Case No. 158

An attractive, amiable boy from a working-class background, you struck the study staff as happy, stable, and sociable. “My general impression is that this boy will be normal and well-adjusted—rather dynamic and positive,” the psychiatrist reported.

After college, you got an advanced degree and began to climb the rungs in your profession. You married a terrific girl, and you two played piano together for fun. You eventually had five kids. Asked about your work in education, you said, “What I am doing is not work; it is fun. I know what real work is like.” Asked at age 25 whether you had “any personal problems or emotional conflicts (including sexual),” you answered, “No … As Plato or some of your psychiatrists might say, I am at present just ‘riding the wave.’” You come across in your files as smart, sensible, and hard-working. “This man has always kept a pleasant face turned toward the world,” Dr. Heath noted after a visit from you in 1949. From your questionnaire that year, he got “a hint … that everything has not been satisfactory” at your job. But you had no complaints. After interviewing you at your 25th reunion, Dr. Vaillant described you as a “solid guy.”

Two years later, at 49, you were running a major institution. The strain showed immediately. Asked for a brief job description, you wrote: “RESPONSIBLE (BLAMED) FOR EVERYTHING.” You added, “No matter what I do … I am wrong … We are just ducks in a shooting gallery. Any duck will do.” On top of your job troubles, your mother had a stroke, and your wife developed cancer. Three years after you started the job, you resigned before you could be fired. You were 52, and you never worked again. (You kept afloat with income from stock in a company you’d done work for, and a pension.)

Seven years later, Dr. Vaillant spoke with you: “He continued to obsess … about his resignation,” he wrote. Four years later, you returned to the subject “in an obsessional way.” Four years later still: “It seemed as if all time had stopped” for you when you resigned. “At times I wondered if there was anybody home,” Dr. Vaillant wrote. Your first wife had died, and you treated your second wife “like a familiar old shoe,” he said.

But you called yourself happy. When you were 74, the questionnaire asked: “Have you ever felt so down in the dumps that nothing could cheer you up?” and gave the options “All of the time, some of the time, none of the time.” You circled “None of the time.” “Have you felt calm and peaceful?” You circled “All of the time.” Two years later, the study asked: “Many people hope to become wiser as they grow older. Would you give an example of a bit of wisdom you acquired and how you came by it?” You wrote that, after having polio and diphtheria in childhood, “I never gave up hope that I could compete again. Never expect you will fail. Don’t cry, if you do.”

What fascinates me is the absolute novelty of this kind of data. Normally, when someone relates their “life story,” we willingly participate in something of a shared lie. Both listener and story-teller know that the “life story” is being told in hindsight: Memory is not perfect and humans sometimes (often, perhaps) add meaning and create unifying themes in stories where they may be none. We emphasize the good parts and try to forget the not-so-good parts. In a sense, history recounted is never truly veridical but instead tainted with everything that happened after. Which is precisely why the availability of an objective history than spans an entire lifetime (or, as objective as possible) of both a qualitative (interview) and quantitative (medical) nature is so novel.

As you might expect, the data is confusing and hard conclusions are not easy to come by. There are however some tangible factors that seemed to correlate/predict success in life, which I’ve included after the jump. What predicts success in life? What predicts failure?

What allows people to work, and love, as they grow old? By the time the Grant Study men had entered retirement, Vaillant, who had then been following them for a quarter century, had identified seven major factors that predict healthy aging, both physically and psychologically.

Employing mature adaptations was one. The others were education, stable marriage, not smoking, not abusing alcohol, some exercise, and healthy weight. Of the 106 Harvard men who had five or six of these factors in their favor at age 50, half ended up at 80 as what Vaillant called “happy-well” and only 7.5 percent as “sad-sick.” Meanwhile, of the men who had three or fewer of the health factors at age 50, none ended up “happy-well” at 80. Even if they had been in adequate physical shape at 50, the men who had three or fewer protective factors were three times as likely to be dead at 80 as those with four or more factors.

What factors don’t matter? Vaillant identified some surprises. Cholesterol levels at age 50 have nothing to do with health in old age. While social ease correlates highly with good psychosocial adjustment in college and early adulthood, its significance diminishes over time. The predictive importance of childhood temperament also diminishes over time: shy, anxious kids tend to do poorly in young adulthood, but by age 70, are just as likely as the outgoing kids to be “happy-well.” Vaillant sums up: “If you follow lives long enough, the risk factors for healthy life adjustment change. There is an age to watch your cholesterol and an age to ignore it.”

The study has yielded some additional subtle surprises. Regular exercise in college predicted late-life mental health better than it did physical health. And depression turned out to be a major drain on physical health: of the men who were diagnosed with depression by age 50, more than 70 percent had died or were chronically ill by 63. More broadly, pessimists seemed to suffer physically in comparison with optimists, perhaps because they’re less likely to connect with others or care for themselves.

There is also a nice video of the George Valliant (who has run the study for the last 40 years) along with the article.

Atul Gawande also recently wrote a New Yorker article about treating phantom itch with Ramachandran’s mirror box. I found this part of Gawande’s article on statistical inference in perception most interesting:

You can get a sense of this from brain-anatomy studies. If visual sensations were primarily received rather than constructed by the brain, you’d expect that most of the fibres going to the brain’s primary visual cortex would come from the retina. Instead, scientists have found that only twenty per cent do; eighty per cent come downward from regions of the brain governing functions like memory. Richard Gregory, a prominent British neuropsychologist, estimates that visual perception is more than ninety per cent memory and less than ten per cent sensory nerve signals. When Oaklander theorized that M.’s itch was endogenous, rather than generated by peripheral nerve signals, she was onto something important.

I’m not familiar with this field but I wonder if anyone has tried to quantify what percent of our conscious experience that we normally believe to be 100% due to sensory input is actually recall from memory/inference based on past observation. Also, can this percentage adaptively change? Perhaps there are situations where the brain chooses to rely more heavily on memory and other cases where it relies more on primary sensory input.

Apparently, Harvard gets one of the worst grades among med schools for mixing drug company money with research with very little regulation:

BOSTON — In a first-year pharmacology class at Harvard Medical School, Matt Zerden grew wary as the professor promoted the benefits of cholesterol drugs and seemed to belittle a student who asked about side effects.

Mr. Zerden later discovered something by searching online that he began sharing with his classmates. The professor was not only a full-time member of the Harvard Medical faculty, but a paid consultant to 10 drug companies, including five makers of cholesterol treatments.

“I felt really violated,” Mr. Zerden, now a fourth-year student, recently recalled. “Here we have 160 open minds trying to learn the basics in a protected space, and the information he was giving wasn’t as pure as I think it should be.”

Mr. Zerden’s minor stir four years ago has lately grown into a full-blown movement by more than 200 Harvard Medical School students and sympathetic faculty, intent on exposing and curtailing the industry influence in their classrooms and laboratories, as well as in Harvard’s 17 affiliated teaching hospitals and institutes.

UPDATE: The NYT is reporting that at US Senator Chuck Grassley has asked Pfizer to provide details of its payments to 149 HMS faculty members (a frankly astonishing number) and for more information about a Pfizer employee taking pictures at a demonstration by med students against corporate influences at HMS.

The program’s methodology is still evolving, but for the first dozen or so patients it worked this way: A primary-care physician sent in a letter describing the case, followed by reams of records documenting the diagnostic dead ends the patient had already confronted. Gahl personally reviewed all the cases and discarded about three-quarters of them, usually because the problem was insufficiently documented, seemed to be psychosomatic or, for some other reason, left Gahl with the impression that the N.I.H. had little new to offer. Then he took the most promising cases to his medical-review board, made up of several dozen clinical investigators from all over the N.I.H. The board reviewed 10 or so cases at each monthly meeting, out of which it accepted just a handful, the ones that seemed most likely to lead to a new insight into a known disease, or, even better, to a diagnosis of a disease never before seen. Then Gahl’s staff arranged to bring in each patient for a week of assessment in Bethesda. There, the patient would meet an array of specialists who did physical exams, took histories and conducted whatever additional tests they needed: ultrasound scans, M.R.I. scans, X-rays, electroencephalograms, maybe a spinal tap or a biopsy of skin or other tissue.

This approach seems in many ways more fruitful than bouncing patients from one specialist to another. Instead get the specialists together for a short period and focus on the patient. But even more tantalizing are the long-term goals:

Gahl’s projected success rate is so low because his aim is so high. His holy grail is a molecular diagnosis: finding not just a description of a new disease but also an understanding of how it works at the level of the gene. With this goal, the Undiagnosed Diseases Program aspires to be a model for how genomic medicine will be done in the 21st century.

The article documents NIH use of a “one-million SNP chip” on these patients and discovering potential molecular targets by combining insertion-deletion analysis with standard practice differential diagnosis. Combined with the recent addition of the National Center for Complementary and Alternative Medicine, NIH seems to be focusing on building clinical expertise in more integrative medicine.

