Molecular Scars of Child Abuse

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Can traumatic events during early childhood permanently affect the way the brain responds to stress at a molecular level? Moshe Szyf, a McGill University epigeneticist, and Michael Meaney, a McGill University neurologist previously found evidence for long-lasting molecular changes in stress-response brain regions of rats exposed to poor parental care. Now, in a follow-up study, they show that similar changes may occur in human suicide victims who suffered childhood abuse.

Dr. Szyf and Dr. Meaney focus on epigenetic changes, or changes “on top of the genome.” While childhood experience cannot change the actual DNA basepairs that form the genetic code, experience may permanently mark certain regions of the genome in ways that change gene expression and have long-lasting consequences on behavior. These marks include methylation of DNA basepairs and acetylation of histones, the proteins that DNA is wrapped around inside the nucleus. We are only now beginning to understand how experience can change these epigentic tags, and in turn how these epigentic tags can feedback and affect our behavior.

In 2004, Dr. Szyf and Dr. Meaney published a paper on epigenetic changes caused by maternal behavior in rats. Rats whose mothers did less licking and grooming and arched-back nursing had exaggerated behavioral and hypothalamic-pituitary-adrenal responses to stressful stimuli compared with rats whose mothers groomed them more. These rats also had altered epigentic tags — increased DNA methylation and reduced histone acetylation — in the promoter of an important stress response gene, the glucocorticoid receptor gene in the hippocampus, and reduced expression of this gene. In order to show that the maternal behavior caused the epigenetic changes, some rats whose birth mothers did not groom were fostered by mothers with high grooming behaviors, and vice versa. These adopted rats showed methylation patterns similar to the mothers that reared them, instead of their biological mothers. Interestingly, the effects of neglectful maternal behavior on methylation in the promotor, altered hippocampal glucocorticoid receptor expression, and the hypothalamic-pituitary-adrenal response to stress were reversed when the adult offspring were given a histone deacetylase inhibitor, which globally removes many epigentic tags.

Does childhood abuse and neglect produce similar epigenetic tags on this stress response gene in humans? In another study, Dr. Meaney’s group compared expression of the neuron-specific glucocorticoid receptor gene in the hippocampus of 12 suicide victims with a history of childhood abuse (including severe neglect) to those of 12 suicide victims who had no history of abuse and those of 12 controls. Again, they found increased methylation of a glucocorticoid receptor promotor, and less glucocorticoid receptor gene expression. This finding, that childhood abuse and neglect is associated with methylation of a glucocorticoid receptor promotor in the hippocampus mirrors the result in their 2004 paper that found the same epigenetic change in rats who were neglected by their mothers.

Dr. Szyf and Dr. Meaney also looked more broadly for epigentic tags associated with abuse. In a recent paper, they compared the brains of 13 people who had suffered early childhood abuse (sexual contact, severe physical abuse and/or severe neglect) and committed suicide and 11 people who had no history of abuse and had died suddenly in accidents. The hippocampus in the brains of suicide victims had higher methylation levels in DNA regions controlling the expression of ribosomal RNA (rRNA), a general purpose gene, broadly important for protein syntehsis in a given cell. The epigentic tags resulted in reduced rRNA expression in the hippocampus. Whether or not the person had had a psychiatric illness or a substance abuse problem did not account for any difference in methylation level. The methylation differences were specific to the hippocampus, which is commonly associated with psychopathology, and did not exist in the cerebellum, which is not associated with pathology (using samples from 8 brains, 4 from each of the conditions). Thus the authors provide two examples of long-lasting molecular “scars” in humans that may affect gene expression and behavior.

This research is very interesting but not without caveats. The authors acknowledge that they have not been able to account for other environmental factors besides childhood abuse and neglect that might cause these epigenetic changes. Future studies would require much larger sample sizes to address other possible causative environmental variables. Also, the authers show “scars” on two genes, one important for stress-response and one for protein synthesis, but there are twenty-thousand genes in the human genome. With new technologies to look at epigentic tags on a genome-wide level (the epigenome), future studies can look at all genes in an unbiased manner for a more complete picture of epigentic “scars” that are enriched in people who suffered from childhood abuse and neglect. Finally, we should be careful not to conflate suicidality with abuse; this research does not directly address suicide risk from abuse.

Possible legal and policy implications of this area of research remain far in the future, but could include identifying earlier critical periods for childhood intervention programs, better understanding abuse as a mitigating factor if the person is later convicted of a crime related to an abnormal stress response, or calculating damages in a civil lawsuit against the abusive caregiver. The most significant implication is better understanding epigenetic pathology caused by childhood abuse and neglect, which may be an important part of a multi-faceted approach towards treating survivors of abuse who continue to suffer from its lasting effects.

– Kelly Lowenberg (Hat tip to Alex Pollen)

What a dead salmon reminds us about fMRI analysis

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This has been making the rounds in the neuroscience world, but deserves attention in cross-disciplinary fields.  A group of top-notch fMRI researchers presented an unusual paper at June’s Human Brain Mapping conference.

