Monday, September 22, 2014

The Genetics of Smoking

Evidence from a 40-year study. 
(First published March 28, 2013)

Pediatricians have often remarked upon it: Give one adolescent his first cigarette, and he will cough and choke and swear never to try another one. Give a cigarette to a different young person, and she is off to the races, becoming a heavily dependent smoker, often for the rest of her life. We have strong evidence that this difference in reaction to nicotine is, at least in part, a genetic phenomenon.

But so what? Is there any practical use to which such knowledge can be put? As it turns out, the answer may be yes. People with the appropriate gene variations on chromosomes 15 and 19 move very quickly from the first cigarette to heavy use of 20 or more cigarettes per day, and have more difficulty quitting, according to a report  published in JAMA Psychiatry. From a public health point of view, these findings add a strong genetic rationale to early smoking prevention efforts— especially programs that attempt to “disrupt the developmental progression of smoking behavior” by means of higher prices and aggressive enforcement of age restrictions on smoking.

What the researchers found were small but identifiable differences that separated people with these genetic variations from other smokers. The gene clusters in question “provide information about smoking risks that cannot be ascertained from a family history, including information about risk for cessation failure,” according to authors Daniel W. Belsky, Avshalom Caspi, and colleagues at the University of North Carolina and Duke University.

The group looked at three prominent genome-wide association studies of adult smoking to see if the results could be applied to “the developmental progression of smoking behavior.” They used the data from the genome work to analyze the results of a 38-year prospective study of 1,037 New Zealanders, known as the Dunedin Study. A total of 405 cohort members in this study ended up as daily smokers, and only 20% of the daily smokers ever achieved cessation, defined as a year or more of continual abstinence.

The researchers came up with a multilocus genetic risk score (GRS) based on single-nucleotide polymorphisms associated with smoking behaviors. Previous meta-analyses had identified several suspects, specifically a region of chromosome 15 containing the CHRNA5-CHRNA3-CHRNB4 gene cluster, and a region of chromosome 19 containing the gene CYP2A6. These two clusters were already strong candidate genes for the development of smoking behaviors. For purpose of the study, the GRS was calculated by adding up the alleles associated with higher smoking quantity. The genetic risk score did not pertain to smoking initiation, but rather to the number of cigarette smoked per day.

When the researchers applied these genetic findings to the Dunedin population cohort, representing ages 11 to 38, they found that an unfortunate combination of gene types seemed to be pushing some smokers toward heavy smoking at an early age. Individuals with a high GRS score “progressed more rapidly to heavy smoking and nicotine dependence, were more likely to become persistent heavy smokers and persistently nicotine dependent, and had more difficulty quitting,” according to the study. However, these effects took hold only when young smokers “progressed rapidly from smoking initiation to heavy smoking during adolescence.” The variations found on chromosomes 15 and 19 influence adult smoking “through a pathway mediated by adolescent progression from smoking initiation to heavy smoking.”

Curiously, the group of people who had the lowest Genetic Risk Scores were not people who had never smoked, but rather people who smoked casually and occasionally—the legendary “chippers,” who can take or leave cigarettes, sometimes have one late at night, or a couple at parties, without ever falling victim to nicotine addiction. These “light but persistent smokers” were accounted for “with the theory that the genetic risks captured in our score influence response to nicotine, not the propensity to initiate smoking.”

Naturally, the study has limitations. Everyone in the Dunedin Study was of European descent, and the life histories ended at age 38. Nor did the study take smoking bans or different ages into account. The study cries out for replication, and hopefully that won’t be long in coming.

Could information of this sort be used to identify high-risk young people for targeted prevention programs? That is the implied promise of such research, but no, probably not. The gene associations are not so dramatic as to cause youngsters with the “bad” alleles to inevitably become chain smokers, nor do the right set of genes confer protection against smoking. It’s not that simple. However, the study is definitely one more reason to push aggressive smoking prevention efforts aimed at adolescents.

Belsky D.W.  Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine DependenceEvidence From a 4-Decade Longitudinal StudyDevelopmental Progression of Smoking Behavior, JAMA Psychiatry,   1. DOI: 10.1001/jamapsychiatry.2013.736

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Wednesday, September 17, 2014

Why Will Power Fails

How to strengthen your self-control.

(First published August 12, 2013)

Reason in man obscured, or not obeyed,
Immediately inordinate desires,
And upstart passions, catch the government
From reason; and to servitude reduce
Man, till then free.

—John Milton, Paradise Lost

What is will power? Is it the same as delayed gratification? Why is will power “far from bulletproof,” as researchers put it in a recent article for Neuron? Why is willpower “less successful during ‘hot’ emotional states”? And why do people “ration their access to ‘vices’ like cigarettes and junk foods by purchasing them in smaller quantities,” despite the fact that it’s cheaper to buy in bulk?

