Jonah Lehrer's Blog, page 3

Cages and Cancer

Cages and Cancer

There's an absolutely fascinating new paper by scientists at Ohio State University in the latest Cell. In short, the paper demonstrates that mice living in an enriched environments - those spaces filled with toys, running wheels and social interactions - are less likely to get tumors, and better able to fight off the tumors if they appear.

The experiment itself was simple. A large group of mice were injected with melanoma cells. After six weeks, the mice living in enriched environments had tumors that were approximately 75 percent smaller than mice raised in standard lab cages. Furthermore, while every mouse in the standard cages developed cancerous growths, 17 percent of the mice in the enriched enclosures showed no sign of cancer at all.

What explains this seemingly miraculous result? Why does having a few toys in a cage help prevent the proliferation of malignant cells? While the story is bound to get more complicated - there nothing is simple about cancer, or brain-body interactions - the researchers present a strikingly straightforward chemical pathway underlying the effect:

In short, the enriched environments led to increases in BDNF in the hypothalamus. (BDNF is a trophic factor, a class of proteins that support the survival and growth of neurons. What water and sun do for plants, trophic factors do for brain cells.) This, in turn, led to significantly reduced levels of the hormone leptin throughout the body. (Leptin is involved in the regulation of appetite and metabolism, and seemed to be down-regulated by slightly elevated levels of stress hormone.) Although a few earlier studies have linked leptin to accelerated tumor growth, it remains unclear how this happens, or if this link is really causal.

It's important to not overhype the results of this study. Nobody knows if this data has any relevance for humans. Nevertheless, it's a startling demonstration of the brain-body loop. While it's no longer too surprising to learn that chronic stress increases cardiovascular disease, or that actors who win academy awards live much longer than those who don't, there is something spooky about this new link between nice cages and reduced tumor growth. Cancer, after all, is just stupid cells run amok. It is life at its most mechanical, nothing but a genetic mistake. And yet, the presence of toys in a cage can dramatically alter the course of the disease, making it harder for cancerous cells to take root and slowing their growth once they do. A slight chemical tweak in the cortex has ripple effects throughout the flesh.

It strikes me that we need a new metaphor for the interactions of the brain and body. They aren't simply connected via some pipes and tubes. They are emulsified together, so hopelessly intertwined that everything that happens in one affects the other. Holism is the rule.

cortex
Fri, 07/09/2010 - 06:09

Soda

There's been lots of chatter about Pepsi lately, so I thought I'd run with the theme. I don't have much to add to the media commentary - I'm just sad to see some of my favorite bloggers leave this space - but I've got plenty to say about soft drinks. And little of it will please Pepsi.

The first thing is that a soda tax is a great idea. Here's a compelling chart from a recent report published by US Department of Agriculutre's Economic Research Service (via Yglesias):

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Some of these...

Soda

There’s been lots of chatter about Pepsi lately, so I thought I’d run with the theme. I don’t have much to add to the media commentary – I’m just sad to see some of my favorite bloggers leave this space – but I’ve got plenty to say about soft drinks. And little of it will please Pepsi.

The first thing is that a soda tax is a great idea. Here’s a compelling chart from a recent report published by US Department of Agriculutre’s Economic Research Service (via Yglesias):

Some of these calories, of course, will be shifted to other categories of food – we’ll drink less Pepsi, but we’ll consume more Doritos. Nevertheless, there’s compelling evidence that such “sin” taxes are actually quite effective. Just look at cigarettes: If you want to decrease the numbers of smokers, raising the price of cigarettes is the only proven solution. In fact, a 10 percent increase in the price of cigarettes causes a 4 percent reduction in demand. Teenagers are especially sensitive to these price changes: a 10 percent increase in price causes a 12 percent drop in teenage smoking. (The only bad news is that raising the price of cigarettes tends to increase the demand for marijuana. Apparently, the two products are in competition.) And let’s not forget that nicotine is an extremely addictive substance. So I think there’s good reason to think that a 10 percent hike in the price of sodas might be even more effective than a cigarette tax.

And while we’re on the subject of Pepsi, it’s also worth noting that diet sodas don’t work.