Paper titleNeural correlates of interspecies perspective taking in the post-mortem Atlantic Salmon: An argument for multiple comparisons correction

Blog headline: fMRI Gets Slap in the Face with a Dead Fish

Salmons have very small brains.

Salmons have very small brains.

In short, researchers scanned a dead fish while it was “shown a series of photographs depicting human individuals in social situations. The salmon was asked to determine what emotion the individual in the photo must have been experiencing.”

Clearly, the fish did not perform well at the task, and thus we have not learned much about interspecies perspective taking.  The work is, however, a compelling and humorous demonstration of the problem of multiple comparisons.  This is a principle in statistics that basically says when you’re looking at enough bits of information (i.e. doing lots of statistical tests), some will seem to be what you’re looking for – purely by chance.  In fMRI experiments, there are a LOT of pieces of data to compare, and without statistical correction for this phenomenon (which is not always done), some will indeed be significant, just by chance.

Lead author Craig Bennett explains further on his blog:

In early 2008 I was working with my co-adviser George Wolford on a presentation he was giving regarding the multiple comparisons problem in fMRI. We were discussing false positives in MRI phantom data and I brought up the idea of processing the salmon fMRI data to look for some ‘active’ voxels. I ran the fish data through my SPM processing pipelines and couldn’t believe what I saw. Sure, there were some false positives. Just about any volume with 65,000 voxels is going to have some false positives with uncorrected statistics. Rather, it was where the false positives occurred that really floored me. A cluster of three significant voxels were arranged together right along the midline of the salmon’s brain.

Remember that the fish was dead.  There was surely no BOLD signal changes going on in a dead fish’s brain.  This is likely not a physiological artifact; it is a statistical one.  Furthermore, the voxels were clustered together – something that may be expected to happen in an “actual” activation and thus used as a threshold for analysis.  Also, it was just one fish!  (No apparent speculation in the paper about what may have happened if this were a school of fish compared to appropriate control school of fish.)

Bennett et al are apparently having a hard time getting the paper published.  The use of multiple comparisons corrections in fMRI studies is a contentious one, as some researchers think it may be overly conservative and thus miss true positives.  As a solution, Bennett suggests reporting both sets of data, corrected and uncorrected.

The moral of the story for interdisciplinary folks: note whether multiple comparisons correction data have been reported (or not).  And always bear in mind that there are a lot of assumptions and decisions being made behind the ultimately reported data in any neuroimaging study.

– Emily Murphy (h/t Alexis Madrigal @ Wired)

Book Note: My Lobotomy, by Howard Dully and Charles Fleming

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The lobotomy continues to fascinate and to haunt.  How could the 1949 Nobel Prize for Medicine or Physiology go to Egas Moniz for the invention of a procedure that, within two decades, was rejected, with horror, as barbaric?  As a matter of inside Nobel politics, there has long been some thought that Moniz really won the prize for inventing angiography, but the Prize is given for an invention or discovery, not for a body of work, and the citation is for the “frontal leucotomy.”  The terms frontal lobotomy or prefrontal lobotomy were popularized by the procedure’s American exponent – Walter Freeman, the neurologist who invented the surgical procedure that allowed out-patient use of the procedure, the “ice pick” (literally in the first cases) through the orbit behind the eye.

This same Walter Freeman ended his career with an office in the wealthy Silicon Valley (then in its silicon infancy) suburb of Los Altos.  And, in 1960, he “gave” (the verb seems wrong) a prefrontal lobotomy to a 12 year-old boy named Howard Dully. My Lobotomy is Dully’s story, told by the now 60 year-old Dully himself, with the aid of writer Charles Fleming.

The book began as a result of a National Public Radio program on lobotomies, which, in effect, became a program on Dully.  Dully had been a difficult boy, but not, at least as he tells the story, a particularly abnormal one.  He speculates, plausibly, that today he might have been diagnosed with ADD or ADHD.  He believes his stepmother hated him, irrationally, and was willing to do anything to make him disappear, before and after his “successful” lobotomy.  Freeman, he thinks, was gripped by an overriding urge to keep experimenting with his procedure, extending it still further to children, including Howard, whom he diagnosed as having had juvenile schizophrenia since age 4.

After the procedure Dully did not become a zombie or an idiot. It sounds, from his description (the main one we have) that he became more detached and vague, at least for a while. (Freeman, however, thought his improvement was remarkable.)   His stepmother still would not take him back into the home so he drifted back and forth from the juvenile hall to Agnews, a state hospital for the insane, to a special school for the disabled.  As an adult he lived mainly on social security disability payments and a few women in his life, engaging in too many drugs, too much alcohol, and occasional petty crime, until, at about age 45, he decided to straighten out his life.  He seems to have done well; he has supported himself and his wife through driving a school bus and training other bus drivers for most of the last fifteen years.

The book is mainly Howard’s story, of his family and his early life.  His misbehavior in school, his childhood trips to the mountains, or his complex and painful relationship with his stepmother may or may not interest you, depending on your tastes.  The discussion of Freeman, and the contents of the notes Freeman took on Howard, are more interesting from the perspective of neuroethics. I would have liked more scientific discussion of the lobotomy generally and of Howard’s case in particular.  But this is Howard’s memoir, not a scientific report on him.

The latter may be coming.  According to the afterward of the paperback edition of the book, Dully has now been scanned in an MRI.  The researchers found major brain damage that they would expect to render a person completely incompetent.  They can only attribute his normal or close to normal life to the remarkable brain plasticity of the young.  I understand that they hope to have a manuscript submitted around the end of 2009.  That paper should be well worth reading and will make this already interesting memoir even more useful in neuroethics.

Hank Greely

The Politics of Disease Definition: A Summer of DSM-V Controversy in Review

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On June 23rd, 2009, an article in press at Psychiatric Times was posted by Doug Bremner, MD on his health blog, igniting debate through the medical community.  That article was an editorial authored by Allan Frances, MD, chair of the committee that collaboratively authored the DSM-IV, in which he passionately criticizes the team presently working on the DSM-V. Frances expresses disappointment in the “confidentiality agreement” which has lent secrecy to the DSM-V authorship process, warns of the possibility of overdiagnosis and unintended consequences in revising disease definitions, and is especially worried about published interviews where David Kupfer, MD, chairman of the DSM-V Task Force has claimed: “There are no constraints on the degree of change”. This boldness is a cause for concern, according to Frances because:

“The simple truth is that descriptive psychiatric diagnosis does not need and cannot support a paradigm shift. There can be no dramatic improvements in psychiatric diagnosis until we make a fundamental leap in our understanding of what causes mental disorders. The incredible recent advances in neuroscience, molecular biology, and brain imaging that have taught us so much about normal brain functioning are still not relevant to the clinical practicalities of everyday  psychiatric diagnosis. The clearest evidence supporting this disappointing fact is that not even one biological test is ready for inclusion in the criteria sets for DSM‐5.”

Shortly after the Frances editorial began lighting up medical blogs, the American Psychiatric Association released a scathing riposte, signed off by prominent APA members, including Dr. Kupfer and APA President Alan Schatzberg, MD. The response only partially addresses Frances’ arguments, suggesting that the confidentiality agreements Frances criticizes are really legal documents meant to protect intellectual property, that many clinicians feel the DSM-IV does not adequately meet the needs of the patients they encounter in practice, that many of the changes proposed for DSM-V are in fact supported by current research, and that, in fact, that the DSM-V process is the most open and inclusive “ever.” Perhaps most surprisingly, the article, penned by the heads of a prestigious medical association and task force, begins and ends dramatically by injuriously emphasizing Frances’ own conflict of interest:

“The commentary “A Warning Sign on the Road to DSM-5: Beware of its Unintended Consequences” by Allen Frances, M.D., submitted to Psychiatric Times contains factual errors and assumptions about the development of DSM-V that cannot go unchallenged. Frances now joins a group of individuals, many involved in development of previous editions of DSM, who repeat the same accusations about DSM-V with disregard for the facts.

Both Dr. Frances and Dr. Spitzer have more than a personal “pride of authorship” interest in preserving the DSM-IV and its related case book and study products. Both continue to receive royalties on DSM-IV associated products. The fact that Dr. Frances was informed at the APA Annual Meeting last month that subsequent editions of his DSM-IV associated products would cease when the new edition is finalized, should be considered when evaluating his critique and its timing.”

Another response, penned by William Carpenter, Professor of Psychiatry at the University of Maryland, and chairman of the DSM-V work group on psychosis, was published in the Psychiatric Times only a few days later, on July 7th, 2009. In this article, Dr. Carpenter is much more dispassionate than the APA piece, and systematically addresses some of the concrete arguments and concerns Dr. Frances put forward in his article, giving a bit more detail about the “confidentiality agreements” (they are in place to prevent task force members from publishing their own diagnostic manuals), and generally arguing that reality is less sensational than Dr. Frances had suggested. Daniel Carlat, MD, helpfully summarizes this article as follows:

“In actuality, there will be very few substantive changes in the DSM-V. Most of the diagnostic criteria will be the same. We might add a handful of rating scales. There will be no ‘paradigm shift.’ We are considering adding a sub-threshold psychosis diagnosis but then again we may not–it’s a complex scientific issue and we, like you, are concerned about overdiagnosis and stigma.”