Right now, it appears that there’s a bit of controversy in the field. Earlier this year, in Science, a group from Rockefeller found that DEET masked sensitivity to human odors by interfering with a particular odorant receptor. This impressive result was recently question by entomologists from UC-Davis in a PNAS paper claiming that DEET acts directly on a particular olfactory receptor neuron and does not attenuate the response to the same human-emitted odorant, as found in the earlier paper. Although the results appear to be conflicting, the studies use different techniques and thus it is likely that DEET’s action might be more complex than either paper claims. Still, the idea of identifying a target for chemical intervention by looking at electrophysiological responses to DEET is smart.

In related work, earlier this year a group from Colorado State University, as described in this PNAS overview, “conducted a rigorous search of a library of N-acylpiperidines, using an artificial neural network to identify strong candidates, and then tested them in the laboratory on human volunteers.” They found a candidate molecule that has a ~4X longer repellency effect than DEET. Here’s a photo from the experiments (DEET vs. untreated hand)… ouch!

Surprising facts from the video:

1. 23andme co-founder Anne Wojcicki is married to Google co-founder Sergei Brin
2. Data portability is already available. According to the video, users can download the raw data from the 580,000 SNP array and do whatever they want with it.
3. The SNP array is 580,000 SNPs! Wow. I assumed that the number of genetic features was on the order of 100-1000, giving a rough haplotype.
4. Sharing/Web 2.0 features: The real power is 23andwe, an effort to data mine and leverage the power of a large database with many people’s genetic information. The founders mention that they want to contribute back to science and healthcare by surveying their customers behaviors and medical issues to uncover further correlations with genes. Like Facebook, the service becomes more valuable and more informative as the network grows.

Description of the talk from Google:

The 23andMe Personal Genome Service offers customers a glimpse at their own DNA sequence, a 750-megabyte string that functions as the operating system for a human being. Common variations in this code can influence the structure and function of the associated wetware in predictable ways. Some of these variations and their effects on traits such as athletic talent, pain sensitivity and avoidance of errors will be discussed in reference to three well-documented examples.

There was a high rate of treatment discontinuation due to adverse events; 15.7% in the rimonabant 20mg group compared to 7.8% in the placebo group.

For more info, see page 33 of EMEA(Europe’s FDA)’s Scientific Discussion document.

This strengthens my earlier stance that patients should weigh the decision of whether to chronically consume a CB1 antagonist as carefully as if they were considering regularly taking a CB1 agonist (such as marijuana).

For decades, psychiatrists have known that users of PCP, a street drug sometimes called angel dust, have symptoms nearly identical to those of people with schizophrenia. By the 1980s, scientists had discovered that PCP blocked brain receptors that are triggered by an amino acid called glutamate. This led some companies and scientists to study ways to stimulate glutamate receptors as a treatment for schizophrenia.

But the brain has many different kinds of glutamate receptors, and figuring out how to stimulate or block them in medically beneficial ways has proved complicated. Instead of focusing on the receptors blocked by PCP, Dr. Schoepp concentrated on modulating the action of glutamate receptors in the brain’s prefrontal cortex, an area responsible for personality and learning.

The drug, “LY2140023″, is an mGlu2/3 agonist. It showed statistically significant results in a (mid-sized?) clinical trial. Here’s the paper:

Sandeep T Patil, Lu Zhang, Ferenc Martenyi, Stephen L Lowe, Kimberley A Jackson, Boris V Andreev, Alla S Avedisova, Leonid M Bardenstein, Issak Y Gurovich, Margarita A Morozova, Sergey N Mosolov, Nikolai G Neznanov, Alexander M Reznik, Anatoly B Smulevich, Vladimir A Tochilov, Bryan G Johnson, James A Monn & Darryle D Schoepp. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine 13, 1102 – 1107 (2007).

Neurocritic also has a blog post about this.

Is there a future for therapeutic use of transcranial magnetic stimulation?

The past year has seen the publication of a remarkable number of papers about the potential therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in conditions ranging from cocaine addiction to stroke and depression. Are we witnessing the discovery of a miraculous cure-all or will this bubble burst like the magnetotherapies of the Victorian era1? We argue below that there is good evidence that rTMS can produce after-effects on the brain, and that these translate into effects on simple behaviours. However, the rationale for applying the same methods to treat disease is in many cases unclear.

Guest speakers on May 9th will include MIT professors (Roz Picard, Hugh Herr, myself, etc.) and many acclaimed speakers such as Oliver Sacks and John Donoghue. Registration may be close to being full, but it will be webcast.

More information at:
http://h20.media.mit.edu

- Ed