Consider this recent paper in Behavioral Neuroscience, which found that rats fed artificial sweeteners gained more weight than rats fed actual sugar. Here’s the abstract:

Animals may use sweet taste to predict the caloric contents of food. Eating sweet noncaloric substances may degrade this predictive relationship, leading to positive energy balance through increased food intake and/or diminished energy expenditure. Adult male Sprague-Dawley rats were given differential experience with a sweet taste that either predicted increased caloric content (glucose) or did not predict increased calories (saccharin). We found that reducing the correlation between sweet taste and the caloric content of foods using artificial sweeteners in rats resulted in increased caloric intake, increased body weight, and increased adiposity, as well as diminished caloric compensation and blunted thermic responses to sweet-tasting diets. These results suggest that consumption of products containing artificial sweeteners may lead to increased body weight and obesity by interfering with fundamental homeostatic, physiological processes.

The scientists argue that fake sugar is dangerous because it subverts a crucial homeostatic mechanism, as the the brain uses the sweetness of a food to keep track of its intake. More sugar implies more calories; the tongue is a natural energy detector. The problem with diet sodas is that they make this system unreliable, so that the presence of of intense sweetness no longer means anything. (And it’s not just rodents: a similar effect has been observed in humans.) The hypothalamus gets confused. The end result is that we lose touch with the energetic needs of our body. Instead of eating to sate a hunger, we just eat. And eat.

This is the curse of soda: it’s so bad for us that even diet sodas make us fat.

Soda

Soda

There's been lots of chatter about Pepsi lately, so I thought I'd run with the theme. I don't have much to add to the media commentary - I'm just sad to see some of my favorite bloggers leave this space - but I've got plenty to say about soft drinks. And little of it will please Pepsi.

The first thing is that a soda tax is a great idea. Here's a compelling chart from a recent report published by US Department of Agriculutre's Economic Research Service (via Yglesias):

Some of these calories, of course, will be shifted to other categories of food - we'll drink less Pepsi, but we'll consume more Doritos. Nevertheless, there's compelling evidence that such "sin" taxes are actually quite effective. Just look at cigarettes: If you want to decrease the numbers of smokers, raising the price of cigarettes is the only proven solution. In fact, a 10 percent increase in the price of cigarettes causes a 4 percent reduction in demand. Teenagers are especially sensitive to these price changes: a 10 percent increase in price causes a 12 percent drop in teenage smoking. (The only bad news is that raising the price of cigarettes tends to increase the demand for marijuana. Apparently, the two products are in competition.) And let's not forget that nicotine is an extremely addictive substance. So I think there's good reason to think that a 10 percent hike in the price of sodas might be even more effective than a cigarette tax.

And while we're on the subject of Pepsi, it's also worth noting that diet sodas don't work.

Consider this recent paper in Behavioral Neuroscience, which found that rats fed artificial sweeteners gained more weight than rats fed actual sugar. Here's the abstract:

Animals may use sweet taste to predict the caloric contents of food. Eating sweet noncaloric substances may degrade this predictive relationship, leading to positive energy balance through increased food intake and/or diminished energy expenditure. Adult male Sprague-Dawley rats were given differential experience with a sweet taste that either predicted increased caloric content (glucose) or did not predict increased calories (saccharin). We found that reducing the correlation between sweet taste and the caloric content of foods using artificial sweeteners in rats resulted in increased caloric intake, increased body weight, and increased adiposity, as well as diminished caloric compensation and blunted thermic responses to sweet-tasting diets. These results suggest that consumption of products containing artificial sweeteners may lead to increased body weight and obesity by interfering with fundamental homeostatic, physiological processes.

The scientists argue that fake sugar is dangerous because it subverts a crucial homeostatic mechanism, as the the brain uses the sweetness of a food to keep track of its intake. More sugar implies more calories; the tongue is a natural energy detector. The problem with diet sodas is that they make this system unreliable, so that the presence of of intense sweetness no longer means anything. (And it's not just rodents: a similar effect has been observed in humans.) The hypothalamus gets confused. The end result is that we lose touch with the energetic needs of our body. Instead of eating to sate a hunger, we just eat. And eat.

This is the curse of soda: it's so bad for us that even diet sodas make us fat.

cortex
Thu, 07/08/2010 - 05:48


Categories

Brain and Behavior

LSD

There's a fascinating article in the latest Vanity Fair (not online) about the prevalence of LSD (aka lysergic acid diethylamide) among movie stars in 1950s Hollywood:

Aldous Huxley was one of the first in Los Angeles to take LSD and was soon joined by others, including the writer Anais Nin. The screenwriter Charles Brackett discovered "infinitely more pleasure" from music on LSD than he had ever before, and the director Sidney Lumet tried it under the supervision of a former chief of...