 Everyone, from children to grandparents, can be lured by the pull of immediate gratification, at the expense of large—but delayed—rewards. By means of a process known as temporal discounting, the subjective value of a reward declines as the delay to its receipt increases. Rational Man, Economic Man, shouldn’t behave in a manner clearly contrary to his or her own best interest. However, as Crockett et. al. point out in a recent paper in Neuron “struggles with self-control pervade daily life and characterize an array of dysfunctional behaviors, including addiction, overeating, overspending, and procrastination.”

Previous research has focused primarily on “the effortful inhibition of impulses” known as will power. Crockett and coworkers wanted to investigate another means by which people resist temptations. This alternative self-control strategy is called precommitment, “in which people anticipate self-control failures and prospectively restrict their access to temptations.” Good examples of this approach include avoiding the purchase of unhealthy foods so that they don’t constitute a short-term temptation at home, and putting money in financial accounts featuring steep penalties for early withdrawal. These strategies are commonplace, and that’s because people generally understand that will power is far from foolproof against short-term temptation. People adopt strategies, like precommitment, precisely because they are anticipating the possibility of a failure of self-control. We talk a good game about will power and self-control in addiction treatment, but the truth is, nobody really trusts it—and for good reason.  The person who still trusts will power has not been sufficiently tempted.

The researchers were looking for the neural mechanisms that underlie precommitment, so that they could compare them with brain scans of people exercising simple self-control in the face of short-term temptation.

After behavioral and fMRI testing, the investigators used preselected erotic imagery rated by subjects as either less desirable ( smaller-sooner reward, or SS), or more highly desirable ( larger-later reward, or LL). The protocol is complicated, and the analysis of brain scans is inherently controversial. But previous studies have shown heightened activity in three brain areas when subjects are engaged in “effortful inhibition of impulses.” These are the dorsolateral prefrontal cortex (DLPFC), the inferior frontal gyrus (IFG), and the posterior parietal cortex (PPC). But when presented with opportunities to precommit by making a binding choice that eliminated short-term temptation, activity increased in a brain region known as the lateral frontopolar cortex (LFPC).  Study participants who scored high on impulsivity tests were inclined to precommit to the binding choice.

In that sense, impulsivity can be defined as the abrupt breakdown of will power. Activity in the LFPC has been associated with value-based decision-making and counterfactual thinking. LFPC activity barely rose above zero when subjects actively resisted a short-term temptation using will power.  Subjects who chose the option to precommit, who were sensitive to the opportunity to make binding choices about the picture they most wanted to see, showed significant activity in the LFPC. “Participants were less likely to receive large delayed reward when they had to actively resist smaller-sooner reward, compared to when they could precommit to choosing the larger reward before being exposed to temptation.”

Here is how it looks to Molly Crockett and her fellow authors of the Neuron article:

Precommitment is adaptive when willpower failures are expected…. One computationally plausible neural mechanism is a hierarchical model of self-control in which an anatomically distinct network monitors the integrity of will-power processes and implements precommitment decisions by controlling activity in those same regions. The lateral frontopolar cortex (LFPC) is a strong candidate for serving this role.

None of the three brain regions implicated in the act of will power were active when opportunities to precommit were presented.  Precommitment, the authors conclude, “may involve recognizing, based on past experience, that future self-control failures are likely if temptations are present. Previous studies of the LFPC suggest that this region specifically plays a role in comparing alternative courses of action with potentially different expected values.” Precommitment, then, may arise as an alternative strategy; a byproduct of learning and memory related to experiences “about one’s own self-control abilities.”

There are plenty of caveats for this study: A small number of participants, the use of pictorial temptations, and the short time span for precommitment decisions, compared to real-world scenarios where delays to greater rewards can take weeks or months. But clearly something in us often knows that, in the immortal words of Carrie Fisher, “instant gratification takes too long.” For this unlucky subset, precommitment may be a vitally important cognitive strategy. “Humans may be woefully vulnerable to self-control failures,” the authors conclude, “but thankfully, we are sometimes sufficiently far-sighted to circumvent our inevitable shortcomings.” We learn—some of us—not to put ourselves in the path of temptation so readily.

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Monday, September 8, 2014

In Praise of Neurogenesis

A little sweat pays big dividends in recovery.

