on the other hand, feel little pressure to explain exactly how the drugs work or what they do, as long as they can come with a study that shows some difference in some condition that fits the DSM-IV standards. With each new antidepressant the endless debate about whether the drugs "work" continues, and we grow barely closer in understanding how they work and no closer at all in defining what we want them to do.
One question that studies like this raise for me is whether say more about the drugs or about the criteria for the illness the drugs are supposed to address. Folks who read that antidepressants are not more effective than a placebo pill come away with the idea that these drugs don't do anything. But this is obviously untrue. Anybody who has taken antidepressants knows that they have dramatic effects. They certainly are not always the effects that you might want—they can be bad effects—but that they do something is very clear.
The gap between the results of studies that show little effect from drugs and the experience of people (some of whom swear by antidepressants, some of who detest them) who have used them underlines a more profound split between drugs and the criteria againt which they are tested. The expectation that a drug will have effects that neatly line up with the definitions of the DSM-IV yields the preposterous conclusion that the drugs have little effect when the problem of something like “depression” is so badly defined that it may well be made better or worse by the very same drugs in different people—or in the same people at different times.
Oddly, this situation benefits both critics of drugs such as antidepressants and their developers. Critics can point to studies that show unclear or unpromising results. Drug companies, on the other hand, feel little pressure to explain exactly how the drugs work or what they do, as long as they can come with a study that shows some difference in some condition that fits the DSM-IV standards. With each new antidepressant the endless debate about whether the drugs "work" continues, and we grow barely closer in understanding how they work and no closer at all in defining what we want them to do.
9.22.2008
Last Meal In Budapest
The immediate impetus for this blog was the experience of watching my father's last two months as he was dying of multiple cancers. Those two months made me look in a new way at the relationship between the brain, the body and the mind, so it's a period I expect to come back to fairly often for a while.
On one of his last days, my father, delirious from the cancer, pneumonia, the long weeks in the hospital, and the cumulative effects of a half dozen medicines, believed that he was in Budapest. He had never, in fact, been to Budapest, and was eager to get out and see the city. He was angry that the taxi that was to take us from the airport was taking so long to arrive. He wanted some good Hungarian coffee. He ordered four espressos. He couldn't understand why the waitress was taking so long to bring them.
The waitress, who was in fact the nurse, called down not for espressos but for a meal of beef stew. We'd ordered it for him several times before, but my father could never eat more than a bite. It was good, reminiscent of goulash. But for most of the last weeks that my father spent in the hospital, he was essentially unable to swallow, and so unable to eat. His doctors seemed to think that this had to do with with a lack of appetite. The hospital's "swallow lady" had come by and conducted a brief test. A spoonful of juice, a bite of vegetables.The test went fine. But as soon as the swallow lady went away, the problem returned.
On the day that he thought he was in Budapest, my father was suddenly able to swallow. He ate half the stew, then the rest of it. Then the potatoes that came with it. He ate like a starving man, which in fact he was. The delirium lasted only a day. That was the last day he ate a real meal.
I've thought a lot about that day since, and tried to understand this strange fact that something that seems as automatic as swallowing would be affected by the kind of delirium that made my father believe he was in a country he'd never seen. But in fact in retrospect it is not at all difficult to explain. We often think of swallowing as a reflex but in fact it is a voluntary action. Like other voluntary actions, it requires the action of the neurotransmitter dopamine to disinhibit central nervous system signalling. Difficulties in swallowing are routinely the first sign of issues in the dopaminergic system. They are often the earliest of the string of problems--foot shuffling, tremor, repetitive muscle movements and rigidity--that characterize Parkinson's syndrome (Symptoms that in fact as the weeks went on my father would develop). Parkinson's disease arises from the destruction of dopaminergic neurons in a part of the brain called the substantia nigra. But very similar symptoms, known collectively as Parkinson's syndrome, can be caused by a more general shortage or imbalance of dopamine.
But dopamine has much more than a muscular function. The disinhibition of the voluntary muscles that is necessary for swallowing is intimately related to the disinhibition of nerve impulses that is needed for higher order thinking--and that is in turn related to delirium. The change in dopaminergic functioning that made my father able to swallow was in fact, in retrospect, clearly the very same change that made him imagine he was ordering espressos from a truculent Hungarian waitress. It is surprising, but ultimately it is not difficult to explain. Seen in this light, even the fact that a person would be unable to swallow except when the swallow-expert comes to check is no longer baffling: it is a consequence of the ratcheting up of the dopaminergic system--a physical manifestation of something that you can see all the time when people with Parkinson's or Alzheimer's "perk up" for a short while when visitors come by before retreating back into the shell of their illness.