LSD

There’s a fascinating article in the latest Vanity Fair (not online) about the prevalence of LSD (aka lysergic acid diethylamide) among movie stars in 1950s Hollywood:

Aldous Huxley was one of the first in Los Angeles to take LSD and was soon joined by others, including the writer Anais Nin. The screenwriter Charles Brackett discovered “infinitely more pleasure” from music on LSD than he had ever before, and the director Sidney Lumet tried it under the supervision of a former chief of psychiatry for the U.S. Navy. Lumet says his three sessions were “wonderful,” especially the one where he relived his birth…Another early experimenter was Clare Boothe Luce, the playwright and former American ambassador to Italy, who in turn encouraged her husband, Time publisher Henry Luce, to try LSD. He was impressed and several very positive articles about the drug’s potential ran in his magazine.

[SNIP]

There is no question that, at least for a period of time, LSD truly transformed Cary Grant…Much to his friends’ surprise, Cary Grant began talking about his therapy in public, lamenting, “Oh those wasted years, why didn’t I do this sooner?”

“The Curious Story Behind the New Cary Grant,” headlined the September 1, 1959 issue of Look magazine, and inside was a glowing account of how, because of LSD therapy, “at last I am close to happiness.” He later explained that “I wanted to rid myself of all my hypocrises. I wanted to work through the events of my childhood, my relationship with my parents and my former wives.” More articles followed, and LSD even received a variation of the Good Housekeeping Seal of Approval.

Of course, celebrities no longer brag about their hallucinogenic experiments. (Instead, we’re stuck with the slow motion tragedy of Lindsay Lohan.) Furthermore, the government now treats hallucinogens (such as LSD and mushrooms) as legally equivalent to heroin, crack and opium. Because LSD is a Schedule 1 drug, if you’re arrested with more than a single dose (roughly .5 grams), and it’s your first offense, the federal sentencing guidelines are as follows: “Not less than 5 years, and not more than 40 years”. State penalties are similar, with possession typically leading to 1-3 years in jail. (This despite the fact that study after study shows that prescription drugs kill more people by overdose than illicit drugs.) If it were up to me, our classification of drugs would depend largely on their addictive potential, so that drugs with limited addiction potential (such as LSD) were far less regulated than highly addictive substances, such as crack, oxycontin, heroin, etc. But don’t get me started on our endless war on drugs, which is an incoherent disaster.

Back to LSD. Because the drug is so tightly regulated, there has been minimal research on how the drug works in the brain. Just look at these search results: The most cited papers are more than thirty years old. (One scientist I talked to last year said the two main disincentives to use LSD in the lab were the lack of grants – the big funding institutions are only interested in addictive drugs – and the paperwork.) The end result is that we really don’t know how LSD alters our sensory experience, except that it binds to a vast array of G-protein coupled receptors, including every dopamine receptor subtype and various serotonin receptor subtypes. All this excess neural activity leads to excitation in the upper echelons of the cortex, such as layers IV and V. And, somehow, those squirts of chemical lead people to conclude that they’ve found the secret of the universe.

What’s unfortunate is that LSD could be a powerful experimental tool. And not in the Timothy Leary sense: I’m talking about rigorous investigations into the neural substrate of consciousness. After all, one of the challenges of investigating human consciousness is that it’s a continuous stream. As William James noted in 1890, “Consciousness does not appear to itself chopped up in bits. Such words as ‘chain’ or ‘train’ do not describe it fitly as it presents itself in the first instance. It is nothing jointed; it flows. A ‘river’ or a ‘stream’ are the metaphors by which it is most naturally described.” The paradox, of course, is that the brain is composed of a trillion different joints, a seeming infinitude of binary neurons switching on and off. So how does that create this? How does three pounds of wet stuff give rise to the ceaseless cinema of subjective experience?

To begin to answer this profound mystery – and it is the mystery of modern neuroscience – researchers have come up with a clever set of experimental paradigms. My favorite is Christof Koch’s version of binocular rivalry. In theory, binocular rivalry is a simple phenomenon. We have two eyeballs; as a result, we are constantly being confronted with two slightly separate views of the world. The brain, using a little unconscious trigonometry, slyly erases this discrepancy, fusing our multiple visions into a single image.

But Koch throws a wrench into this visual process. “What happens,” he wondered, “if corresponding parts of your left and right eyes see two quite distinct images, something that can easily be arranged using mirrors and a partition in front of your nose?” Under ordinary circumstances, we superimpose the two separate images from our two separate eyes on top of each other. For example, if the left eye is shown horizontal stripes and the right eye is shown vertical stripes, we will consciously perceive a plaid pattern. Sometimes, however, the brain gets a little confused, and decides to pay attention to only one of our eyes. After a few seconds, we realize our mistake, and begin to pay attention to our other eye. As Koch notes, “The two percepts can alternate in this manner indefinitely.”