Scientists have long known that activities like learning, socialization and physical activity—key components of “environmental enrichment”—lead to the growth and development of nerve tissue that will become new brain cells, a process called neurogenesis. Such enrichment can include all manner of stimuli, but a group of researchers at the National Institute on Aging and the National Institute on Drug Abuse (NIDA) wanted to find out exactly how much of that neurogenic stimulus is due solely to exercise. Writing in the journal Learning and Memory, Tali Kobilo and coworkers went back to that most basic of lab experiments, mice running on an exercise wheel. Using a variety of conditions to permutate the mix of enrichment, running, running with other enrichment, and controls, the investigators concluded: “Here we show that running is the critical factor in stimulating adult hippocampal neurogenesis and enhancing mature BDNF [brain-derived neurotrophic factor] peptide levels. Moreover, enrichment in the absence of running does not increase adult hippocampal neurogenesis or BDNF levels in the hippocampus.” In addition: “New cell proliferation, survival, neuron number, and neurotrophin levels were enhanced only when running was accessible” to the test animals. “We conclude that exercise is the critical factor mediating increased BDNF levels and adult hippocampal neurogenesis.”

As a treatment modality for drug and alcohol addiction, physical exercise is often effective, quite well studied—and free. It is the most boring, the most mundane, the most predictable exhortation of them all—or perhaps the second most predictable, after the admonition to Eat Less.

Perhaps, suggests Jennifer Matesa in her book, The Recovering Body , it would be well to remember that doctors are not “paid to prescribe exercise.” She quotes Harvard’s biology professor Daniel E. Lieberman: “It is often said that exercise is medicine, but a more correct statement is that insufficient regular exercise is abnormal and pathological.” Matesa musters a chorus of trainers and exercise-oriented recovery experts to bolster her argument that simple exercise remains the single most overlooked element in most people’s recovery programs.

Matesa, whom I first encountered as the author of the excellent blog Guinevere Gets Sober, and later worked with at the online addiction and recovery magazine, The Fix, offers advice to “clean up the wreckage and recover the body’s health” during sobriety, and divides her book into five practices: exercise, nutrition, sleep, sexuality, and mindfulness meditation.

Body recovery is complex, Matesa writes. “You’re raising the levels of endorphins and dopamine in the body. You’re reregulating the body’s metabolism—its capacity to burn energy efficiently. You’re not just exercising biceps and triceps and deltoids or even chest, back, legs, and core. You’re also exercising the internal organs: heart, lungs, circulatory system, central nervous system (including the brain), and digestive system. You’re even exercising the skin by making it sweat.”

While one of the best things about exercise is that you can start at any point, with or without prior experience, there is a sense in which former jocks may have an edge here. Matesa interviews a former sports freak and recovering heroin addict who found her way back to the “cognitive- and muscle-memory” that gave her a head start in understanding what a fitness program is composed of. One thing that prevents people from working out, the former jock says, “is that they don’t know what to do and they feel overwhelmed. And we addicts get overwhelmed easily.”

A medical director of a Palm Beach detox center suggested that “twelve minutes of exercise per day with a heart rate of greater than one hundred twenty beats per minute” is enough to restore healthy sleeping patterns, for example. “The people who do that, their sleep architecture returns to normal in half the time that it takes people who don’t exercise. Twelve minutes.”

Matesa’s credentials as a recovering addict are impressive: alcohol abuse and opiate addiction, compulsive overeating, and shoplifting. As with many addictive shoplifters, she didn’t even need the things she stole. “The security woman pulled me into a messy, windowless back room, shut the door, looked me up and down, noted my Coach bag and middle-class clothing, regarded the stolen property in her hand [cheap earbuds], and said slowly, ‘you need to seek help.’” The book is published by Hazelden, and Matesa hews to the basic structure of 12 Step recovery programs. She also backs the controversial thinking of Dr. Gabor Mate, who believes that all addictions are the result of adverse childhood experiences, not genetics or any other physiological predilection.

Despite the years she logged with opiates, “my first chemical of abuse was sugar, my first addictive behavior was eating…. I eat sugar because it does all kinds of things drugs do…. when I was a kid, my diet was at least 80 percent refined and processed food, and almost all of that, essentially, was sugar. At age ten, I looked forward to my after-school snack the way my Dad looked forward to his first beer when he got home.”

She notes that a number of published studies have shown that “addicts in the first six months of recovery use sweet foods and refined, processed foods—junk food—to satisfy cravings for drugs and alcohol.” In addition, “sensible eating habits are seldom part of recovery strategies in detox and rehab facilities—this was a concern echoed by a number of treatment experts I talked with.”

“Recovery does not promise beauty or riches, everlasting affection and security or even sustained peace of mind,” Matesa concludes. “It promises that we’ll be able to negotiate one day—this one—in our right minds, awake. We get good at what we practice.”

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