Personalized genetics and medicine

An article by Pauline C. Ng, Sarah S. Murray, Samuel Levy and J. Craig Venter finds differences in results from two direct to consumer genetics testing companies. Their summary:

* For seven diseases, 50% or less of the predictions of two companies agreed across five individuals
* Companies should communicate high risks better and test for drug response markers
* Community should study markers in all ethnicities and look at behaviour after tests

Also Lahn and Ebenstein argue that the discovery of genetic diversity among groups of people as well as among individuals should be embraced, not feared. Their summary:

* Promoting biological sameness in humans is illogical, even dangerous
* To ignore the possibility of group diversity is to do poor science and poor medicine
* A robust moral position is one that embraces this diversity as among humanity's great assets

Gene therapy restores vision to color-blind monkeys

An Editor's summary in the Oct. 8 Nature describes a remarkable finding, and Shapley discusses the work described in the paper by Mancuso et al. :

It is often assumed that critical periods exist for the development of vision and other neural capabilities and that they end prior to adolescence. For example, it might be expected that gene therapy in adults with congenital vision disorders would be impossible. But experiments in adult spider monkeys who are normally red–green colour blind show that it is possible to add a third photopigment (human opsin) into some of their retinal cells by gene therapy. The monkeys acquire a new dimension of colour vision as a result. Not only does this suggest a possible therapy for a common congenital visual defect in humans (clinical trials are now under way), but also it demonstrates the extreme neuroplasticity of visual processing and points to possible routes by which trichromatic vision evolved.

How nonsense sharpens our intellect

Benedict Carey points to an article in Psychological Science that I scanned past without realizing its interest. Proulx and Heine show that a threat to our sense of coherence or meaning in one area (such as reading an absurd short story by Kafka) enhances our ability to unconsciously detect patterns within letter strings (an artificial grammar task). Encountering incoherence apparently primes our brains to detect patterns they might otherwise miss. The idea is that the brain evolved to predict, and it does so by identifying patterns. The process is enhanced by a threat to meaning. (It is also important to evaluate the possibility that nervousness, not a search for meaning, leads to heightened vigilance.)

Mummy Recipe Hard to Follow

Another gem from the Random Samples section of the Oct. 2 Science Magazine:

Frank Rühli wants to know just how the Egyptians did it. So he is trying to mummify human legs.

Rühli, a physician and head of the Swiss Mummy Project at the University of Zurich, and his collaborators severed the legs from a female donor body. One, the "control leg," was kept in an oven at 40°C and low humidity to replicate "natural mummification" in the Egyptian desert. The other leg, as described in ancient Egyptian records, was put on a pine board and covered with natron, a blend of four sodium compounds that pulls moisture out of the tissue. The researchers left it at 23°C to see what natron would do in the Swiss environment.

Other researchers have tried mummifying human remains. But the Swiss group is using advanced imaging technology, biopsies, and tests of DNA degradation for moment-by-moment analysis of the mummification process.

So far, the researchers have found that mummification in Zurich takes longer than expected: After 3 months, scans showed that the natron leg still had pockets of humidity, Rühli says. They have also discovered that storing an untreated leg in the heat doesn't work well. The control leg failed to dry out and started to decompose after a week. Rühli plans to repeat the experiment, this time encasing the control leg in hot sand.

Where our brain computes value.

From Chib et al.:

To make economic choices between goods, the brain needs to compute representations of their values. A great deal of research has been performed to determine the neural correlates of value representations in the human brain. However, it is still unknown whether there exists a region of the brain that commonly encodes decision values for different types of goods, or if, in contrast, the values of different types of goods are represented in distinct brain regions. We addressed this question by scanning subjects with functional magnetic resonance imaging while they made real purchasing decisions among different categories of goods (food, nonfood consumables, and monetary gambles). We found activity in a key brain region previously implicated in encoding goal-values: the ventromedial prefrontal cortex (vmPFC) was correlated with the subjects' value for each category of good. Moreover, we found a single area in vmPFC to be correlated with the subjects' valuations for all categories of goods. Our results provide evidence that the brain encodes a "common currency" that allows for a shared valuation for different categories of goods.

Shrinking the Shrinks

From the Random Samples section of the Oct. 2 Science Magazine (I was not successful in spotting the report mentioned on the APS website):

Many training programs for clinical psychologists in the United States should be scrapped, an organization of psychologists says. In a report to be released this month, the Association for Psychological Science (APS) calls for more scientific rigor in psychotherapy. "Clinical psychology resembles medicine at a point in its history when practitioners were operating in a largely prescientific manner," it says. Therapists' "lack of adequate science training ... leads them to value personal clinical experience over research evidence." The report lambastes the American Psychological Association (APA)—which comprises mainly clinical psychologists—for lax accreditation standards and proposes a new mechanism for certifying Ph.D. training programs.