The end result of all this experimentally induced confusion is that the subject becomes aware – if only for a moment – of the artifice underlying perception. We realize that we have two separate eyes, which see two separate things. Koch wants to know where in the brain the struggle for ocular dominance occurs. Which neurons decide which eye to pay attention to? What cells impose a unity onto our sensory disarray?

This is an elegant experimental paradigm. But it’s also profoundly limited. Even if we can locate the cells that govern binocular rivalry, that’s only a single “neural correlate of consciousness”. It remains entirely unclear if those to-be-determined cells in the visual cortex govern all visual experience, or just the contradictions between our eyeballs.

And this leads me back to LSD. Here’s a compound that can consistently alter our entire sensory experience, so that the brain is made aware of its own machinery. We see ourselves seeing the world. (I wish Kant had tried LSD – he would have loved it.*) From the perspective of neuroscience, the hallucinogen is like a systematic version of binocular rivalry. If we knew how LSD worked, we might also gain insight into how ordinary experience works, and how that chemical soup creates the feeling of this, here, now. In other words, the molecular “joints” tweaked by the illegal compound can tell us something very interesting about the source of our unjointed stream of consciousness. Cary Grant was on to something.

*Kant: “The imagination is a necessary ingredient of perception itself.”

LSD

LSD

There's a fascinating article in the latest Vanity Fair (not online) about the prevalence of LSD (aka lysergic acid diethylamide) among movie stars in 1950s Hollywood:

Aldous Huxley was one of the first in Los Angeles to take LSD and was soon joined by others, including the writer Anais Nin. The screenwriter Charles Brackett discovered "infinitely more pleasure" from music on LSD than he had ever before, and the director Sidney Lumet tried it under the supervision of a former chief of psychiatry for the U.S. Navy. Lumet says his three sessions were "wonderful," especially the one where he relived his birth...Another early experimenter was Clare Boothe Luce, the playwright and former American ambassador to Italy, who in turn encouraged her husband, Time publisher Henry Luce, to try LSD. He was impressed and several very positive articles about the drug's potential ran in his magazine.

[SNIP]

There is no question that, at least for a period of time, LSD truly transformed Cary Grant...Much to his friends' surprise, Cary Grant began talking about his therapy in public, lamenting, "Oh those wasted years, why didn't I do this sooner?"

"The Curious Story Behind the New Cary Grant," headlined the September 1, 1959 issue of Look magazine, and inside was a glowing account of how, because of LSD therapy, "at last I am close to happiness." He later explained that "I wanted to rid myself of all my hypocrises. I wanted to work through the events of my childhood, my relationship with my parents and my former wives." More articles followed, and LSD even received a variation of the Good Housekeeping Seal of Approval.

Of course, celebrities no longer brag about their hallucinogenic experiments. (Instead, we're stuck with the slow motion tragedy of Lindsay Lohan.) Furthermore, the government now treats hallucinogens (such as LSD and mushrooms) as legally equivalent to heroin, crack and opium. Because LSD is a Schedule 1 drug, if you're arrested with more than a single dose (roughly .5 grams), and it's your first offense, the federal sentencing guidelines are as follows: "Not less than 5 years, and not more than 40 years". State penalties are similar, with possession typically leading to 1-3 years in jail. (This despite the fact that study after study shows that prescription drugs kill more people by overdose than illicit drugs.) If it were up to me, our classification of drugs would depend largely on their addictive potential, so that drugs with limited addiction potential (such as LSD) were far less regulated than highly addictive substances, such as crack, oxycontin, heroin, etc. But don't get me started on our endless war on drugs, which is an incoherent disaster.

Back to LSD. Because the drug is so tightly regulated, there has been minimal research on how the drug works in the brain. Just look at these search results: The most cited papers are more than thirty years old. (One scientist I talked to last year said the two main disincentives to use LSD in the lab were the lack of grants - the big funding institutions are only interested in addictive drugs - and the paperwork.) The end result is that we really don't know how LSD alters our sensory experience, except that it binds to a vast array of G-protein coupled receptors, including every dopamine receptor subtype and various serotonin receptor subtypes. All this excess neural activity leads to excitation in the upper echelons of the cortex, such as layers IV and V. And, somehow, those squirts of chemical lead people to conclude that they've found the secret of the universe.