Carpenter put forth an ostensibly reasonable voice in what was rapidly becoming a vicious battle, but the summer of drama was still unfolding.  Concomitantly with the Carpenter response, Dr. Jane Costello, Professor at the Duke Institute for Brain Sciences where she also co-directs the Center for Developmental Epidemiology and an international expert on the course of mental illness, publicly circulated her letter of resignation from the DSM-V Work Group on Disorders in Childhood and Adolescence. Sharing Dr. Carpenter’s more academic style, she nevertheless contradicts him in expressing a general discomfort with the underlying principle of rewriting psychiatric taxonomy all at once, claiming “I am not aware of any other branch of medicine that does anything like this.”  She further suggests that the taxonomic changes being made by the team are in fact overly dramatic given available data:

“When we began this process, we agreed that changes would only be made if there were empirical evidence to support them. Sometimes (as with Charlie’s work on preschool PTSD) this has been the case. But as time has gone by, the gap between what we need to know in order to make revisions and what we do know has grown wider and wider, while the time to fill these gaps is shrinking rapidly. More and more, changes seem to be made for reasons that have little basis in new scientific findings or organized clinical or epidemiological studies.”

This observation parallels the speculative worry Frances expressed in his editorial that time pressures on the DSM-V task force may soon lead to an unconsidered rush of last minute decisions without empirical support.

The work that the DSM-V task force is doing is of a significance barely comprehensible at present, as it will determine both disease categories for millions of individuals, and delineate drug markets for the world’s largest pharmaceutical companies.

Given this fact, how important is it for social scientists, lawyers, historians and philosophers to monitor the internal politics of this process? Genetics researchers have the assistance and resource of ELSI scholars, but is there an equivalent, well-organized network of researchers devoted to critically analyzing the social, ethical and legal ramifications of the work on the DSM?

Is the DSM-V process really the most open and inclusive process of its kind to date?  It may be the case that some of Frances’ arguments misapprehend the actual situation, but would he be making these kinds of worried, speculative arguments if it were truly an open process? Is it possible that controversy of this sort could lead to more transparency from the DSM-V task force?

Does the proliferation of medical blogs penned by high-profile academic researchers help or hinder the process of disease definition? What will be the public health impact of the universal accessibility of this information?

CJ Murdoch

Militarized Neurotechnology: Incapacitating chemical agents

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Two recent pieces in Nature, an opinion and an editorial, discuss how non-lethal neuroactive chemical agents have been used by military forces (e.g. fentanyl-induced unconsciousness) and speculate about the potential development of more non-lethal weaponized chemicals (drug-induced lack of aggression, oxytocin-induced trust). Although using these chemical agents is prohibited by the Chemical Weapons Convention, an exception allows their use by law enforcement, for example, in domestic riot control (which may or may not include intrastate military actions).

The author of the opinion article is strongly opposed to allowing the military to use non-lethal chemical agents (including incapacitating agents that result in unconsciousness, like fentanyl), and recommends removing the exception for law enforcement. Some people, however, would like to see the CWC be amended to include a new exception permitting incapacitating agents to be used in warfare, which  increasingly takes place in population-dense areas where using lethal force could put civilians’ lives at risk.   The divergent views on policy regarding incapacitating neuroactive chemicals leads me to ask, what about these chemicals makes them more alarming than other weapons?  An understanding about why incapacitating chemical agents are uniquely worrisome should inform how they will be regulated.

Is it that they are difficult to defend against and therefore more effective? Is this a problem even though these weapons create non-lethal alternatives in otherwise deadly situations? Or is our real concern that, by incapacitating, they facilitate brutality toward a defenseless prisoner? If so, then the conversation should be about illegal soldier/police abuse, not the chemical agents themselves. Or is there something inherently unacceptable about militarized neuroactive chemical agents? Is acceptability determined by the intended effect (temporary unconsciousness)? By the mechanism (manipulating the brain)? By the amount of pain (fentanyl was developed as an anesthetic, so likely none)? By the size of its therapeutic index and how safe it is (when used to end a siege in a Moscow theater, fentanyl-derived gas killed 124 of the over 750 hostages)?

Should the Chemical Weapons Convention be amended to prohibit the use of incapacitating chemical agents by law enforcement?  Or to permit their use by the military?  Does permitting them in either context place us at the tip of a too steep slope of biological weapons with more prolonged and devastating effects (attacking fertility or the immune system)?  Or does it save lives?

Comments, thoughts, or answers welcome!

– Kelly Lowenberg

Why Everyone’s Afraid of the Big, Bad Socialist (and why it’s a sheep in wolves’ clothing)

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If you want to destroy a program, call it “socialist.”  Unfortunately, most people who invoke this term of late have no idea what it means.  For those defacing pictures of Obama to make him look like Hitler, Socialism is not Nazism.  Hitler was a fascist – meaning that he crushed opposition, symbols of power and race were paramount, and the nation was exalted above the people. Socialism, on the other hand, merely means that the government manages the production or distribution of certain goods.  For the love of God, please stop conflating socialism with the Nazis or communists. Socialism may be ugly in its extreme, but there is nothing ugly about many stripes of socialism.

Public education is socialist.  The preservation of streams and clean air is socialist.  Public libraries are socialist.  Requiring car insurance is socialist.  Disaster relief is socialist.  Medicare is socialist.

