Archive for the ‘Stanford University’ Category

Rothman

STOCKHOLM (AP) — Two Americans and a German-American won the Nobel Prize in medicine on Monday for discovering how key substances are transported within cells, a process involved in such important activities as brain cell communication and the release of insulin.

James Rothman, 62, of Yale University, Randy Schekman, 64, of the University of California, Berkeley, and Dr. Thomas Sudhof, 57, of Stanford University shared the $1.2 million prize for their research on how tiny bubbles called vesicles act as cargo carriers inside cells.

This traffic control system ensures that the cargo is delivered to the right place at the right time and keeps activities inside cells from descending into chaos, the committee said. Defects can be harmful, leading to neurological diseases, diabetes and disorders affecting the immune system.

“Imagine hundreds of thousands of people who are traveling around hundreds of miles of streets; how are they going to find the right way? Where will the bus stop and open its doors so that people can get out?” Nobel committee secretary Goran Hansson said. “There are similar problems in the cell.”

The winners’ discoveries in the 1970s, ’80s and ’90s have helped doctors diagnose a severe form of epilepsy and immune deficiency diseases in children, Hansson said. In the future, scientists hope the research could lead to medicines against more common types of epilepsy, diabetes and other metabolism deficiencies, he added.

Schekman said he was awakened at 1 a.m. at his home in California by the chairman of the prize committee, just as he was suffering from jetlag after returning from a trip to Germany the night before.

“I wasn’t thinking too straight. I didn’t have anything elegant to say,” he told The Associated Press. “All I could say was ‘Oh my God,’ and that was that.”

He called the prize a wonderful acknowledgment of the work he and his students had done and said he knew it would change his life.

“I called my lab manager and I told him to go buy a couple bottles of Champagne and expect to have a celebration with my lab,” he said.

In the 1970s, Schekman discovered a set of genes that were required for vesicle transport, while Rothman revealed in the 1980s and 1990s how vesicles delivered their cargo to the right places. Also in the ’90s, Sudhof identified the machinery that controls when vesicles release chemical messengers from one brain cell that let it communicate with another.

“This is not an overnight thing. Most of it has been accomplished and developed over many years, if not decades,” Rothman told the AP.

Rothman said he lost grant money for the work recognized by the Nobel committee, but he will now reapply, hoping the Nobel prize will make a difference in receiving funding.

Sudhof, who was born in Germany but moved to the U.S. in 1983 and also has U.S. citizenship, told the AP he received the call from the committee while driving toward the city of Baeza, in southern Spain, where he was due to give a talk.

“I got the call while I was driving and like a good citizen I pulled over and picked up the phone,” he said. “To be honest, I thought at first it was a joke. I have a lot of friends who might play these kinds of tricks.”

The medicine prize kicked off this year’s Nobel announcements. The awards in physics, chemistry, literature, peace and economics will be announced by other prize juries this week and next. Each prize is worth 8 million Swedish kronor ($1.2 million).

Rothman and Schekman won the Albert Lasker Basic Medical Research Award for their research in 2002 — an award often seen as a precursor of a Nobel Prize. Sudhof won the Lasker award this year.

“I might have been just as happy to have been a practicing primary-care doctor,” Sudhof said after winning that prize. “But as a medical student I had interacted with patients suffering from neurodegeneration or acute clinical schizophrenia. It left an indelible mark on my memory.”

Jeremy Berg, former director of the National Institute of General Medical Sciences in Bethesda, Maryland, said Monday’s announcement was “long overdue” and widely expected because the research was “so fundamental, and has driven so much other research.”

Berg, who now directs the Institute for Personalized Medicine at the University of Pittsburgh, said the work provided the intellectual framework that scientists use to study how brain cells communicate and how other cells release hormones. In both cases, vesicles play a key role by delivering their cargo to the cell surface and releasing it to the outside, he told the AP.

So the work has indirectly affected research into virtually all neurological disease as well as other diseases, he said.

Established by Swedish industrialist Alfred Nobel, the Nobel Prizes have been handed out by award committees in Stockholm and Oslo since 1901. The winners always receive their awards on Dec. 10, the anniversary of Nobel’s death in 1896.

Last year’s Nobel medicine award went to Britain’s John Gurdon and Japan’s Shinya Yamanaka for their contributions to stem cell science.

http://news.yahoo.com/americans-german-american-win-medicine-nobel-132221489.html

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How far should doctors go in attempting to cure addiction? In China, some physicians are taking the most extreme measures. By destroying parts of the brain’s “pleasure centers” in heroin addicts and alcoholics, these neurosurgeons hope to stop drug cravings. But damaging the brain region involved in addictive desires risks permanently ending the entire spectrum of natural longings and emotions, including the ability to feel joy.

In 2004, the Ministry of Health in China banned this procedure due to lack of data on long term outcomes and growing outrage in Western media over ethical issues about whether the patients were fully aware of the risks.

However, some doctors were allowed to continue to perform it for research purposes—and recently, a Western medical journal even published a new study of the results. In 2007, The Wall Street Journal detailed the practice of a physician who claimed he performed 1000 such procedures to treat mental illnesses such as depression, schizophrenia and epilepsy, after the ban in 2004; the surgery for addiction has also since been done on at least that many people.

The November publication has generated a passionate debate in the scientific community over whether such research should be published or kept outside the pages of reputable scientific journals, where it may find undeserved legitimacy and only encourage further questionable science to flourish.

The latest study is the third published since 2003 in Stereotactic and Functional Neurosurgery, which isn’t the only journal chronicling results from the procedure, which is known as ablation of the nucleus accumbens. In October, the journal World Neurosurgery also published results from the same researchers, who are based at Tangdu Hospital in Xi’an.

The authors, led by Guodong Gao, claim that the surgery is “a feasible method for alleviating psychological dependence on opiate drugs.” At the same time, they report that more than half of the 60 patients had lasting side effects, including memory problems and loss of motivation. Within five years, 53% had relapsed and were addicted again to opiates, leaving 47% drug free.

(MORE: Addicted: Why We Get Hooked)

Conventional treatment only results in significant recovery in about 30-40% of cases, so the procedure apparently improves on that, but experts do not believe that such a small increase in benefit is worth the tremendous risk the surgery poses.  Even the most successful brain surgeries carry risk of infection, disability and death since opening the skull and cutting brain tissue for any reason is both dangerous and unpredictable. And the Chinese researchers report that 21% of the patients they studied experienced memory deficits after the surgery and 18% had “weakened motivation,” including at least one report of lack of sexual desire. The authors claim, however, that “all of these patients reported that their [adverse results] were tolerable.” In addition, 53% of patients had a change in personality, but the authors describe the majority of these changes as “mildness oriented,” presumably meaning that they became more compliant. Around 7%, however, became more impulsive.

The surgery is actually performed while patients are awake in order to minimize the chances of destroying regions necessary for sensation, consciousness or movement.  Surgeons use heat to kill cells in small sections of both sides of the brain’s nucleus accumbens.  That region is saturated with neurons containing dopamine and endogenous opioids, which are involved in pleasure and desire related both to drugs and to ordinary experiences like eating, love and sex.

(MORE: A Drug to End Drug Addiction)

In the U.S. and the U.K., reports the Wall Street Journal, around two dozen stereotactic ablations are performed each year, but only in the most intractable cases of depression and obsessive-compulsive disorder and after extensive review by institutional review boards and intensive discussions with the patient, who must acknowledge the risks. Often, a different brain region is targeted, not the nucleus accumbens. Given the unpredictable and potentially harmful consequences of the procedure, experts are united in their condemnation of using the technique to treat addictions. “To lesion this region that is thought to be involved in all types of motivation and pleasure risks crippling a human being,” says Dr. Charles O’Brien, head of the Center for Studies of Addiction at the University of Pennsylvania.

David Linden, professor of neuroscience at Johns Hopkins and author of a recent book about the brain’s pleasure systems calls the surgery “horribly misguided.”  He says “This treatment will almost certainly render the subjects unable to feel pleasure from a wide range of experiences, not just drugs of abuse.”

But some neurosurgeons see it differently. Dr. John Adler, professor emeritus of neurosurgery at Stanford University, collaborated with the Chinese researchers on the publication and is listed as a co-author.  While he does not advocate the surgery and did not perform it, he believes it can provide valuable information about how the nucleus accumbens works, and how best to attempt to manipulate it. “I do think it’s worth learning from,” he says. ” As far as I’m concerned, ablation of the nucleus accumbens makes no sense for anyone.  There’s a very high complication rate. [But] reporting it doesn’t mean endorsing it. While we should have legitimate ethical concerns about anything like this, it is a bigger travesty to put our heads in the sand and not be willing to publish it,” he says.

(MORE: Anesthesia Study Opens Window Into Consciousness)

Dr. Casey Halpern, a neurosurgery resident at the University of Pennsylvania makes a similar case. He notes that German surgeons have performed experimental surgery involving placing electrodes in the same region to treat the extreme lack of pleasure and motivation associated with otherwise intractable depression.  “That had a 60% success rate, much better than [drugs like Prozac],” he says. Along with colleagues from the University of Magdeburg in Germany, Halpern has just published a paper in the Proceedings of the New York Academy of Sciences calling for careful experimental use of DBS in the nucleus accumbens to treat addictions, which have failed repeatedly to respond to other approaches. The paper cites the Chinese surgery data and notes that addiction itself carries a high mortality risk.

DBS, however, is quite different from ablation.  Although it involves the risk of any brain surgery, the stimulation itself can be turned off if there are negative side effects, while surgical destruction of brain tissue is irreversible. That permanence—along with several other major concerns — has ethicists and addiction researchers calling for a stop to the ablation surgeries, and for journals to refuse to publish related studies.

Harriet Washington, author of Medical Apartheid:  The Dark History of Medical Experimentation on Black Americans from Colonial Times to the Present, argues that by publishing the results of unethical studies, scientists are condoning the questionable conditions under which the trials are conducted. “When medical journals publish research that violates the profession’sethical guidelines, this serves not only to sanction such abuses, but to encourage them,” she says. “In doing so, this practice encourages a relaxing of moral standards that threatens all patients and subjects, but especially  the medically vulnerable.”

(MORE: Real-Time Video: First Look at a Brain Losing Consciousness Under Anesthesia)

Shi-Min Fang, a Chinese biochemist who became a freelance journalist and recently won the journal Nature‘s Maddox prize for his exposes of widespread fraud in Chinese research, has revealed some of the subpar scientific practices behind research conducted in China, facing death threats and, as the New York Times reported, a beating with a hammer. He agrees that publishing such research only perpetuates the unethical practices. Asked by TIME to comment on the addiction surgery studies, Fang writes that publishing the research, particularly in western journals, “would encourage further unethical research, particularly in China where rewards for publication in international journals are high.”

While he doesn’t have the expertise to comment specifically on the ablation data, he says “the results of clinical research in China are very often fabricated. I suspect that the approvals by Ethics Committee mentioned in these papers were made up to meet publication requirement. I also doubt if the patients were really informed in detail about the nature of the study.” Fang also notes that two of the co-authors of the paper are advertising on the internet in Chinese, offering the surgery at a cost of 35,000 renminbi, about $5,600.  That’s more than the average annual income in China, which is about $5,000.

Given the available evidence, in fact, it’s hard to find a scientific justification for even studying the technique in people at all. Carl Hart, associate professor of psychology at Columbia University and author of the leading college textbook on psychoactive drugs, says animal studies suggest the approach may ultimately fail as an effective treatment for addiction; a 1984 experiment, for example, showed that destroying the nucleus accumbens in rats does not permanently stop them from taking opioids like heroin and later research found that it similarly doesn’t work for curbing cocaine cravings. Those results alone should discourage further work in humans. “These data are clear,” he says, “If you are going to take this drastic step, you damn well better know all of the animal literature.” [Disclosure:  Hart and I have worked on a book project together].

(MORE: Top 10 Medical Breakthroughs of 2012)

Moreover, in China, where addiction is so demonized that execution has been seen as an appropriate punishment and where the most effective known treatment for heroin addiction— methadone or buprenorphine maintenance— is illegal, it’s highly unlikely that addicted people could give genuinely informed consent for any brain surgery, let alone one that risks losing the ability to feel pleasure. And even if all of the relevant research suggested that ablating the nucleus accumbens prevented animals from seeking drugs, it would be hard to tell from rats or even primates whether the change was due to an overall reduction in motivation and pleasure or to a beneficial reduction in desiring just the drug itself.

There is no question that addiction can be difficult to treat, and in the most severe cases, where patients have suffered decades of relapses and failed all available treatments multiple times, it may make sense to consider treatments that carry significant risks, just as such dangers are accepted in fighting suicidal depression or cancer.  But in the ablation surgery studies, some of the participants were reportedly as young as 19 years old and had only been addicted for three years.  Addiction research strongly suggests that such patients are likely to recover even without treatment, making the risk-benefit ratio clearly unacceptable.

The controversy highlights the tension between the push for innovation and the reality of risk. Rules on informed consent didn’t arise from fears about theoretical abuses:  they were a response to the real scientific horrors of the Holocaust. And ethical considerations become especially important when treating a condition like addiction, which is still seen by many not as an illness but as a moral problem to be solved by punishment.  Scientific innovation is the goal, but at what price?
Read more: http://healthland.time.com/2012/12/13/controversial-surgery-for-addiction-burns-away-brains-pleasure-center/#ixzz2ExzobWQq

Thanks to Dr. Lutter for bringing this to the attention of the It’s Interesting community.

 

 

 

Stanford researchers have designed the fastest, most accurate mathematical algorithm yet for brain-implantable prosthetic systems that can help disabled people maneuver computer cursors with their thoughts. The algorithm’s speed, accuracy and natural movement approach those of a real arm.

 

 

On each side of the screen, a monkey moves a cursor with its thoughts, using the cursor to make contact with the colored ball. On the left, the monkey’s thoughts are decoded with the use of a mathematical algorithm known as Velocity. On the right, the monkey’s thoughts are decoded with a new algorithm known as ReFITT, with better results. The ReFIT system helps the monkey to click on 21 targets in 21 seconds, as opposed to just 10 clicks with the older system.

 

 

When a paralyzed person imagines moving a limb, cells in the part of the brain that controls movement activate, as if trying to make the immobile limb work again.

Despite a neurological injury or disease that has severed the pathway between brain and muscle, the region where the signals originate remains intact and functional.

In recent years, neuroscientists and neuroengineers working in prosthetics have begun to develop brain-implantable sensors that can measure signals from individual neurons.

After those signals have been decoded through a mathematical algorithm, they can be used to control the movement of a cursor on a computer screen – in essence, the cursor is controlled by thoughts.

The work is part of a field known as neural prosthetics.

A team of Stanford researchers have now developed a new algorithm, known as ReFIT, that vastly improves the speed and accuracy of neural prosthetics that control computer cursors. The results were published Nov. 18 in the journal Nature Neuroscience in a paper by Krishna Shenoy, a professor of electrical engineering, bioengineering and neurobiology at Stanford, and a team led by research associate Dr. Vikash Gilja and bioengineering doctoral candidate Paul Nuyujukian.

In side-by-side demonstrations with rhesus monkeys, cursors controlled by the new algorithm doubled the performance of existing systems and approached performance of the monkey’s actual arm in controlling the cursor. Better yet, more than four years after implantation, the new system is still going strong, while previous systems have seen a steady decline in performance over time.

“These findings could lead to greatly improved prosthetic system performance and robustness in paralyzed people, which we are actively pursuing as part of the FDA Phase-I BrainGate2 clinical trial here at Stanford,” said Shenoy.

The system relies on a sensor implanted into the brain, which records “action potentials” in neural activity from an array of electrode sensors and sends data to a computer. The frequency with which action potentials are generated provides the computer important information about the direction and speed of the user’s intended movement.

The ReFIT algorithm that decodes these signals represents a departure from earlier models. In most neural prosthetics research, scientists have recorded brain activity while the subject moves or imagines moving an arm, analyzing the data after the fact. “Quite a bit of the work in neural prosthetics has focused on this sort of offline reconstruction,” said Gilja, the first author of the paper.

The Stanford team wanted to understand how the system worked “online,” under closed-loop control conditions in which the computer analyzes and implements visual feedback gathered in real time as the monkey neurally controls the cursor toward an onscreen target.

The system is able to make adjustments on the fly when guiding the cursor to a target, just as a hand and eye would work in tandem to move a mouse-cursor onto an icon on a computer desktop.

If the cursor were straying too far to the left, for instance, the user likely adjusts the imagined movements to redirect the cursor to the right. The team designed the system to learn from the user’s corrective movements, allowing the cursor to move more precisely than it could in earlier prosthetics.

To test the new system, the team gave monkeys the task of mentally directing a cursor to a target – an onscreen dot – and holding the cursor there for half a second. ReFIT performed vastly better than previous technology in terms of both speed and accuracy.

The path of the cursor from the starting point to the target was straighter and it reached the target twice as quickly as earlier systems, achieving 75 to 85 percent of the speed of the monkey’s arm.

“This paper reports very exciting innovations in closed-loop decoding for brain-machine interfaces. These innovations should lead to a significant boost in the control of neuroprosthetic devices and increase the clinical viability of this technology,” said Jose Carmena, an associate professor of electrical engineering and neuroscience at the University of California-Berkeley.

Critical to ReFIT’s time-to-target improvement was its superior ability to stop the cursor. While the old model’s cursor reached the target almost as fast as ReFIT, it often overshot the destination, requiring additional time and multiple passes to hold the target.

The key to this efficiency was in the step-by-step calculation that transforms electrical signals from the brain into movements of the cursor onscreen. The team had a unique way of “training” the algorithm about movement. When the monkey used his arm to move the cursor, the computer used signals from the implant to match the arm movements with neural activity.

Next, the monkey simply thought about moving the cursor, and the computer translated that neural activity into onscreen movement of the cursor. The team then used the monkey’s brain activity to refine their algorithm, increasing its accuracy.

The team introduced a second innovation in the way ReFIT encodes information about the position and velocity of the cursor. Gilja said that previous algorithms could interpret neural signals about either the cursor’s position or its velocity, but not both at once. ReFIT can do both, resulting in faster, cleaner movements of the cursor.

Early research in neural prosthetics had the goal of understanding the brain and its systems more thoroughly, Gilja said, but he and his team wanted to build on this approach by taking a more pragmatic engineering perspective. “The core engineering goal is to achieve highest possible performance and robustness for a potential clinical device,” he said.

To create such a responsive system, the team decided to abandon one of the traditional methods in neural prosthetics.

Much of the existing research in this field has focused on differentiating among individual neurons in the brain. Importantly, such a detailed approach has allowed neuroscientists to create a detailed understanding of the individual neurons that control arm movement.

But the individual neuron approach has its drawbacks, Gilja said. “From an engineering perspective, the process of isolating single neurons is difficult, due to minute physical movements between the electrode and nearby neurons, making it error prone,” he said. ReFIT focuses on small groups of neurons instead of single neurons.

By abandoning the single-neuron approach, the team also reaped a surprising benefit: performance longevity. Neural implant systems that are fine-tuned to specific neurons degrade over time. It is a common belief in the field that after six months to a year they can no longer accurately interpret the brain’s intended movement. Gilja said the Stanford system is working very well more than four years later.

“Despite great progress in brain-computer interfaces to control the movement of devices such as prosthetic limbs, we’ve been left so far with halting, jerky, Etch-a-Sketch-like movements. Dr. Shenoy’s study is a big step toward clinically useful brain-machine technology that has faster, smoother, more natural movements,” said James Gnadt, a program director in Systems and Cognitive Neuroscience at the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health.

For the time being, the team has been focused on improving cursor movement rather than the creation of robotic limbs, but that is not out of the question, Gilja said. Near term, precise, accurate control of a cursor is a simplified task with enormous value for people with paralysis.

“We think we have a good chance of giving them something very useful,” he said. The team is now translating these innovations to people with paralysis as part of a clinical trial.

This research was funded by the Christopher and Dana Reeve Paralysis Foundation, the National Science Foundation, National Defense Science and Engineering Graduate Fellowships, Stanford Graduate Fellowships, Defense Advanced Research Projects Agency (“Revolutionizing Prosthetics” and “REPAIR”) and the National Institutes of Health (NINDS-CRCNS and Director’s Pioneer Award).

Other contributing researchers include Cynthia Chestek, John Cunningham, Byron Yu, Joline Fan, Mark Churchland, Matthew Kaufman, Jonathan Kao and Stephen Ryu.

http://news.stanford.edu/news/2012/november/thought-control-cursor-111812.html

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community

Scientists say they’ve found the gene that sets the common tabby pattern – stripes or blotches.

It’s one of several genes that collaborate to create the distinctive design of a cat’s coat, and it’s the first of the pattern genes to be identified.

Cats with narrow stripes, the so-called “mackerel” pattern, have a working copy of the gene. But if a mutation turns the gene off, the cat ends up with the blotchy “classic” pattern, researchers reported online last week in the journal Science.

It’s called “classic” because “cat lovers really like the blotched pattern,” said one of the authors, Greg Barsh. He works at both Stanford University and the HudsonAlpha Institute of Biotechnology in Huntsville, Ala.

The research team, which included scientists from the National Cancer Institute, examined DNA from wild cats in California to identify the gene.

They also found that a mutation in the same gene produces the blotches and stripes of the rare “king” cheetah, rather than the spots most cheetahs have.

Leslie Lyons, a cat geneticist who studies coat color traits at the University of California, Davis, but didn’t participate in the new work, agreed that the research has identified the tabby’s stripes-versus-blotches gene. She noted that mysteries remain, such as just what genetic machinery gives a tabby spots.