What's unfortunate is that LSD could be a powerful experimental tool. And not in the Timothy Leary sense: I'm talking about rigorous investigations into the neural substrate of consciousness. After all, one of the challenges of investigating human consciousness is that it's a continuous stream. As William James noted in 1890, "Consciousness does not appear to itself chopped up in bits. Such words as 'chain' or 'train' do not describe it fitly as it presents itself in the first instance. It is nothing jointed; it flows. A 'river' or a 'stream' are the metaphors by which it is most naturally described." The paradox, of course, is that the brain is composed of a trillion different joints, a seeming infinitude of binary neurons switching on and off. So how does that create this? How does three pounds of wet stuff give rise to the ceaseless cinema of subjective experience?

To begin to answer this profound mystery - and it is the mystery of modern neuroscience - researchers have come up with a clever set of experimental paradigms. My favorite is Christof Koch's version of binocular rivalry. In theory, binocular rivalry is a simple phenomenon. We have two eyeballs; as a result, we are constantly being confronted with two slightly separate views of the world. The brain, using a little unconscious trigonometry, slyly erases this discrepancy, fusing our multiple visions into a single image.

But Koch throws a wrench into this visual process. "What happens," he wondered, "if corresponding parts of your left and right eyes see two quite distinct images, something that can easily be arranged using mirrors and a partition in front of your nose?" Under ordinary circumstances, we superimpose the two separate images from our two separate eyes on top of each other. For example, if the left eye is shown horizontal stripes and the right eye is shown vertical stripes, we will consciously perceive a plaid pattern. Sometimes, however, the brain gets a little confused, and decides to pay attention to only one of our eyes. After a few seconds, we realize our mistake, and begin to pay attention to our other eye. As Koch notes, "The two percepts can alternate in this manner indefinitely."

The end result of all this experimentally induced confusion is that the subject becomes aware - if only for a moment - of the artifice underlying perception. We realize that we have two separate eyes, which see two separate things. Koch wants to know where in the brain the struggle for ocular dominance occurs. Which neurons decide which eye to pay attention to? What cells impose a unity onto our sensory disarray?

This is an elegant experimental paradigm. But it's also profoundly limited. Even if we can locate the cells that govern binocular rivalry, that's only a single "neural correlate of consciousness". It remains entirely unclear if those to-be-determined cells in the visual cortex govern all visual experience, or just the contradictions between our eyeballs.

And this leads me back to LSD. Here's a compound that can consistently alter our entire sensory experience, so that the brain is made aware of its own machinery. We see ourselves seeing the world. (I wish Kant had tried LSD - he would have loved it.*) From the perspective of neuroscience, the hallucinogen is like a systematic version of binocular rivalry. If we knew how LSD worked, we might also gain insight into how ordinary experience works, and how that chemical soup creates the feeling of this, here, now. In other words, the molecular "joints" tweaked by the illegal compound can tell us something very interesting about the source of our unjointed stream of consciousness. Cary Grant was on to something.

*Kant: "The imagination is a necessary ingredient of perception itself."

cortex
Wed, 07/07/2010 - 07:04

Alcoholism

Brendan Koerner has a really fantastic article in the latest Wired on Alcoholics Anonymous (AA). It's a fascinating exploration of the organization, from its hallucinogen inspired birth (Bill Wilson was tripping on belladonna when he found God in a hospital room) to the difficulty of accurately measuring the effectiveness of AA:

The group's "cure rate" has been estimated at anywhere from 75 percent to 5 percent, extremes that seem far-fetched. Even the most widely cited (and carefully...

Alcoholism

Brendan Koerner has a really fantastic article in the latest Wired on Alcoholics Anonymous (AA). It’s a fascinating exploration of the organization, from its hallucinogen inspired birth (Bill Wilson was tripping on belladonna when he found God in a hospital room) to the difficulty of accurately measuring the effectiveness of AA:

The group’s “cure rate” has been estimated at anywhere from 75 percent to 5 percent, extremes that seem far-fetched. Even the most widely cited (and carefully conducted) studies are often marred by obvious flaws. A 1999 meta-analysis of 21 existing studies, for example, concluded that AA members actually fared worse than drinkers who received no treatment at all. The authors acknowledged, however, that many of the subjects were coerced into attending AA by court order. Such forced attendees have little shot at benefiting from any sort of therapy–it’s widely agreed that a sincere desire to stop drinking is a mandatory prerequisite for getting sober.

Yet a growing body of evidence suggests that while AA is certainly no miracle cure, people who become deeply involved in the program usually do well over the long haul. In a 2006 study, for example, two Stanford psychiatrists chronicled the fates of 628 alcoholics they managed to track over a 16-year period. They concluded that subjects who attended AA meetings frequently were more likely to be sober than those who merely dabbled in the organization. The University of New Mexico’s Tonigan says the relationship between first-year attendance and long-term sobriety is small but valid: In the language of statistics, the correlation is around 0.3, which is right on the borderline between weak and modest (0 meaning no relationship, and 1.0 being a perfect one-to-one relationship).

Koerner also investigates AA from the perspective of the brain. He focuses on the prefrontal cortex, that chunk of tissue behind the forehead that allows us to exert self-control, to order club soda instead of whiskey:

As dependence grows, alcoholics also lose the ability to properly regulate their behavior. This regulation is the responsibility of the prefrontal cortex, which is charged with keeping the rest of the brain apprised of the consequences of harmful actions. But mind-altering substances slowly rob the cortex of so-called synaptic plasticity, which makes it harder for neurons to communicate with one another. When this happens, alcoholics become less likely to stop drinking, since their prefrontal cortex cannot effectively warn of the dangers of bad habits.

This is why even though some people may be fully cognizant of the problems that result from drinking, they don’t do anything to avoid them. “They’ll say, ‘Oh, my family is falling apart, I’ve been arrested twice,’” says Peter Kalivas, a neuroscientist at the Medical University of South Carolina in Charleston. “They can list all of these negative consequences, but they can’t take that information and manhandle their habits.”The loss of synaptic plasticity is thought to be a major reason why more than 90 percent of recovering alcoholics relapse at some point.

It’s now possible to see these changes in the prefrontal cortex at an extremely precise level. Interestingly, one of the most important changes has to do with how alcoholics (and addicts in general) process “prediction error” signals. In essence, a prediction error signal occurs when we expect to get a reward – and it doesn’t matter if the reward is money, sex, praise or drugs – and we instead get nothing (or maybe even a negative outcome). The brain processes this disappointment as a prediction error. As Wolfram Schultz and others have demonstrated, such prediction errors are an incredibly efficient way to learn about the world, allowing us to update our internal models (all those predictions of good stuff) in light of our mistakes.

This is an essential aspect of decision-making, as it allows us to avoid the mindless repetition of mistakes. Just look at what happens to monkeys when their prediction error pathway is surgically disrupted. The experiment went like this: monkeys were given a joystick that moved in two different directions. At any given moment, only one of the movements would trigger a reward (a pellet of food). To make things more interesting, the scientists switched the direction every twenty-five trials. If the monkeys had previously gotten in the habit of lifting the joystick in order to get a food pellet, they now had to shift their strategy.

So what did the monkeys do? Animals with an intact prediction error pathway had no problem with the task. As soon as they stopped receiving rewards for lifting the joystick – this generated a prediction error – they started turning it in the other direction, which meant they continued to receive their pellets of food. However, monkeys that were missing their prediction error machinery demonstrated a telling defect. When they stopped being rewarded for moving the joystick in a certain direction, they were still able (most of the time) to change directions, just like a normal monkey. However, they were unable to persist in this successful strategy, and soon went back to moving the joystick in the direction that garnered no reward. They never learned how to consistently find the food, to turn a mistake into an enduring lesson.

What do prediction errors have to do with addiction? One way to think about addiction is the abuse of a substance despite serious adverse consequences. We think the alcohol will make us happy – and it does, for a few minutes – but the drug will also lead to withdrawal, hangovers, ruined relationships, an empty wallet, etc. In other words, the costs of the drink far exceed its fleeting rewards. Why, then, do addicts keep on drinking? One possible explanation is that addicts can’t properly process their prediction errors, so that all those negative outcomes get ignored. (In other words, we’re like those monkeys who keep on pressing the joystick in the wrong direction.) The end result is that we never learn from our very costly decision-making mistakes.

A new paper in the Journal of Neuroscience by Soyoung Q Park, et. al. provides compelling support for this hypothesis. The scientists began by giving twenty “abstinent alcohol-dependent patients” a simple reinforcement learning task featuring green smiling faces (positive feedback) and red frowning faces (negative feedback).

The first thing to note is that it took the alcoholic patients significantly longer to figure out the game than a group of control subjects. Because the game was played inside an fMRI machine, the scientists were able to analyze the neural differences that led to the learning problems. Interestingly, the alcoholic patients didn’t have a problem generating prediction errors in the striatum, the dopaminergic source of the prediction error signal. When they made a bad guess and saw the red frowning face, their addicted brains looked identical to brains of control subjects. Both groups instantly and automatically recognized their mistakes.

It’s what happened next that begins to explain the errant behavior of addicts. In the control group, this prediction error signal was quickly passed along to the prefrontal cortex, which used this new information to modulate future decisions. As a result, the control brain was able to quickly learn from its mistakes and minimize the number of red frowning faces.

The alcoholic brain wasn’t nearly as adept. Park et. al. found that, at least in this small group of addicted patients, there appeared to a connectivity problem between the striatum and the prefrontal cortex. As a result, when these subjects made a mistake, their prefrontal cortex wasn’t fully informed – there was a reduced amount of “feedback-related modulation” – and this lack of modulation correlated with 1) an inability to succeed at the simple learning task and 2) the magnitude of their alcohol craving. (This data extends similar results observed in smokers.) In other words, the addicts who couldn’t internalize their prediction errors were the most addicted. This suggests that it is the inability to learn from mistakes – even when these mistakes are destroying our life – that makes addiction so damn hard to escape.

Now here’s some blatant speculation. I think one reason AA is successful, at least for many of those who commit to the program, is that it’s designed to force people to confront their prediction errors. Just look at the twelve steps, many of which are all about the admission of mistakes, from step number 1 (“We admitted we were powerless over alcohol–that our lives had become unmanageable”) to step number 8 (“Made a list of all persons we had harmed, and became willing to make amends to them all”) to step number 10 (“Continued to take personal inventory and when we were wrong promptly admitted it”). I’d suggest that the presence of these steps helps people break through the neuromodulatory problem of addiction, as the prefrontal cortex is forced to grapple with its massive failings and flaws. Because unless we accept our mistakes we will keep on making them.

Alcoholism

Alcoholism

Brendan Koerner has a really fantastic article in the latest Wired on Alcoholics Anonymous (AA). It's a fascinating exploration of the organization, from its hallucinogen inspired birth (Bill Wilson was tripping on belladonna when he found God in a hospital room) to the difficulty of accurately measuring the effectiveness of AA:

The group's "cure rate" has been estimated at anywhere from 75 percent to 5 percent, extremes that seem far-fetched. Even the most widely cited (and carefully conducted) studies are often marred by obvious flaws. A 1999 meta-analysis of 21 existing studies, for example, concluded that AA members actually fared worse than drinkers who received no treatment at all. The authors acknowledged, however, that many of the subjects were coerced into attending AA by court order. Such forced attendees have little shot at benefiting from any sort of therapy--it's widely agreed that a sincere desire to stop drinking is a mandatory prerequisite for getting sober.

Yet a growing body of evidence suggests that while AA is certainly no miracle cure, people who become deeply involved in the program usually do well over the long haul. In a 2006 study, for example, two Stanford psychiatrists chronicled the fates of 628 alcoholics they managed to track over a 16-year period. They concluded that subjects who attended AA meetings frequently were more likely to be sober than those who merely dabbled in the organization. The University of New Mexico's Tonigan says the relationship between first-year attendance and long-term sobriety is small but valid: In the language of statistics, the correlation is around 0.3, which is right on the borderline between weak and modest (0 meaning no relationship, and 1.0 being a perfect one-to-one relationship).

Koerner also investigates AA from the perspective of the brain. He focuses on the prefrontal cortex, that chunk of tissue behind the forehead that allows us to exert self-control, to order club soda instead of whiskey:

As dependence grows, alcoholics also lose the ability to properly regulate their behavior. This regulation is the responsibility of the prefrontal cortex, which is charged with keeping the rest of the brain apprised of the consequences of harmful actions. But mind-altering substances slowly rob the cortex of so-called synaptic plasticity, which makes it harder for neurons to communicate with one another. When this happens, alcoholics become less likely to stop drinking, since their prefrontal cortex cannot effectively warn of the dangers of bad habits.

This is why even though some people may be fully cognizant of the problems that result from drinking, they don't do anything to avoid them. "They'll say, 'Oh, my family is falling apart, I've been arrested twice,'" says Peter Kalivas, a neuroscientist at the Medical University of South Carolina in Charleston. "They can list all of these negative consequences, but they can't take that information and manhandle their habits."The loss of synaptic plasticity is thought to be a major reason why more than 90 percent of recovering alcoholics relapse at some point.

It's now possible to see these changes in the prefrontal cortex at an extremely precise level. Interestingly, one of the most important changes has to do with how alcoholics (and addicts in general) process "prediction error" signals. In essence, a prediction error signal occurs when we expect to get a reward - and it doesn't matter if the reward is money, sex, praise or drugs - and we instead get nothing (or maybe even a negative outcome). The brain processes this disappointment as a prediction error. As Wolfram Schultz and others have demonstrated, such prediction errors are an incredibly efficient way to learn about the world, allowing us to update our internal models (all those predictions of good stuff) in light of our mistakes.

This is an essential aspect of decision-making, as it allows us to avoid the mindless repetition of mistakes. Just look at what happens to monkeys when their prediction error pathway is surgically disrupted. The experiment went like this: monkeys were given a joystick that moved in two different directions. At any given moment, only one of the movements would trigger a reward (a pellet of food). To make things more interesting, the scientists switched the direction every twenty-five trials. If the monkeys had previously gotten in the habit of lifting the joystick in order to get a food pellet, they now had to shift their strategy.

So what did the monkeys do? Animals with an intact prediction error pathway had no problem with the task. As soon as they stopped receiving rewards for lifting the joystick - this generated a prediction error - they started turning it in the other direction, which meant they continued to receive their pellets of food. However, monkeys that were missing their prediction error machinery demonstrated a telling defect. When they stopped being rewarded for moving the joystick in a certain direction, they were still able (most of the time) to change directions, just like a normal monkey. However, they were unable to persist in this successful strategy, and soon went back to moving the joystick in the direction that garnered no reward. They never learned how to consistently find the food, to turn a mistake into an enduring lesson.

What do prediction errors have to do with addiction? One way to think about addiction is the abuse of a substance despite serious adverse consequences. We think the alcohol will make us happy - and it does, for a few minutes - but the drug will also lead to withdrawal, hangovers, ruined relationships, an empty wallet, etc. In other words, the costs of the drink far exceed its fleeting rewards. Why, then, do addicts keep on drinking? One possible explanation is that addicts can't properly process their prediction errors, so that all those negative outcomes get ignored. (In other words, we're like those monkeys who keep on pressing the joystick in the wrong direction.) The end result is that we never learn from our very costly decision-making mistakes.

A new paper in the Journal of Neuroscience by Soyoung Q Park, et. al. provides compelling support for this hypothesis. The scientists began by giving twenty "abstinent alcohol-dependent patients" a simple reinforcement learning task featuring green smiling faces (positive feedback) and red frowning faces (negative feedback).

The first thing to note is that it took the alcoholic patients significantly longer to figure out the game than a group of control subjects. Because the game was played inside an fMRI machine, the scientists were able to analyze the neural differences that led to the learning problems. Interestingly, the alcoholic patients didn't have a problem generating prediction errors in the striatum, the dopaminergic source of the prediction error signal. When they made a bad guess and saw the red frowning face, their addicted brains looked identical to brains of control subjects. Both groups instantly and automatically recognized their mistakes.

It's what happened next that begins to explain the errant behavior of addicts. In the control group, this prediction error signal was quickly passed along to the prefrontal cortex, which used this new information to modulate future decisions. As a result, the control brain was able to quickly learn from its mistakes and minimize the number of red frowning faces.

The alcoholic brain wasn't nearly as adept. Park et. al. found that, at least in this small group of addicted patients, there appeared to a connectivity problem between the striatum and the prefrontal cortex. As a result, when these subjects made a mistake, their prefrontal cortex wasn't fully informed - there was a reduced amount of "feedback-related modulation" - and this lack of modulation correlated with 1) an inability to succeed at the simple learning task and 2) the magnitude of their alcohol craving. (This data extends similar results observed in smokers.) In other words, the addicts who couldn't internalize their prediction errors were the most addicted. This suggests that it is the inability to learn from mistakes - even when these mistakes are destroying our life - that makes addiction so damn hard to escape.

Now here's some blatant speculation. I think one reason AA is successful, at least for many of those who commit to the program, is that it's designed to force people to confront their prediction errors. Just look at the twelve steps, many of which are all about the admission of mistakes, from step number 1 ("We admitted we were powerless over alcohol--that our lives had become unmanageable") to step number 8 ("Made a list of all persons we had harmed, and became willing to make amends to them all") to step number 10 ("Continued to take personal inventory and when we were wrong promptly admitted it"). I'd suggest that the presence of these steps helps people break through the neuromodulatory problem of addiction, as the prefrontal cortex is forced to grapple with its massive failings and flaws. Because unless we accept our mistakes we will keep on making them.

cortex
Thu, 07/01/2010 - 04:55


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Brain and Behavior