If Medicare is a federal program overseeing health benefits for those over 65, then why does it stir up hysteria when the government suggests a similar option for the rest of us who are under 65?   Probably because lobbyists have done a great job of confusing the issues.  They are making it seem like the government will take away your insurance and replace it with sub-standard care.  This is a misconception. The president’s current plan does not limit choice, it expands it.  If you are under-insured, the plan merely provides another option similar to what members of Congress have.  There would be no “death panel” that decides whether you receive care.   Rather, you would be given information on options and risks of intubation and feeding tubes, and YOU would decide what to do.  Incidentally, we have data that indicate that people who receive end-of-life counseling are not less likely to get care; in fact, it improves quality of life and attitude.

We also have data on health care reform.  It all points in the same direction.  We need to cut costs.  We need to insure more people and divorce employment from insurance.  We need to stop incentivizing the liberal ordering of unnecessary tests.  We need to realize that for every dollar we spend on futile measures, we are taking away resources from effective prevention and treatment.

When it comes to highly politicized issues, we almost never have access to the kind of data that we have here.  For starters, we know that Americans pay twice as much as other industrialized nations and we have far worse outcomes.  We rank in the bottom percentiles on life expectancy and infant mortality, and we have roughly two times the rate of heart disease, stroke, and diabetes. Apparently, more is less.

But insurance company lobbyists would have you believe that the status quo is amazing and no one wants change.  In order to get a sense of the true health care climate, what we really need to do is chat with those who are sick.  They will tell you that they spend their Saturdays fighting insurance companies to pay for claims. They are forced into bankruptcy due to cancer and they’re kicked out of their homes despite having a lifetime of good credit.  We need to stop listening to corn-fed cattle, herded to the townhall meetings by insurance lobbyists who are hoping to create a real-life episode of the Simpsons – complete with the mob psychology. Maybe if they confuse us enough we will shoot ourselves in the foot and squash important change.

But why is change so unattractive?  Are we dragging our feet because we believe that only other people get sick, and if they do, it’s their fault? Are we naively wedded to the American ideal that we don’t need the government to help us out of problems (unless, of course we are “too big to fail,” then please send the government checks.  Sincerely, Corporate America.)  Surely, now more than ever, we realize that none of us is immune from losing our jobs and insurance.

Health care is a public good – like libraries, education, and the environment.  Should the free market provide education, while poor kids slip through the cracks?  Should capitalism decide how much of our forests to destroy?  Of course not. We need to stop invoking socialism as an automatic conversation stopper.  Widespread socialism can be wasteful.  But in some cases, socialism is not only moral, it’s critical to the sustainability of our society.  — Teneille Brown

fMRI and Lying – An Interesting, Different Approach

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The number of published, peer-reviewed articles exploring the use of fMRI as a lie detector is now around 20 and at least two companies continue to sell fMRI-based lie detection services in the United States (in my much-repeated view, very prematurely).  A new article, though, uses fMRI in a different and interesting way to explore lying.

Josh Greene and Joseph Paxton have just published a paper in the Proceedings of the National Academy of Sciences looking cleverly at some of the processes involved in one kind of lying.  Greene and Paxton, Patterns of Neural Activity Associated with Honest and Dishonest Moral Decisions, PNAS 106:12506-12511 (July 28, 2009).

http://www.pnas.org/content/106/30/12506.full?sid=5e3b601b-662c-424d-aa90-1696fc469431

Greene and Paxton enrolled subjects in what they thought was a study of paranormal abilities to predict the future.  They were asked, while in a scanner, to predict the outcome of computer-generated, random coin flips.  Some of the time the subjects had to record their prediction in advance (the “no opportunity” condition), other times they just reported whether their prediction was correct after they were told the “true” result (the “opportunity” condition).   Each trial was a gamble of $3, 4, 5, 6, or 7 – a correct guess won that amount, an incorrect guess lost that amount.

They got useful data from 35 subjects, each of whom had 70 repetitions under the “opportunity” condition.  Fourteen of them were classed by the investigators as “honest” in the opportunity condition because they were right about 50% of the time.  Fourteen were classified as “dishonest” –  they were “right” 69 percent of the time or more, which should have happened fewer than one time in a thousand.  (The investigators do not accept their own cover story about paranormal ability!) Seven, who were right “too much” but not enormously too much, were classified as ambiguous.

The investigators talk about two models for honesty – “will” and “grace” (thus, perhaps, betraying that at least one of them watched television during the 1998-2006 run of Will and Grace).  The “will” model assumed one’s brain has to work harder to overcome the temptation to cheat.  The “grace” model assumes that some people never even considered cheating and that the cheaters’ brains would have to work harder.

The investigators looked at reaction time and found that the honest group had no significant response time differences in the opportunity and no opportunity conditions or between their wins and losses.   The dishonest group took longer in its opportunity condition “losses” than in its “wins” – took longer to decide to be honest.  It also took longer in its opportunity condition losses than the honest group did.

The fMRI data showed that the dishonest group had greater activation in the dorsolateral prefrontal cortex when it had opportunity “wins” (when it could have cheated to win) than with no opportunity wins.  It also showed more activation in the control network (anterior cingulate cortex, dorsolateral prefrontal cortex, and ventrolateral prefrontal cortex) when it had opportunity “losses” (decided not to cheat) than when it had no opportunity losses.  The honest group showed no differences.

