Even single neurons have a big impact on behavior, studies show
By E.J. Mundell
Posted 12/19/07
WEDNESDAY, Dec. 19 (HealthDay News) -- The human brain constantly sorts through its 1 trillion cells, looking for perhaps only one or a handful of neurons to carry out a particular action, a trio of new studies says.
The research, conducted with rodents and published in the Dec. 20 issue of Nature, could rewrite the textbooks on just how important individual brain cells or cell clusters are to the working mind.
Before these insights, "The thinking was that very large ensembles of neurons [brain cells] had to be activated at some point for the animal to feel or perceive" a stimulus, explained the senior researcher of two of the studies, Karel Svoboda, a group leader at the Howard Hughes Medical Institute in Ashburn, Va.
"But it turns out that a remarkably small number -- on the order of 50 or so activated neurons -- is sufficient to drive reliable behaviors," said Svoboda, who is also associated with the Cold Spring Harbor Laboratory, in New York.
Another study, this one conducted by scientists at Humboldt University Berlin and Erasmus Medical Center in Rotterdam, the Netherlands, found that stimulating just one out of the estimated 100 million neurons in a rat's brain was enough to cause the rodent to act differently.
"The fact that a single cell can influence behavior in the cortex is fascinating," said neuroscientist Paul Sanberg, director of the Center for Excellence for Aging and Brain Repair at the University of South Florida, Tampa. The new findings are "allowing us to answer questions about how the brain controls behavior at the cellular level," added Sanberg, who was not involved in the studies.
In one of the studies, Svoboda and his colleagues genetically engineered a select few brain cells in active mice so that the cells would react to a light stimulus.
Then they exposed a part of the rodent's brain and placed a small light-emitting diode over the area. The experiment "was essentially a trick to stimulate [only] these cells," Svoboda explained.
Finally, they adjusted the amount of light downward until they found the lowest number of brain cells needed to evoke a measurable response in the mice. That number turned out to be less than 50 -- much fewer than the wide-flung networks of cellular activation neuroscientists had previously assumed would be necessary, Svoboda said.
The mouse brain's ability to tap into a mere 50 cells is even more remarkable when you consider that the activity of this cluster of cells takes place amid a background roar of other neurological "noise" from millions of cells, he said.
"At the same time, the functional brain area just chatters along and produces perhaps a hundred thousand spontaneous action potentials [electrical signals]," he noted. "So, the brain can actually distinguish the tiny, tiny number of action potentials from that huge background."
According to Svoboda, the experiment strongly supports a theory of brain function called "sparse coding," in which "neurons that listen to the neurons that we have activated have to be able to pull out very sparse subsets of activity."
In another study, Svoboda and co-researcher Christopher Harvey, also of the HHMI and Cold Spring Harbor Laboratory, focused on the synapse -- the microscopic gap separating individual neurons. Messages are passed neuron-to-neuron across the synapse by a complex mechanism of electrochemical signaling.
"Scientists had shown that synapses behave rather independently," Svoboda said, so that long-term electrical activation ("potentiation") of one synapse didn't directly affect a neighboring synapse. Long-term potentiation is, in essence, the key cellular step in how the brain lays down memory.
However, computer models had suggested that activation at one synapse might more subtly strengthen the synapses around it. In their experiments, Svoboda and Harvey found this to be true.
They report that "neighborhoods" of 10 or 20 synapses "influence each other cooperatively," strengthening discrete groups of synapses.
What's more, this type of synaptic teamwork happens within a specific time-frame -- about 10 minutes, a perfect amount of time for laying down the kinds of memories that can lead to learning, Svoboda said.
"That's a very behavioral timescale for learning and memory," he said. For example, a mouse can be placed in a chamber, explore it for a few minutes, then be removed from the chamber and yet retain a working memory of that chamber once it has been reintroduced to it.
That's probably due to the fact that the mouse's brain formed synaptic clusters (i.e., memory) specific to the new chamber while it was exploring it, Svoboda explained.
"In this way, they can be dissociated [from the stimulus] over several minutes but still lead to learning," he said.
While many of these experiments were done in mice, the human brain should work similarly, albeit on a much larger scale, Svoboda said. While the mouse brain contains about 100 million neurons, human brains top out at a trillion such cells, he said.
And even though the research looked at healthy brain function, it may have implications for research into aging or diseased brains, as well.
"You need to understand the fundamental mechanisms. Then you can gain better insight into what might go wrong during neurodevelopmental and neurodegenerative disorders," Svoboda said.
Sanberg agreed.
"This work clearly shows us that all cells are important, and we should try and maintain and keep as many brain cells as possible," he said. "But the number is always flexible and, as you can see, even one cell can influence a number of others."
More information
Learn more about the human brain at The Franklin Institute.
Copyright © 2007 ScoutNews, LLC. All rights reserved.
Saturday, December 22, 2007
FDA renews alert on painkiller patch
The drug, which the agency says has been misused and wrongly prescribed, is a suspect in 3,500 deaths. Heat can increase the absorption rate.
By Ricardo Alonso-Zaldivar, Los Angeles Times Staff Writer December 22, 2007
WASHINGTON -- The government issued a new safety warning Friday for a skin patch containing a potent painkiller that has been implicated in hundreds of deaths, saying the patch poses unique risks that doctors and patients often fail to understand.The Food and Drug Administration said the widely used fentanyl patch was being wrongly prescribed by doctors and being misused by patients unaware that something as routine as taking a hot shower while wearing the patch could trigger a potentially fatal overdose.A study published in a medical journal last summer identified fentanyl, a narcotic up to 100 times more powerful than morphine, as the suspect drug in more than 3,500 accidental deaths reported to the FDA from 1998 to 2005.
Safety advocates said the agency's latest warning, which echoes an alert issued in 2005, was too little, too late.The patch was developed for cancer patients who suffer severe chronic pain and in some cases have trouble swallowing pills. But Dr. Bob Rappaport, head of the FDA division that oversees painkillers, said some doctors had been prescribing the patch to patients who didn't need such a powerful narcotic -- and in at least one case, even used it to treat headaches.
Patches can be more convenient than pills; the fentanyl patch is designed to deliver the drug at a steady rate for as long as three days, so patients don't have to take medication several times a day. But there are also drawbacks: A single patch contains a substantially larger quantity of the medication than individual pills; heat and exercise can increase the rate at which the drug is absorbed through the skin.Rappaport said the FDA had not found such serious problems with other methods of delivering fentanyl, including by injection. "It's a unique problem with patches because of . . . the way that the drug is delivered to the body and the way that it's metabolized," he said. "It's complicated by the patch formulation.
"The FDA said doctors should not prescribe the patch for patients whose pain was expected to go away, such as those recovering from an operation. The patch should be used only by patients who are in chronic pain and are already safely taking opioid-type drugs.The agency warned patients to call their doctors if they have trouble breathing, because fentanyl can shut down the respiratory system. It said patients wearing the patch should avoid hot showers and heating pads.Rappaport said the situation was "very concerning" because such patch-related deaths could easily be prevented.And adult patients are not the only ones at risk: At least one child has died after applying a parent's patch.
Not only is the fentanyl patch strong medicine, it is also widely used. About 4.7 million prescriptions were filled in 2006, according to Verispan, a market analysis firm. The patch was introduced in 1990 under the brand name Duragesic by Johnson & Johnson, but generic versions by Mylan Inc. and other manufacturers now dominate the market.Friday's advisory reinforced an FDA alert in 2005, which all sides acknowledge did not do enough to reduce the risk to patients. This time, the agency is directing drug makers to issue brochures that explain the dangers in plain language.That was not enough to satisfy safety advocates who have been tracking problems with the patch for years."I think there is more that needs to be done, or else we're just going to see this [warning] happen again another two years from now," said Michael Cohen, president of the Institute for Safe Medication Practices. "The deaths are going to continue." The Pennsylvania group advises hospitals and doctors on how to prevent medication errors.Cohen has called on the FDA to limit the number of doctors allowed to prescribe the drug.
That could be done by requiring physicians to take special instruction in assuring safety.But the FDA's Rappaport said such restrictions could prevent some patients who need the medication from getting prescriptions. About 60 million Americans suffer from chronic pain, he said, but only several thousand doctors in the country are certified pain specialists.Nonetheless, Cohen said, he is worried the FDA's latest warning won't register with busy doctors, particularly those who don't regularly deal with powerful narcotics. He recommended that hospitals, which usually have pain experts on staff, require their specialists to review all prescriptions for the fentanyl patch.
Several deaths reported to his group involved patients inappropriately prescribed the patch for pain relief after surgery.Last summer, a study named fentanyl as the second-deadliest drug in accidental deaths, behind painkiller oxycodone. Analyzing reports to the FDA from 1998 to 2005, researchers identified 3,545 deaths linked to fentanyl. The study looked at all forms of fentanyl, but "the patch was by far the largest contributor," lead author Thomas J. Moore said in an interview.
By comparison, the paper found that Vioxx -- the painkiller whose 2004 withdrawal was the catalyst for safety reforms at the FDA -- was a suspect in 932 deaths.Rappaport said the FDA did not have a definitive count of deaths caused by the patch and was working to develop one. He suggested the number could be smaller than reported because many patients using the patch were severely ill and could have died from underlying diseases.Spokesmen for Ortho-McNeil Inc., the subsidiary that makes Duragesic, and for Mylan said the manufacturers supported the FDA's action.Greg Panico of Ortho-McNeil said the company's research indicated that the safety warnings might be working. Reports of unapproved uses of Duragesic have declined significantly since the summer of 2006, he said.
By Ricardo Alonso-Zaldivar, Los Angeles Times Staff Writer December 22, 2007
WASHINGTON -- The government issued a new safety warning Friday for a skin patch containing a potent painkiller that has been implicated in hundreds of deaths, saying the patch poses unique risks that doctors and patients often fail to understand.The Food and Drug Administration said the widely used fentanyl patch was being wrongly prescribed by doctors and being misused by patients unaware that something as routine as taking a hot shower while wearing the patch could trigger a potentially fatal overdose.A study published in a medical journal last summer identified fentanyl, a narcotic up to 100 times more powerful than morphine, as the suspect drug in more than 3,500 accidental deaths reported to the FDA from 1998 to 2005.
Safety advocates said the agency's latest warning, which echoes an alert issued in 2005, was too little, too late.The patch was developed for cancer patients who suffer severe chronic pain and in some cases have trouble swallowing pills. But Dr. Bob Rappaport, head of the FDA division that oversees painkillers, said some doctors had been prescribing the patch to patients who didn't need such a powerful narcotic -- and in at least one case, even used it to treat headaches.
Patches can be more convenient than pills; the fentanyl patch is designed to deliver the drug at a steady rate for as long as three days, so patients don't have to take medication several times a day. But there are also drawbacks: A single patch contains a substantially larger quantity of the medication than individual pills; heat and exercise can increase the rate at which the drug is absorbed through the skin.Rappaport said the FDA had not found such serious problems with other methods of delivering fentanyl, including by injection. "It's a unique problem with patches because of . . . the way that the drug is delivered to the body and the way that it's metabolized," he said. "It's complicated by the patch formulation.
"The FDA said doctors should not prescribe the patch for patients whose pain was expected to go away, such as those recovering from an operation. The patch should be used only by patients who are in chronic pain and are already safely taking opioid-type drugs.The agency warned patients to call their doctors if they have trouble breathing, because fentanyl can shut down the respiratory system. It said patients wearing the patch should avoid hot showers and heating pads.Rappaport said the situation was "very concerning" because such patch-related deaths could easily be prevented.And adult patients are not the only ones at risk: At least one child has died after applying a parent's patch.
Not only is the fentanyl patch strong medicine, it is also widely used. About 4.7 million prescriptions were filled in 2006, according to Verispan, a market analysis firm. The patch was introduced in 1990 under the brand name Duragesic by Johnson & Johnson, but generic versions by Mylan Inc. and other manufacturers now dominate the market.Friday's advisory reinforced an FDA alert in 2005, which all sides acknowledge did not do enough to reduce the risk to patients. This time, the agency is directing drug makers to issue brochures that explain the dangers in plain language.That was not enough to satisfy safety advocates who have been tracking problems with the patch for years."I think there is more that needs to be done, or else we're just going to see this [warning] happen again another two years from now," said Michael Cohen, president of the Institute for Safe Medication Practices. "The deaths are going to continue." The Pennsylvania group advises hospitals and doctors on how to prevent medication errors.Cohen has called on the FDA to limit the number of doctors allowed to prescribe the drug.
That could be done by requiring physicians to take special instruction in assuring safety.But the FDA's Rappaport said such restrictions could prevent some patients who need the medication from getting prescriptions. About 60 million Americans suffer from chronic pain, he said, but only several thousand doctors in the country are certified pain specialists.Nonetheless, Cohen said, he is worried the FDA's latest warning won't register with busy doctors, particularly those who don't regularly deal with powerful narcotics. He recommended that hospitals, which usually have pain experts on staff, require their specialists to review all prescriptions for the fentanyl patch.
Several deaths reported to his group involved patients inappropriately prescribed the patch for pain relief after surgery.Last summer, a study named fentanyl as the second-deadliest drug in accidental deaths, behind painkiller oxycodone. Analyzing reports to the FDA from 1998 to 2005, researchers identified 3,545 deaths linked to fentanyl. The study looked at all forms of fentanyl, but "the patch was by far the largest contributor," lead author Thomas J. Moore said in an interview.
By comparison, the paper found that Vioxx -- the painkiller whose 2004 withdrawal was the catalyst for safety reforms at the FDA -- was a suspect in 932 deaths.Rappaport said the FDA did not have a definitive count of deaths caused by the patch and was working to develop one. He suggested the number could be smaller than reported because many patients using the patch were severely ill and could have died from underlying diseases.Spokesmen for Ortho-McNeil Inc., the subsidiary that makes Duragesic, and for Mylan said the manufacturers supported the FDA's action.Greg Panico of Ortho-McNeil said the company's research indicated that the safety warnings might be working. Reports of unapproved uses of Duragesic have declined significantly since the summer of 2006, he said.
Subscribe to:
Posts (Atom)
