Cryonics never really delivered. But can we now develop the technology to preserve neural structures? Ken Hayworth thinks we can and advocates a brain preservation technology prize. It’s nice to see such big ideas.
The Atlantic‘s Joshua Shenk has a fascinating story about a long-running study, started in the 1930s (!), that attempts to discern what makes people happy in life. The study has collected extensive data on subjects over a 70 year period. I couldn’t stop reading the article… what an amazing dataset. But, before I say more about that, here is Shenk’s synopsis of a single case file (ie. actual data) from the study:
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. (more…)
I came across this fantastic review of tools for the Genetic Dissection of Neural Circuits in Neuron a few days ago. It’s by Liqun Luo, Ed Callaway, and Karel Svoboda. I highly recommend it, as it spans the gamut from genetic targeting (recombination, binary logic, viral delivery) to circuit reconstruction (super resolution LM, EM, brainbow) to activity modulation and functional mapping (uncaging, artificial GPCRs, light-gated channels, MIST). I don’t think I’ve ever seen quite a review of so many cutting edge neurotechnologies in one place. I can’t recommend this piece enough really. For me, with my lack of molecular expertise, the first sections on combinatorial gene targeting/expression techniques were great, pulling together Gal4, Cre/Flp, and Tet systems into a unified framework, along with more general concepts like site-directed integration, enhancer-trap, and repressor trap (eg. Thy1 mice).
Over the last week, it seems like everyone has sent me this NYT piece on PKM-zeta (about work in Todd Sacktor’s lab). I’m not sure why this work is being featured in the Times right now, since it’s a few years old. But it was news to me and I think it is of interest to anyone trying to understand structure-function relationships in the brain. In the original Science paper (from 2007), a pseudosubstrate inhibitor of PKM-zeta caused irreversible loss of a conditioned taste aversion memory (news and views here). I was unfamiliar with PKM-zeta, which appears to be a constitutively active form of PKC-zeta (a kinase that some might be more familiar with) and that lacks the autoinhibitory regulatory domain of PKC. The amazing phenomena is that, after treatment with ZIP (the pseudosubstrate that ties up PKM-zeta), the memory is permanently erased and doesn’t seem to return.
What’s going on? One tantalizing possibility is that the enzyme itself is directly related to the memory trace. This contradicts the (unproven) assumption of modern neuroscience that memories are stored solely in the synaptic strengths (ie. membrane-bound receptors) of a neuron. The other suggestion is that PKM-zeta is actively maintaining synapses and that enzymatic inhibition disrupts the precise maintenance of receptors or synaptic machinery. The effects happen quite fast (within 2 hours after drug injection), which seems short for receptor recycling but perhaps long enough for structural change to occur. I’m no expert on receptor movement: Is 2 hours long enough to add/remove a significant number of receptors?
Fascinating work but the method is blunt, wiping all experimentally-induced memories (and probably others too). Last month, another group reported (also in Science) selective erasure of a fear-conditioned memory using an interesting new genetic tool. Here, neurons in the amgydala that overexpressed CREB were found to be preferentially recruited into a fear memory trace (as shown in a previous Science paper). Incorporation into the memory trace was assayed by expression of the immediate-early gene (ie. activity-dependent) Arc. In the present study, they combine overexpression of CREB in a subset of neurons with cell death (via Diphtheria toxin in a transgenic mouse vulnerable to diphtheria). Apparently, normal mice lack the receptor (here a simian version is used) that confers pathogenicity for diphtheria. Thus, the viral construct both overexpresses CREB in a subset of neurons and selectively makes the same subset vulnerable to diphtheria. Ablation of just these neurons causes a permanent loss of the memory. Subsequent similar learning proceeds just fine (using the remaining neurons).
Can we say that the race is officially on to ablate just the synapses involved in the memory? I think so. Extra points if the ablation is reversible too!
Although I’ve been a longtime fan of Ramachandran’s excellent book Phantoms in the Brain, this TED talk is like a compressed summary of the highlight’s of his research. He’s a great speaker and he covers in 20 minutes my two favorite examples in the book (Capgras delusion and mirror treatment for phantom limb syndrome). Perhaps the best part of the talk is that, after listening to it, I was convinced more than ever before of the statistical nature of sensory perception (ie. the brain attempts to find the most likely explanation for sensory observations) and the integrative nature of central processing of multiple modalities.
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.
Harvard Medical School in Ethics Quandary [NYT]
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.
Brain, Machine and In-Between from Nature Opinion forum on Nature Network
Nature sent me a press release about this today and it seemed like it might be of interest to ND readers. There is also a related commentary in the journal this week.
Today’s NYT has a fascinating article about NIH‘s new Undiagnosed Diseases Program.
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.
The First International Conference on Neuroprosthetic Devices will take place at National Chiao Tung University, Hsinchu, Taiwan on March 19th and 20th, 2009. The mission of this newly founded conference is to foster West-East interaction and collaboration in the rapidly advancing clinical use of neuroprosthetics. The specific aim of the first conference is to expose unique technological and neurological research opportunities in Taiwan. National Chaio Tung University is one of the best universities in Taiwan and is located right next to the world-famous HsinChu Science Park hosting hundreds of biotechnology, semiconductor, and electronics companies.
The conference sessions will cover several key areas in the neuroprosthetic development, such as deep brain stimulation for treatment of Parkinson’s disease and epilepsy, devices for restoring hearing and overcoming muscle paralysis, microelectrode biocompatibility, and novel microelectrode technologies. For detailed conference program and registration information, please visit http://www.bsrc.nctu.edu.tw/ICND/.
Bi-stable neural state switches : Article : Nature Neuroscience
Another channelrhodopsin breakthrough from Deisseroth’s lab. This time light is not required to keep the channel open. Light merely triggers opening and closing behavior. Blue-shifted light opens channels and red-shifted light closes them. This looks like another potentially powerful neurotechnology for interrogating circuits and systems.
Relevant fig:
