Archive for January 5, 2013

Brain Ethics

Decisions are never perfect, with confidence in one’s choices fluctuating over time. How subjective confidence and valuation of choice options interact at the level of brain and behavior is unknown. A recent study using a dynamic model of the decision process shows that confidence reflects the evolution of a decision variable over time, explaining the observed relation between confidence, value accuracy and reaction time. The dynamic model showed that a functional magnetic resonance imaging signal in human ventromedial prefrontal cortex reflects both value comparison and confidence in the value comparison process. Significantly, individuals vary in how they relate confidence to accuracy and this introspective ability is predicted by a measure of functional connectivity between ventromedial prefrontal cortex and rostrolateral prefrontal cortex. The study provided a mechanistic link between noise in value comparison and metacognitive awareness of choice, enabling us both to want and to express knowledge of what we want.

The subjective confidence we have in our decision-making, and that of others, has far-reaching consequences. For example, the recommendations of a financial advisor who expresses high confidence in a particular investment option will carry more weight than one who is ambivalent. An expression of doubt or caution concerning a particular course of action can lead one to question or revisit a previous decision. It is already established that the ventromedial prefrontal cortex has a central role in computing the value of potential choice options, with activity in this region reflecting the dynamic evolution of a value comparison. The study focused exclusively on the choice process, without considering the subject’s level of confidence in the decision. Accordingly, it is unknown how a process of value comparison, instantiated in ventromedial prefrontal cortex, relates to subjective confidence.

Earlier studies have reported neural correlates of decision confidence in brain regions associated with a value representation. For example, functional magnetic resonance imaging signals in human ventromedial prefrontal cortex showed graded changes as perceptual decisions became more difficult. However, as these earlier studies delineate confidence in terms of factors governing choice, they are unable to tease apart the relationship between trial-to-trial subjective confidence and decision value. In contrast, the field of perceptual decision-making has noted that confidence can be measured independently of the choice process itself, where it is conceptualized as reflecting a ‘second-order’ metacognitive evaluation. Critically, dissociating confidence from other features of the decision process requires acquisition of separate measures of choice and confidence.

This study implemented such an approach to dissociate value and confidence during decision-making and to identify their respective neural substrates. The study collected trial-by-trial estimates of decision confidence while healthy volunteers chose between pairs of snack items. The study also measured the subjective value of each snack item by means of a standard incentive-compatible bidding procedure. This permits to dissociate confidence from value, and in so doing provide evidence that confidence reflects an assessment of choice accuracy. To explore systematic relationships between confidence, accuracy, choice and reaction time, the study modeled data using a variant of a race model; one of a larger class of dynamic models of decision-making. This model predicts that subjective confidence reflects the stochastic accumulation of evidence during the value comparison process. This showed that the same anatomical region in ventromedial prefrontal cortex not only reflects a difference in value between available options, but also the confidence associated with a value comparison process. The study also showed that individual differences in participants’ abilities to relate confidence to decision performance is linked to increased functional connectivity between ventromedial prefrontal cortex and rostrolateral prefrontal cortex, a region previously shown to function in metacognitive appraisal.

It is to be noted that confidence or certainty, in this study is conceptually distinct from risk, in that each choice determined a known outcome. Confidence here reflects the degree of subjective certainty in having made the best choice, which equates to choosing the higher valued item. To establish value for individual items, participants were asked at the end of the scanning session to place a bid for each food item using a standard incentive-compatible procedure, the Becker-DeGroot-Marschak mechanism. Becker-DeGroot-Marschak is widely used in behavioral economics and neuroeconomics to elicit nonstrategic reservation prices, also known as willingness-to-pay. In this study, participants were required to state their maximum willingness-to-pay for each food item. Several studies have shown that this mechanism reliably elicits goal values.

Credits: Benedetto De Martino, Stephen M Fleming, Neil Garrett and Raymond J Dolan.

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Posted January 5, 2013 by dranilj1 in Neuroscience

Miracle Molecule Refuted

                                                                                                                                                        

Two studies refute an enzyme’s vital role in remembering and forgetting. For years, a particular protein has been cast as a cornerstone of long-term memory. Inhibiting this enzyme could erase old memories, whereas adding it could strengthen faded ones. But two independent groups of US scientists have now seriously challenged the role of this memory molecule by developing mice that completely lack it and showing that these mice have no noticeable memory problems. The excitement around the enzyme, called Protein kinase M zeta started building in 2006, when Todd Sacktor at the SUNY Downstate Medical Center in New York City cleaned out established spatial memories in rats. He did so by injecting their brains with zeta inhibitory peptide; a small peptide that is meant to block the enzyme.

Other teams obtained similar results, erasing different types of memory by injecting zeta inhibitory peptide into various brain regions in rodents, flies and sea slugs. In 2011, Sacktor did the opposite. He strengthened rats’ memory of unpleasant tastes by injecting their brains with viruses carrying extra copies of Protein kinase M zeta. These fascinating studies suggested that long-term memory, rather than being static and stable is surprisingly delicate, and depends on the continuous activity of a single enzyme.

Richard Huganir of Johns Hopkins University in Baltimore, Maryland, was aroused with curiosity by these results, but was concerned that much of the data depended on the actions of zeta inhibitory peptide. He and his collaborators took a different course; by deleting two genes — one for Protein kinase M zeta and one for a related protein called Protein kinase C zeta in embryonic mice. Working independently, Robert Messing and colleagues at the University of California, San Francisco, created similar mice and neither group of mice showed any memory problems. Robert’s animals formed persistent memories for fears, objects, places and movements across a battery of behavioral tests. Huganir’s mice showed normal levels of long-term potentiation like the strengthening of synapses between two neurons that is thought to underlie learning and memory.

The study pretty conclusively says that Protein kinase M zeta does not regulate memory. Even more surprisingly, both teams found that zeta inhibitory peptide could still disrupt established memories in their mice, despite their lack of Protein kinase M zeta. The study doesn’t rule out the possibility that Protein kinase M zeta may play a role in some forms of memory, but it is not the essential master regulator of memory that the current literature suggests it to be. Sacktor disagrees thinking that the results are not too surprising because a different gene might have compensated for the loss, as routinely happens in mice that have had some genes deleted. He suspects that related proteins like Protein kinase M-iota or Protein kinase M-lambda may be involved. He thinks the future will be to try to find the back-up mechanisms for memory.

However, Huganir’s team also created mice whose Protein kinase M zeta gene could be deleted at will by giving them a specific drug. This allowed the researchers to deplete the enzyme during adulthood, after mice had grown up with normal levels. The animals still showed normal long-term potentiation. These results do not show that Protein kinase M zeta is unimportant. But they show that the situation is complicated and that there are multiple possible pathways involved. These other pathways are still a mystery. Without Protein kinase M zeta, there are not many compelling alternatives for how long-term memory is maintained. His team is now trying to explore other mechanisms by identifying zeta inhibitory peptide’s true targets. The mechanisms underlying the maintenance of long-term memory will be one of the more exciting areas of neuroscience research for many years to come.

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Posted January 5, 2013 by dranilj1 in Neuroscience

American Higher Education

To provide good care, physicians must understand the communities and cultures in which they work. An important way to ensure that physicians understand the lives of their patients and to reduce health disparities is to promote racial and ethnic diversity in the physician workforce. However, a crucial tool that has made such diversity possible is currently in danger. Within the next few months, the U.S. Supreme Court will announce its decision in a case destined to chart the future of affirmative action in American higher education. The outcome in Fisher versus University of Texas at Austin will determine whether race may continue to be taken into account as a factor in university admissions, including admission of students to our nation’s medical schools.

I believe, though, that it would be a grave mistake with serious negative consequences for the physician workforce and for American society. Medical students learn in great part from one another, and a multicultural classroom is vital to effective learning. I agree with Justice Powell’s opinion in Bakke that race should be permitted in medical-school admissions as one factor among others, because it is essential that “physicians serve a heterogeneous population.” I support the amicus curiae brief submitted by the Association of American Medical Colleges in Fisher, which states, “Medical schools strongly believe that diversity in the educational environment is integral to instilling in new physicians the cultural competence necessary to more effectively serve a diverse society.

Future generations of physicians need to mirror the society they serve, and this will not happen unless medical schools are permitted to pursue holistic admission policies that consider race and ethnic group along with factors that characterize students who become outstanding physicians. In reaching their judgment in Fisher, we hope the justices will agree.

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Posted January 5, 2013 by dranilj1 in Social

Your Own Brain Can Shape It and Override It with Its Internal Deliberations

Neuroscience research involving epileptic patients with brain electrodes surgically implanted in their medial temporal lobes shows that patients learned to consciously control individual neurons deep in the brain with thoughts. People can learn to control mouse cursors, play video games and alter focus of digital images with their thoughts using brain computer interfaces, deep brain electrodes and software designed for the research. Five years ago, neuroscientist Christof Koch of the California Institute of Technology, neurosurgeon Itzhak Fried of UCLA, found that a single neuron in the human brain can function much like a sophisticated computer and recognize people, landmarks, and objects, suggesting that a consistent and explicit code may help transform complex visual representations into long-term and more abstract memories. Now it is found that individuals can exert conscious control over the firing of these single neurons regardless of the neurons’ location in an area of the brain previously thought inaccessible to conscious control and, in doing so, manipulate the behavior of an image on a computer screen.

Individuals can rapidly, consciously, and voluntarily control neurons deep inside their head. The study was conducted on 12 epilepsy patients at the David Geffen School of Medicine at UCLA, where Fried directs the Epilepsy Surgery Program. All of the patients suffered from seizures that could not be controlled by medication. To help localize where their seizures were originating in preparation for possible later surgery, the patients were surgically implanted with electrodes deep within the centers of their brains. Moran Cerf used these electrodes to record the activity, as indicated by spikes on a computer screen, of individual neurons in parts of the medial temporal lobe—a brain region that plays a major role in human memory and emotion.

Prior to recording the activity of the neurons, Moran Cerf learned about patient’s interests. He wanted to see what they liked. Using that information, he created for each patient a data set of around 100 images reflecting the things he or she cares about. The patients then viewed those images, one after another, as Moran Cerf monitored their brain activity to look for the targeted firing of single neurons. He found of 100 pictures, maybe 10 would have a strong correlation to a neuron and those images might represent cached memories—things the patient has recently seen. The four most strongly responding neurons, representing four different images, were selected for further investigation. Here the goal was to get patients to control things with their minds. By thinking about the individual images—a picture of Marilyn Monroe, for example—the patients triggered the activity of their corresponding neurons, which was translated first into the movement of a cursor on a computer screen. In this way, patients trained themselves to move that cursor up and down, or even play a computer game.

Taking one step further than just brain–machine interfaces; we can tap into the competition for attention between thoughts that race through our mind. To do that, a situation was created in which two concepts competed for dominance in the mind of the patient. They had patients sit in front of a blank screen and asked them to think of one of the target images. As they thought of the image, and the related neuron fired, the image was made to appear on the screen. That image is the “target.” Then one of the other three images is introduced, to serve as distractor. The patient starts with a 50/50 image, a hybrid, representing the ‘marriage’ of the two images, and then has to make the target image fade in—just using his or her mind—and the distractor fade out. Patients came up with their own personal strategies for making the right images appear; some simply thought of the picture, while others repeated the name of the image out loud or focused their gaze on a particular aspect of the image. Regardless of their tactics, they quickly got the hang of the task, and they were successful in around 70 percent of trials.

The patients clearly found this task to be incredibly fun as they started to feel that they control things in the environment purely with their thought. They were highly enthusiastic to try new things and see the boundaries of ‘thoughts’ that still allow them to activate things in the environment. Notably, even in cases where the patients were on the verge of failure—with, say, the distractor image representing 90 percent of the composite picture, so that it was essentially all the patients saw—they were able to pull it back. Imagine, for example, that the target image is Bill Clinton and the distractor George Bush. When the patient is failing the task, the George Bush image will dominate. The patient will see George Bush, but they’re supposed to be thinking about Bill Clinton. So they shut off Bush—somehow figuring out how to control the flow of that information in their brain—and make other information appear. The imagery in their brain is stronger than the hybrid image on the screen.

What is most exciting is the part of the brain that stores the instruction reaches into the deep recess of temporal lobe and excites the set of neurons to make their targeted image completely visible, simultaneously suppressing the population of neurons representing the distracting image, while leaving the vast majority of cells representing other concepts or familiar person untouched.

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Posted January 5, 2013 by dranilj1 in Neuroscience

How We Perceive Loving Caresses of Our Mothers?

Mother

Gentle soft touch producing joy is scientifically authenticated by proven molecular basis of gentle touch, one of the most fundamental but least well understood of our senses. Our ability to sense gentle touch is known to develop early and to remain ever-present in our lives, from the first loving caresses our mothers lavish on us as newborns to the fading tingle we feel as our lives slip away. But until now, scientists have not known exactly how humans and other organisms perceive such sensations.

In an article published online weeks back in the journal Nature, the University Of California, San Francisco team has identified the exact compartment of nerve cells responsible for communicating gentle touch to the brains of Drosophila larvae, called class III neurons. Team also bared a particular protein called No Mechanoreceptor Potential C, which was found abundantly at the spiky ends of the nerves and appeared to be critical for sensing gentle touch in flies.

Without this key molecule, the team found, flies were insensitive to any amount of eyelash stroking, and if No Mechanoreceptor Potential C is inserted into neurons that cannot sense gentle touch, those neurons gain the ability to do so. No Mechanoreceptor Potential C is sufficient to confer sensitivity to gentle touch. The work sheds light on a poorly understood yet fundamental sense through which humans experience the world and derive pleasure and comfort. While the new work reveals much; many unanswered questions remain, including the exact mechanism through which No Mechanoreceptor Potential C detects mechanical force and the identity of the analogous human molecules that confer gentle touch sensitivity in people. This discovery is a good example of basic brain research paving the way toward answering questions like why is touch still such a mystery?

Though it is basic to our experience of the world, our sense of gentle touch has been the least well understood of our senses scientifically, because, unlike with vision or taste, scientists have not known the identity of the molecules that mediate it. The idea is, like other senses, the sense of touch is governed by peripheral nerve fibers stretching from the spine to nerve endings all over the body. Special molecules in these nerve endings detect the mechanical movement of the skin surrounding them when it is touched, and they respond by opening and allowing ions to rush in. The nerve cell registers this response, and if the signal is strong enough, it will fire, signaling the gentle touch to the brain.

What had been missing were the details of this process. The new finding is a milestone in that it defines the exact nerves and reveals the identity of the No Mechanoreceptor Potential C channel, one of the major molecular players involved, at least in Drosophila larvae. Team made this discovery through a strange route. Team was looking at the basic physiology of the developing fruit fly, examining how class III neurons develop in larvae. They noticed that when these cells developed in the insects, their nerve endings would always branch into spiky dendrites.

Wanting to know what these neurons are responsible for, they examined them closely and found the protein No Mechanoreceptor Potential C was abundant at the spiky ends. The team then examined a fly genetically engineered to have a non-functioning form of No Mechanoreceptor Potential C and showed that it was insensitive to gentle touch. Team also showed that they could induce touch sensitivity in neurons that do not normally respond to gentle touch by inserting copies of the No Mechanoreceptor Potential C protein into them.

How our bodies can perceive mechanical stimuli at the molecular level is one of the great mysteries in Biology. The tiny Drosophila larvae were used to study and identify eukaryotic channel that can be activated by mechanical force in a heterologous expression system and is required for mechanotransduction of gentle touch in vivo. This could lead to greater understanding of touch sensation in humans, and a fundamental understanding of how these channels actually function. It came as a great surprise that this protein alone can function as a sensor although it was previously thought to require considerably more complex and multi-component systems.

Team discovered that one kind of multidendritic neurons that tile the larval body wall can sense the gentle touch of an eye lash. Team further identified an ion channel of the Transient Receptor Potential family as specifically required for the sensation in these neurons. Team even further showed that this ion channel alone can function as a bona fide mechanotransduction channel that mediates the gentle-touch sensation in-vivo. The study also suggests that different mechanosensitive channels may be used to sense gentle touch versus noxious mechanical stimuli.

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