So – at least in this kind of trial, honesty might be a matter of not thinking about cheating, not of controlling an impulse to cheat:  grace, not will.  The article has a much richer discussion of its findings than this poor summary, including a good summary of the limitations of the experiment and I recommend it.  It is particularly noteworthy among the fMRI-based lie detection tests in one way – it is based on “real” lies, situations where the research participant, on his or her own, decides to lie without being instructed to do so (and, in fact, has been at least implicitly instructed to tell the truth).  As such, it may tell us more about at least some kinds of lying than the usual experimental approaches.

Treating Heroin Addiction With Heroin?

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A study published in the August 20, 2009 issue of The New England Journal of Medicine and reported in The New York Times may challenge our conception of how to best treat opioid addiction. The study, conducted in Canada and led by Dr. Martin Schechter, shows promising results for using the active ingredient in heroin, diacetylmorphine, to treat people addicted to opioids, who do not respond to methadone treatment.  Currently no prescriptions can be written for heroin in the U.S.  Heroin is included in Schedule I of the Controlled Substances Act based on its high potential for abuse, the lack of any accepted medical use in the U.S., and the lack of accepted safety for use of the drug under medical supervision. Research on the efficacy of heroin maintenance treatment in reducing opioid dependence may call the basis of that classification into question.

Participants in the study, all of who had previously been unsuccessful in methadone treatment programs, were assigned to either take oral methadone (n=111) or injectable diacetylmorphine (n=115).  Another 25 subjects were given injectable hydromorphone (n=25) in order to verify the self-reported rates of heroin use through urine analysis. Both the participants and the investigators were aware of whether the assigned treatment was methadone or diacetylmorphine.  The assignment of the injectable treatments, however, was double-blind.  The injectables were administered under supervision, and methadone was dispensed at a pharmacy or clinic on a daily basis.

After one year of treatment, the patients receiving diacetylmorphine were more likely than those receiving methadone to have reduced rates of illegal activities including drug use (67% compared to 47.7%, p<.004), and to still be participating in the treatment program (87.8% compared to 54.1%, p<.001).  The diacetylmorphine group also showed “greater improvements with respect to medical and psychiatric status, economic status, employment situation, and family and social relations.”

Interestingly, the investigators “observed similar outcomes” from the two injectables, but did not have enough power to compare the conditions.  They note that if hydromorphone is as effective as diacetylmorphine, then it may be easier to employ as a treatment, avoiding the many hurdles associated with prescribing the active ingredient in heroin.

During the trial, diacetylmorphine was associated with a higher incidence of serious adverse events, raising questions about the safety of the drug.  Twenty-four of the 29 serious adverse events that were related to a study drug, occurred in the diacetylmorphine group (most commonly seizures and overdoses).  The investigators suggest that the drug should only be administered under close medical supervision, so the patient can be treated promptly in event of a seizure or overdose, as was the case in this study.

Based on the data, patients in both the methadone and the diacetylmorphine treatments improved.  The more dramatic improvement in the diacetylmorphine group among these participants indicates that using this drug may be an effective treatment for patients who are unresponsive to methadone treatment, and who would otherwise, having exhausted their medical options, exit the healthcare system and, likely, wind up entering the criminal justice system.

Although the clinical evidence is the first of its kind gathered in North America, European researchers have previously found similar results with heroin maintenance programs, and some countries have applied those findings.  According to Dr. Virginia Berridge’s editorial in the same issue of NEJM, doctors in Switzerland and the Netherlands have already begun prescribing heroin.

Berridge gives a thoughtful analysis of how attitudes about drugs and maintenance treatment depend on context: who the are people using them, the needs of the medical profession, whether the drug was first used as a “medical” drug or a “killer” drug, and how we define treatment and recovery.  Berridge’s editorial is an informative companion to the diacetylmorphine and methadone comparison study, pointing out that policy on treating drug addiction often depends as much on the political and social context as it does on scientific evidence.

– Kelly Lowenberg

Eulogy for John Barton

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I was asked by John’s family to speak at his memorial service on August 16.  Because of his important role in, among many other things, law and the biosciences, especially with regard to intellectual property issues, I thought it might be worthwhile to post here my comments on him.  They focus primarily on his role at Stanford Law School, but do (I hope) give some idea of the breadth and importance of his work and of the fundamental goodness of the man.  He is missed.

* * *

John H. Barton and Stanford Law School

One of the worst things about growing older is the ever increasing number of memorial services.  Sometimes, they do serve as celebrations of lives that had come, through old age or a long struggle with disease, to a natural completeness.  This death, though, was different.  It was tragically premature.  John was in great physical and mental shape and his inquiring spirit was always young.  His family and friends, his colleagues, and all the people around the world who have benefited from his work have been cheated of many more good years of John Barton.

But as John would have been the first to note, life is always uncertain and he had a good run.  It wouldn’t have been like him to complain – a little wistful disappointment, perhaps, but no complaints.  And so, we too should focus on our gratitude for having had so much of John, for so long, to celebrate.

This is particularly true for Stanford Law School.  John arrived at the law school as a first year student in September 1965, almost 44 years ago.  I want to spend the next few minutes telling those of you not from the law school a little bit about what he has meant to us.

John was not our typical law student, a hot shot just out of an elite undergraduate school.  In 1958 he graduated magnum cum laude from Marquette University with joint degrees in physics and in philosophy, an early sign of the breadth of his interests.  The next year, while serving in the Navy, he married Julie and they started their family.  After three years in the Navy, he went to work for a top-secret defense electronics firm.  (I doubt that discrete John ever told anyone what he did there).  As a result, he did not start law school until he was nearing 30, with a wife and four children.  (The fifth made his appearance during Christmas break, John’s second year.)

In 1965 Stanford Law School was in the middle of its steep ascent, from a good regional school, to a very good national school, to one of the world’s top law schools.  In spite of his family obligations and thirty hours a week of paying work throughout law school, John was a spectacular law student.  Our colleague John Merryman remembers John Barton as his student in first year Property. It was, John Merryman says, “the first time I realized the school was getting so good that some of the students were smarter than the faculty.”  He even had first year student John Barton teach one of his class sessions.

After graduating in 1968 (in a rare lapse, only second in his class), John spent one year working for a leading Washington D.C. law firm, Wilmer Cutler and Pickering.  (Those were the days when the largest law firm near Palo Alto had fewer than 20 lawyers.)  But after only a year we pulled him back to the law school. He started teaching in the fall of 1969 and won our teaching award, voted by the students, his very first year.  He was part of  our faculty for the next 40 years.

It’s not quite clear how old the Stanford Law School is – it depends on when you start counting, which may in turn depend on when the Development Office thinks it useful to declare an anniversary – but I estimate that John was at the law school with about half of the students the school has ever had and with about 80 percent of our living alumni.  He taught several thousand Stanford law students, helping them with everything from first year contract law to courses he helped to create, like international business transactions, law in radically different cultures, intellectual property as a business asset, and biotechnology law and policy.  Our colleague, Buzz Thompson was his student in the mid-1970s.  He remembers that John “was the epitome of the absent minded professor.  In those days of chalk, by the end of class, John would be covered by chalk dust — on the front of his shirt and jacket, on his side, on the seat of his pants.  But his lectures were consistently brilliant — packed with interesting and valuable insights.”

John was a particularly important teacher for our foreign graduate students.  The law school has long offered masters and doctoral degrees to lawyers from other countries.  These students, particularly in the doctoral program, can be difficult to teach.  Although they are all very intelligent, they come from many diverse cultures and bring with them vastly different levels of knowledge of the American legal system or American legal thinking – and of scholarly written English.  Even in his retirement, John always took foreign students.  He worked, hard, with them to improve their analysis and insights – and their written English.  He was truly tireless in that role and was greatly appreciated, and loved, for it – and, as a result, he helped populate and improve law faculties around the world.  We’ve gotten several emails from his former international students.  Here’s a sample, from Professor Yahong Li at the University of Hong Kong:

“I have been strongly influenced by his broad knowledge of law, technologies and society, his intellectual curiosity, his work ethic, his kindness, and his love for mankind.  I feel so fortunate to have had the opportunity to be his student, and he will live in my heart as a great mentor forever.”

John retired from the Law School in 2002, which meant that he stopped teaching – except, of course, for all the times when he was brought back to teach courses we needed, to supervise international students who otherwise would have fallen through the cracks, or to deliver guest lectures for colleagues, like me, bent on exploiting him.  In spite of these continuing teaching obligations, retirement increased, not diminished, his research and policy work.

Although I haven’t mentioned it yet, John was always first and foremost a scholar – not an ivory tower scholar but one who wanted to help make policy, with the dirty hands and the occasional scar to prove it.  John’s work covered a very broad range but three aspects of it are especially noteworthy. First, he was interested in how science and law intersected, including but not limited to intellectual property.  Second, he was interested in the whole world, not just the United States.  And third, he was interested in concrete problems, where solutions would make the world a better place.  In the first two, he was a decade or two ahead of his time – forty years ago he picked out fields that had not yet begun their enormous growth in importance to law schools.  In the third, he was timeless.

John’s first topic as an academic was nuclear weapons control.  He then became interested in agriculture – the Green Revolution and its possible successors.  And eventually he came to focus on human health, particularly but not solely through vaccines.  To all of these he brought an engagement with the science along with a deep knowledge and interest in the legal tools that shaped these problems and their possible solutions – public international law, trade law, environmental law, antitrust law, and, increasingly, intellectual property law.  He mastered these legal fields not just because they were fascinating but, primarily, because they were important for people’s lives, including the lives of billions of people who did not know they existed – and whose existence these areas of law often slighted

And so he fought for more food, better drugs, better vaccines, but he did it by working with all sides:  governments, non-governmental organizations, and multi-national corporations.  He idealized none of them, he demonized none of them – he recognized that all were crucial pieces of solutions.  I think John may have been happiest, in recent years, about his role several years ago as chair of the Commission on Intellectual Property Rights and Developing Countries.  It was extraordinary that the British government, which created this commission, should reach out to an American scholar to chair it, but then John was an extraordinary American scholar.

John’s bibliography shows nearly a hundred books, chapters, articles, and other writings.  Very few appear in law reviews, the standard home for our trade’s work.  He wrote and worked with hundreds of collaborators.  Few were law professors or even lawyers.   John was thoroughly interdisciplinary before interdisciplinary was cool – when it was unconventional and even a bit odd.  If that ever bothered him, or worried him, he never showed it.  He did work he thought was important, in the ways that it could best be done, whether or not that fit into the traditional mold of a law school, or law professor.  That mold ultimately changed, in part because John helped break it.

I’ve talked about what John did – what he taught and wrote, but a large part of John’s importance to the law school came from how he was.

Our dean, Larry Kramer, said this about John:

“To me, the most remarkable thing about John was his selflessness and good will.  He never pushed or sought anything for himself and he was always willing to extend himself for others.  He pitched in and just did what needed to be done—without complaint, without needing or seeking recognition.  Even in retirement, he was as active and engaged a colleague as anyone.  And always modest, soft-spoken, and gentle.”

Paul Goldstein calls him “that rarest of beings in the legal academy: a truly humble man.”

And Miguel Mendez recalls “the warm and respectful manner in which he treated everyone: faculty, staff, and students.”

Miguel’s words remind me of a scene from Pygmalion (and My Fair Lady).  Eliza accuses Higgens – Professor Higgins, note – of rudeness.  She holds up Colonel Pickering, who treats a flower girl like a duchess.  Higgins defends himself by saying he treats everyone the same; he treats a duchess like a flower girl.  John treated everyone equally well – with attention, concern, and respect – from the eccentric questioner at a talk to the newest and most clueless student, staff member . . . or colleague.

Pat Adan, who served as John’s assistant in recent years, told me the staff’s general feeling about John:  “Always a gentlemen, never a complaint, always courteous if something needed fixing, he was grateful for anything you did for him.”

Respect, courtesy, and gentleness were certainly important parts of John’s character.  But of his many virtues, the one that strikes me most powerfully was his integrity.  John did what he thought was right, whether or not it was popular or good for his career.  He never even seemed to think about doing anything else – he never seemed to be tempted, because doing anything other than the right thing never seemed to occur to him as an option.

There is a saying so old that it is in Latin:  De mortuis nil nisi bonum dicendum est – speak nothing but good of the dead.  As I realized what a long list of John’s virtues I would have, it occurred to me, as an academic matter, to try to find some failings.  There must have been some – I’m sure humble John would have treated us to a long list – but the best I could come up with was that he wasn’t great at telling jokes . . . although he was very good at laughing at them.

I want to end with a personal word.  To me, John was more than a colleague.  He was a friend, a mentor, a support, and a model of what one could do with an academic life.  I miss him, and I owe him.

And so does all of Stanford Law School – its faculty, alumni, students, and staff for the last 40 years.  We are, individually and collectively, in his debt.  It is comforting, though, to think that John will live on as part of the continuing fabric of the Law School, influencing, as an indelible part of the institution, the lives of countless more students, staff, and colleagues.

We are all worse for his too early death; we are all better for the life he lived so well.  We will miss him.

Professor John Barton is dead

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Stanford Law Professor John H. Barton died on August 3, 2009, nearly three weeks after a bicycle accident had put him into a coma.  John was 72 years old and had retired from Stanford Law School in 2002, but he remained an active presence at the School.  He was still excitedly working on new and continuing projects, mainly aimed at improving health in the developing world.

John graduated with from Marquette University in 1958 with degrees in philosophy and in physics. After three years of service in the US Navy, he worked for several years as an engineer.  In 1965 – married, with children – he became a 1L at Stanford Law School and had a brilliant student career.  After law school he worked as an associate for one year with the firm then known as Wilmer, Cutler, and Pickering before joining the Stanford Law School faculty in 1969.  Until last week, he never left.

From the beginning of his career John was fascinated by the intersections of science, law, and society.  He worked on nuclear weapons control, environmental problems, and human health, almost always with an international field of vision.  From his earliest faculty days through his death, he did not care whether he was doing traditional law professor work – he worked with scientists, lawyers, policy-makers, and anyone else in his effort to make the world a better place.

John was a man of integrity so great that I’m not sure he ever noticed it – I believe it never occurred him not to do the right thing.  He combined curiosity, intellectual rigor, and compassion better than anyone I have known.  He was a great mentor, a great friend, and a very good man. His friends, Stanford Law School, and the world are all diminished by his too early death, but we are all better as a result of his life.

Hank Greely