Psychologist Scott Lilienfeld of Emory University in Atlanta praises the report, saying, "Far too many practitioners are administering unsubstantiated or untested intervention." But he worries that its proposals would freeze out Psy.D. programs, nonresearch degrees begun in the 1970s, which now turn out about half of the nation's clinical psychologists.

Jeffrey Zeig, a clinical psychologist and director of the Milton H. Erikson Foundation in Phoenix, says psychotherapy is much too diverse to be constrained by APS definitions. "There are more than 1,000,000 therapists in the U.S., and only a fraction" have Ph.D.s, says Zeig, who predicts the report "will have as much effect as a breeze has on a leaf."

But report co-author Timothy Baker of the University of Wisconsin School of Medicine and Public Health in Madison predicts that it "will ultimately reshape clinical psychology just as the [1910] Flexner Report reshaped medicine," leading to the closure of almost half the nation's medical schools.

The high price of being a gay couple.

My partner and I live in Madison, Wisconsin. The state legislature recently passed a bill granting domestic partnerships a small fraction of the benefits that go with conventional marriage (like being able to visit your ill partner in the hospital, or by default have health care or legal power of attorney if one partner is incapacitated.) This bill is being challenged in court by the same right wing religious nuts who backed the successful drive to add a state constitutional amendment banning gay marriage. I've become acutely aware of some of the financial downside of being a gay couple over the past 20 years of my current partnership, having been in a conventional marriage for 21 years before that. Now some hard numbers on just how unfair the situation is have been generated by Bernard and Lieber in the New York Times. The lifetime penalty for being in a same-sex couple can range between ~$30,000 and ~$200,000, depending on the circumstance.

How our brain's hard wiring is hooked by texting, twitter, email, googling...

As a companion to the previous post on distinguishing 'wanting' and 'liking' I would like to point you to an engaging article in Slate by Emily Yoffe (thanks to my son Jon for pointing it out to me). She discusses the work from researchers like Jaak Panksepp and Kent Berridge (the subjects of several mindblog posts over the past few years) that suggests the biological basis of our addiction to email, google, twitter, texting, etc.

The juice that fuels the seeking system is the neurotransmitter dopamine. The dopamine circuits "promote states of eagerness and directed purpose," Panksepp writes. It's a state humans love to be in. So good does it feel that we seek out activities, or substances, that keep this system aroused—cocaine and amphetamines, drugs of stimulation, are particularly effective at stirring it.

Ever find yourself sitting down at the computer just for a second to find out what other movie you saw that actress in, only to look up and realize the search has led to an hour of Googling? Thank dopamine. Our internal sense of time is believed to be controlled by the dopamine system. People with hyperactivity disorder have a shortage of dopamine in their brains, which a recent study suggests may be at the root of the problem. For them even small stretches of time seem to drag. An article by Nicholas Carr in the Atlantic last year, "Is Google Making Us Stupid?" speculates that our constant Internet scrolling is remodeling our brains to make it nearly impossible for us to give sustained attention to a long piece of writing. Like the lab rats, we keep hitting "enter" to get our next fix.

Wanting is Berridge's equivalent for Panksepp's seeking system. It is the liking system that Berridge believes is the brain's reward center. When we experience pleasure, it is our own opioid system, rather than our dopamine system, that is being stimulated. This is why the opiate drugs induce a kind of blissful stupor so different from the animating effect of cocaine and amphetamines. Wanting and liking are complementary. The former catalyzes us to action; the latter brings us to a satisfied pause. Seeking needs to be turned off, if even for a little while, so that the system does not run in an endless loop. When we get the object of our desire (be it a Twinkie or a sexual partner), we engage in consummatory acts that Panksepp says reduce arousal in the brain and temporarily, at least, inhibit our urge to seek.

But our brains are designed to more easily be stimulated than satisfied. "The brain seems to be more stingy with mechanisms for pleasure than for desire," Berridge has said. This makes evolutionary sense. Creatures that lack motivation, that find it easy to slip into oblivious rapture, are likely to lead short (if happy) lives. So nature imbued us with an unquenchable drive to discover, to explore. Stanford University neuroscientist Brian Knutson has been putting people in MRI scanners and looking inside their brains as they play an investing game. He has consistently found that the pictures inside our skulls show that the possibility of a payoff is much more stimulating than actually getting one.

Actually all our electronic communication devices—e-mail, Facebook feeds, texts, Twitter—are feeding the same drive as our searches. Since we're restless, easily bored creatures, our gadgets give us in abundance qualities the seeking/wanting system finds particularly exciting. Novelty is one. Panksepp says the dopamine system is activated by finding something unexpected or by the anticipation of something new. If the rewards come unpredictably—as e-mail, texts, updates do—we get even more carried away. No wonder we call it a "CrackBerry."