What makes this especially worth noting is that it underlines in a striking way the falseness of hard distinctions between neurological, psychological, and physical symptoms. It is something that is very clear to, say, people who treat illnesses like Parkinson's. But that such disparate actions of the brain can be so closely linked is something that is easy to overlook, and difficult to harness in a therapeutic way, because it departs so dramatically from our ordinary intuitions.
On one of his last days, my father, delirious from the cancer, pneumonia, the long weeks in the hospital, and the cumulative effects of a half dozen medicines, believed that he was in Budapest. He had never, in fact, been to Budapest, and was eager to get out and see the city. He was angry that the taxi that was to take us from the airport was taking so long to arrive. He wanted some good Hungarian coffee. He ordered four espressos. He couldn't understand why the waitress was taking so long to bring them.
The waitress, who was in fact the nurse, called down not for espressos but for a meal of beef stew. We'd ordered it for him several times before, but my father could never eat more than a bite. It was good, reminiscent of goulash. But for most of the last weeks that my father spent in the hospital, he was essentially unable to swallow, and so unable to eat. His doctors seemed to think that this had to do with with a lack of appetite. The hospital's "swallow lady" had come by and conducted a brief test. A spoonful of juice, a bite of vegetables.The test went fine. But as soon as the swallow lady went away, the problem returned.
On the day that he thought he was in Budapest, my father was suddenly able to swallow. He ate half the stew, then the rest of it. Then the potatoes that came with it. He ate like a starving man, which in fact he was. The delirium lasted only a day. That was the last day he ate a real meal.
I've thought a lot about that day since, and tried to understand this strange fact that something that seems as automatic as swallowing would be affected by the kind of delirium that made my father believe he was in a country he'd never seen. But in fact in retrospect it is not at all difficult to explain. We often think of swallowing as a reflex but in fact it is a voluntary action. Like other voluntary actions, it requires the action of the neurotransmitter dopamine to disinhibit central nervous system signalling. Difficulties in swallowing are routinely the first sign of issues in the dopaminergic system. They are often the earliest of the string of problems--foot shuffling, tremor, repetitive muscle movements and rigidity--that characterize Parkinson's syndrome (Symptoms that in fact as the weeks went on my father would develop). Parkinson's disease arises from the destruction of dopaminergic neurons in a part of the brain called the substantia nigra. But very similar symptoms, known collectively as Parkinson's syndrome, can be caused by a more general shortage or imbalance of dopamine.
But dopamine has much more than a muscular function. The disinhibition of the voluntary muscles that is necessary for swallowing is intimately related to the disinhibition of nerve impulses that is needed for higher order thinking--and that is in turn related to delirium. The change in dopaminergic functioning that made my father able to swallow was in fact, in retrospect, clearly the very same change that made him imagine he was ordering espressos from a truculent Hungarian waitress. It is surprising, but ultimately it is not difficult to explain. Seen in this light, even the fact that a person would be unable to swallow except when the swallow-expert comes to check is no longer baffling: it is a consequence of the ratcheting up of the dopaminergic system--a physical manifestation of something that you can see all the time when people with Parkinson's or Alzheimer's "perk up" for a short while when visitors come by before retreating back into the shell of their illness.
What makes this especially worth noting is that it underlines in a striking way the falseness of hard distinctions between neurological, psychological, and physical symptoms. It is something that is very clear to, say, people who treat illnesses like Parkinson's. But that such disparate actions of the brain can be so closely linked is something that is easy to overlook, and difficult to harness in a therapeutic way, because it departs so dramatically from our ordinary intuitions.
9.20.2008
The Paradoxical Reaction Paradox
One of the most compelling theories about hyperactivity and attention deficit disorder is one that holds that hyperactivity is caused by a malfunction in the dopamine transporter, the molecule that takes the neurotransmitter dopamine out of circulation. The theory is hyperactive kids, and the disaffected adults they turn into, are thus essentially unable to turn their brains off.
The theory is simple and elegant, and makes a stunning prediction—that hyperactive kids will have paradoxical reactions to stimulants like Adderall, Ritalin, and cocaine. The theory is supported by the recent discovery of a pair of brothers who, thanks to an unusual genetic quirk, lack the dopamine transporter entirely and are indeed extremely hyperactive. It's also borne out by experiments with mice genetically engineered to lack the transporter ("knockout mice" that lack individual genes make for about as much fun as you can have in neurobiology, and will come up up often in this blog), who do in fact exhibit the paradoxical reactions the theory predicts.
There is only one key problem with the theory: it works for mice, but it does not, in practice, work for humans. The overwhelming weight of the evidence is that most kids (or for the matter, adults) with ADHD do not, in fact, have paradoxical reactions to drugs. This seminal paper on the effects of dextroamphetamine (substantially similar to Adderall) by Judith Rapoport, will give you an idea of the thrust of most research. But having twice experienced a rare, bona fide paradoxical reaction to Ritalin myself (it made me fall asleep instantly), however, I've been interested in this line of thinking.
I saw a recent paper involving mice and cocaine (enough work has been done along this line to make you start wondering where neuroscientists get the substantial amount of cocaine that these studies need) that starts to provide an answer to the question. The mice involved are “knockdown mice.” Unlike the “knockout mice” that lack the dopamine transporter gene, and on which similar studies have been done, the knockdown mice are not totally missing the gene; they are just bred to have an extreme shortage of transporter molecules. This actually makes them much closer to actual hyperactive kids—they are, in technical terms, “hyperdopaminergic.”
Intuitively you might assume, and pretty much everyone seems to have assumed, that the effect of cocaine on these mice would be similar to its effect on dopamine transporter knockout mice. But this is not the case. Cocaine has a paradoxically calming effect on knockout mice. But the knockdown mice are very different: knockout mice are immune to cocaine's stimulant effects, but knockdown mice are at lower doses actually hypersensitive to the drugs rewarding and especially its stimulating effects:
This is a very counterintuitive result, and it has a lot of implications. It goes a long way toward explaining how people who kids—and adults—with very similar profiles can have startlingly different reactions to the same drugs. The results from cocaine have a lot of implications for prescription drugs like Ritalin, Adderall, and Dexedrine—these are a lot more similar in action to cocaine than you might think. And they have even broader implications if you start looking at the whole range of modern psychotropic drugs, like anti-depressants, a subject I'll address in a later post.
The theory is simple and elegant, and makes a stunning prediction—that hyperactive kids will have paradoxical reactions to stimulants like Adderall, Ritalin, and cocaine. The theory is supported by the recent discovery of a pair of brothers who, thanks to an unusual genetic quirk, lack the dopamine transporter entirely and are indeed extremely hyperactive. It's also borne out by experiments with mice genetically engineered to lack the transporter ("knockout mice" that lack individual genes make for about as much fun as you can have in neurobiology, and will come up up often in this blog), who do in fact exhibit the paradoxical reactions the theory predicts.
There is only one key problem with the theory: it works for mice, but it does not, in practice, work for humans. The overwhelming weight of the evidence is that most kids (or for the matter, adults) with ADHD do not, in fact, have paradoxical reactions to drugs. This seminal paper on the effects of dextroamphetamine (substantially similar to Adderall) by Judith Rapoport, will give you an idea of the thrust of most research. But having twice experienced a rare, bona fide paradoxical reaction to Ritalin myself (it made me fall asleep instantly), however, I've been interested in this line of thinking.
I saw a recent paper involving mice and cocaine (enough work has been done along this line to make you start wondering where neuroscientists get the substantial amount of cocaine that these studies need) that starts to provide an answer to the question. The mice involved are “knockdown mice.” Unlike the “knockout mice” that lack the dopamine transporter gene, and on which similar studies have been done, the knockdown mice are not totally missing the gene; they are just bred to have an extreme shortage of transporter molecules. This actually makes them much closer to actual hyperactive kids—they are, in technical terms, “hyperdopaminergic.”
Intuitively you might assume, and pretty much everyone seems to have assumed, that the effect of cocaine on these mice would be similar to its effect on dopamine transporter knockout mice. But this is not the case. Cocaine has a paradoxically calming effect on knockout mice. But the knockdown mice are very different: knockout mice are immune to cocaine's stimulant effects, but knockdown mice are at lower doses actually hypersensitive to the drugs rewarding and especially its stimulating effects:
While cocaine was capable of increasing locomotor activity in both genotypes, there were differences in each genotype's response. For instance, both 5 and 10 mg/kg cocaine produced stronger locomotor stimulation in DAT-KD mice than it did in wild type mice.
This is a very counterintuitive result, and it has a lot of implications. It goes a long way toward explaining how people who kids—and adults—with very similar profiles can have startlingly different reactions to the same drugs. The results from cocaine have a lot of implications for prescription drugs like Ritalin, Adderall, and Dexedrine—these are a lot more similar in action to cocaine than you might think. And they have even broader implications if you start looking at the whole range of modern psychotropic drugs, like anti-depressants, a subject I'll address in a later post.
9.18.2008
TV and Obesity, A Novel Hypothesis
It won't exactly be a surprise to anyone who's read an article or two about what's become known as "the obesity crisis" to say that watching a lot of television is associated with weight gain, a basic fact borne out by zillions of studies of kids' TV watching. The conventional, obvious, and intuitive explanation for this is that sitting around and eating potato chips instead of playing outside will make kids fat. This is just, well, "common sense," and like most "common sense" is seen as something that doesn't need to be tested. There's lots of evidence, however, that the relationship between TV and weight gain is not common-sensical at all, and that the reason kids who watch lots of television put on weight has less to do with sitting on the couch than with the brain's reaction to watching flickering images.
Two things are scary about this. One is that blocking the 5-HT2A receptor is associated with especially big weight gains in children and teenagers, so it's particularly relevant to the whole obesity question.
But it's the other thing that's really worrying: you don't need to fiddle with psychotropic drugs to affect the 5-HT2A receptors in the brain. The receptors appear to be a key step in the brain's response to outside inputs. And when confronted with constant sensory stimulation the brain may do exactly what antipsychotic drugs do, which is to desensitize 5-HT2A receptors. That would protect the brain from a barrage of stimulation that would otherwise set off a dangerous fireworks of signals in the prefrontal cortex, something that is closely associated with epilepsy--the one illness characterized by attacks that we can say with certainty can be set off by television.
Exactly how much stimulation, and of what sort, could cause the "down-regulation" of 5-HT2A receptors that is linked to weight gain is an open question, but the 5-HT2A receptors provide a mechanism for a much stronger link between TV and obesity than the common "potato chips and lying on the couch" hypothesis. There's some strong evidence from studies of mice that implies that sensory stimulation affects the sensitivity of these receptors, but I haven't seen human research that would be conclusive, or any work that looks specifically at 5-HT2A receptors and TV viewing. If it's out there, I hope someone sends it to me. If it's not, I hope someone does it, because all the indirect evidence is already there. Though if I had a kid of my own, I'd wouldn't be rushing to volunteer him for the study.
A really interesting data point on this comes as something of a byproduct of what we've learned from looking at the effects of psychotropic drugs. It's very hard to make people gain weight by making them eat more, but it's easy to do it with medication. Pretty much any anti-psychotic--Zyprexa was a well publicized one--will do it. This is not an accident. Most modern antipsychotics block a receptor in the brain for the neurotransmitter serotonin called the 5-HT2A receptor. Blocking it stops delusions and hallucinations, and most likely reduced anxiety as well. But for reasons that are as yet unclear, this also makes people gain a lot of weight.
Two things are scary about this. One is that blocking the 5-HT2A receptor is associated with especially big weight gains in children and teenagers, so it's particularly relevant to the whole obesity question.
But it's the other thing that's really worrying: you don't need to fiddle with psychotropic drugs to affect the 5-HT2A receptors in the brain. The receptors appear to be a key step in the brain's response to outside inputs. And when confronted with constant sensory stimulation the brain may do exactly what antipsychotic drugs do, which is to desensitize 5-HT2A receptors. That would protect the brain from a barrage of stimulation that would otherwise set off a dangerous fireworks of signals in the prefrontal cortex, something that is closely associated with epilepsy--the one illness characterized by attacks that we can say with certainty can be set off by television.
Exactly how much stimulation, and of what sort, could cause the "down-regulation" of 5-HT2A receptors that is linked to weight gain is an open question, but the 5-HT2A receptors provide a mechanism for a much stronger link between TV and obesity than the common "potato chips and lying on the couch" hypothesis. There's some strong evidence from studies of mice that implies that sensory stimulation affects the sensitivity of these receptors, but I haven't seen human research that would be conclusive, or any work that looks specifically at 5-HT2A receptors and TV viewing. If it's out there, I hope someone sends it to me. If it's not, I hope someone does it, because all the indirect evidence is already there. Though if I had a kid of my own, I'd wouldn't be rushing to volunteer him for the study.
9.15.2008
Our Favorite Disorders of the Mind
To say anything meaningful about the brain is necessarily to think about what can go wrong with it. Much of what we know about the brain comes from looking at its disorders and accidents: a healthy man walking down the street tells you nothing, but if he suddenly has a bullet go through his pre-frontal cortex and wakes up speaking fluent French, you're in business. The thing is that people tend to start by trying to understand the most complicated and hard to define disorders--like depression. For me at least, trying to understand the brain by starting there is like trying to learn math by staring at the equations of the General Theory of Relativity. I think I have some guess about what "depression" means. I have no idea of whether it's even close to anyone else's.
Some much better places to start: Parkinson's disease; Tourette's; obsessive compulsive disorder; narcolepsy. Parkinson's (the subject of Oliver Sacks's Awakenings) has been on mind a lot, for reasons I'll soon get into. The thing about these is that they're easy to understand. We have only an imperfect idea of what causes them, but we can agree on what we are and have some idea of what can make the symptoms better, or worse. The drug scopalamine will reduce tics in Tourette's, it will also shut down their thinking; amphetamines will make them stunningly fluent, it will make the tics much worse. From these kinds of physical and mental symptoms you can start to figure things out.
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