"Wanting" what was never "liked"

Work from Berridge and collaborators shows in rat experiments that pathways in the ventral pallidum that fire when a cue to a previously liked stimulus (such as sucrose) is presented - but do not fire with a cue of the previously "disliked" taste of intense salt - can suddenly become activated if the salt cue is encountered in a never-before-experienced state of physiological salt depletion. This means that dynamic recomputation of cue-triggered "wanting" signals can occur in real time at the moment of cue re-encounter by combining a previously learned Pavlovian associations with novel physiological information about a current state of specific appetite.

Long live quest gets respect? The 120 Club.

Nicholas Wade notes a recent meeting on aging at Harvard Medical School (Some of the participants belong to the "120 Club," whose members propose to live until they are 120). His article focuses on work of David Sinclair and Sirtris Pharmaceuticals .

...In mice, sirtuin activators are effective against lung and colon cancer, melanoma, lymphoma, Type 2 diabetes, cardiovascular disease and Alzheimer’s disease...SRT-501, the company’s special formulation of resveratrol, is being tested against two cancers, multiple myeloma and colon cancer that has spread to the liver. A chemical mimic of resveratrol, known as SRT-2104, is in a Phase 2 trial for Type 2 diabetes, and in a Phase 1 trial in elderly patients. (Phase 1 trials test for safety, Phase 2 for efficacy.)...unpublished tests in mice showed that another chemical mimic, SRT-1720, increased both health and lifespan; after two years, twice as many mice taking the drug were alive compared with the undosed animals. Resveratrol itself has not been shown to increase lifespan in normal mice, although it does so in obese mice, laboratory roundworms and flies.

Brain organization of our defensive fear system.

Mobbs et al. show that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast more "hard-wired" defensive reactions mediated by our midbrain.

Seeing our body reduces pain

An interesting report from Longo et al. :

Given previous reports of strong interactions between vision and somatic senses, we investigated whether vision of the body modulates pain perception. Participants looked into a mirror aligned with their body midline at either the reflection of their own left hand (creating the illusion that they were looking directly at their own right hand) or the reflection of a neutral object. We induced pain using an infrared laser and recorded nociceptive laser-evoked potentials (LEPs). We also collected subjective ratings of pain intensity and unpleasantness. Vision of the body produced clear analgesic effects on both subjective ratings of pain and the N2/P2 complex of LEPs. Similar results were found during direct vision of the hand, without the mirror. Furthermore, these effects were specific to vision of one's own hand and were absent when viewing another person's hand. These results demonstrate a novel analgesic effect of non-informative vision of the body.

When errors are rewarding

de Bruijn et al. show a clear distinction between error and reward processing in our brains:

For social beings like humans, detecting one's own and others' errors is essential for efficient goal-directed behavior. Although one's own errors are always negative events, errors from other persons may be negative or positive depending on the social context. We used neuroimaging to disentangle brain activations related to error and reward processing, by manipulating the social context (cooperation or competition). Activation in posterior medial frontal cortex (pMFC) was increased for all errors, independent of who made the error or the reward outcome. Conversely, activity in striatum was modulated by reward, independent of whether the action was erroneous or not. The results demonstrate a clear distinction between error and reward processing in the human brain. Importantly, the current study indicates that error detection in pMFC is independent of reward and generalizes beyond our own actions, highlighting its role in optimizing performance in both individual and joint action.

The anxious temperament.

There is an engaging article by Henig in yesterday's New York Times Magazine: "Understanding the anxious mind." It focuses on the famous work of Jerome Kagan at Harvard; who, along with others, has shown that some of us are born with a predisposition to be timid and anxious.

Memory consolidation - a shift from hippocampal to neocortical sites

Work from Takashima et al. confirms the idea that the retrieval network for memories shifts away from using the hippocampus as the memories grow older and are consolidated in the neocortex. They use MRI measurement to observe this shift:

The standard model of system-level consolidation posits that the hippocampus is part of a retrieval network for recent memories. According to this theory, the memories are gradually transferred to neocortical circuits with consolidation, where the connections within this circuit grow stronger and reorganized so that redundant and/or contextual details may be lost. Thus, remote memories are based on neocortical networks and can be retrieved independently of the hippocampus. To test this model, we measured regional brain activity and connectivity during retrieval with functional magnetic resonance imaging. Subjects were trained on two sets of face–location association and were tested with two different delays, 15 min and 24 h including a whole night of sleep. We hypothesized that memory traces of the locations associated with specific faces will be linked through the hippocampus for the retrieval of recently learned association, but with consolidation, the activity and the functional connectivity between the neocortical areas will increase. We show that posterior hippocampal activity related to high-confidence retrieval decreased and neocortical activity increased with consolidation. Moreover, the connectivity between the hippocampus and the neocortical regions decreased and in turn, cortico-cortical connectivity between the representational areas increased. The results provide mechanistic support for a two-level process of the declarative memory system, involving initial representation of new associations in a network including the hippocampus and subsequent consolidation into a predominantly neocortical network.

Mindblog backlog...

Another compilation of items that are potentially interesting to some MindBlog readers:

Two Blogs of interest: Body in Mind (self explanatory) and Phenomics (on more intelligent description of personality dysfunction based on underlying genetic heterogeneity, and how the the Diagnostic and Statistical Manual of Mental Disorders actually impedes research and understanding.)

The robot that breaks and reassembles itself.

Why we need God. From Robert Wright, author of “The Moral Animal,” “Nonzero” and, most recently, “The Evolution of God.”

Eyes Wide Shut - perceived emotionality of music, eye closure, and the amygdala.

Brain pathology in athletes appears at an unusually young age.

Numbers in the Blind's “Eye.” Both blind and sighted people represent numbers through a spatial code, but with different electrophysiological correlates corresponding to cognitive versus sensory processing.

Gates Puts Feynman Lectures Online. These famous lectures can show you that there really is joy in physics. I was overwhelmed when I first saw some of them in my college days.

Knowledge rewards. It turns out that the size of coming rewards is signalled by the same dopamine neurons that signal primitive rewards like sex and food. Two monkeys were trained to glance at one of two targets on a computer screen in order to receive a drink reward, which was randomly large or small. When one target included information about reward size the monkeys preferred to go for that target, rather than be surprised by a randomly sized reward. Neurons in the brain's 'reward' circuitry fired when the monkeys learned information about the future, suggesting that the act of prediction may be intrinsically rewarding.

Yet another theory on why we sleep ...suggestion that sleep evolved to optimize animals’ use of time, keeping them safe and hidden when the hunting, fishing or scavenging was scarce and perhaps risky. In that view, differences in sleep quality, up to and including periods of insomnia, need not be seen as problems but as adaptations to the demands of the environment.

How our brain remembers the consequences of our actions

A fundamental building block in shaping our behavior is the relationship between a sensory event, a chosen action and its consequences. Histed et al. now point to how the brain stores this information by showing that neurons in the monkey prefrontal cortex and basal ganglia display persistent activity that is related to the outcomes of previous actions. Seo and Lee review this work in Nature, noting in the figure the sort of stimulus, action, outcome sequence that is in question :


Basically, the data suggest that the prefrontal cortex and basal ganglia might be essential brain areas for storing information about action–outcome associations

Mindblindness in Asperger's syndrome

Recent work by Senju et al. is summarized in Science:

Placement of Asperger syndrome within the family of autism spectrum disorders (ASD) has always been a bit uneasy; although people with Asperger syndrome do exhibit the core impairments in social interaction and communication that are characteristic of ASD, they nevertheless perform well on tests that are thought to assess the ability to mentalize or to possess Theory of Mind skills. One of the classic tests of mentalizing ability is the false-belief task, in which subjects must be able to represent their own beliefs (true) and another's beliefs, which are false because they have not been given complete information, such as not having seen the transfer of a piece of candy from one drawer to another. People with Asperger syndrome succeed at the verbal form of the false-belief task, yet Senju et al. show that this is owing entirely to their having learned how to cope with an existing and still demonstrable deficit in an implicit version of the false-belief task. That is, the core impairment is present, but conscious and explicit learning allows them to compensate.

Here is the Senju et al. abstract:

Adults with Asperger syndrome can understand mental states such as desires and beliefs (mentalizing) when explicitly prompted to do so, despite having impairments in social communication. We directly tested the hypothesis that such individuals nevertheless fail to mentalize spontaneously. To this end, we used an eye-tracking task that has revealed the spontaneous ability to mentalize in typically developing infants. We showed that, like infants, neurotypical adults’ (n = 17 participants) eye movements anticipated an actor’s behavior on the basis of her false belief. This was not the case for individuals with Asperger syndrome (n = 19). Thus, these individuals do not attribute mental states spontaneously, but they may be able to do so in explicit tasks through compensatory learning.

Green Porno.

In the 25 Sept. issue of Science Magazine, the Gonzo Scientist points us to these humorous performances on the Sundance channel (worth checking out) by Isabella Rossellini. She offers a series of brief video performances, between 1 and 2 minutes long, in which she dresses in elaborate animal costumes to paint a miniportrait of several organisms, describing key features of their physiology and behavior - in particular their reproductive biology.

A new chemical fix for chronic depression??

Maybe, for mice. With the results possibly relevant to us. There is evidence, obtained from both post-mortem human brains and from animal experiments, that persistent depression may involve long term chemical changes in gene-protein complexes called chromatin. Covington et al find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 (a chromatin protein) in the nucleus accumbens, an important limbic brain region. They then find that infusion into this region of inhibitors of the enzyme that removes acetate groups lessens behavioral symptoms of depression and also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens.