Researchers from Cincinnati Children's Hospital Medical Center report June 5 the Annals of Neurology that testing in laboratory mice shows anesthesia's neurotoxic effects depend on the age of brain neurons -- not the age of the animal undergoing anesthesia, as once thought.

Although more research is needed to confirm the study's relevance to humans, the study suggests possible health implications for millions of children and adults who undergo surgical anesthesia annually, according to Andreas Loepke, MD, PhD, a physician and researcher in the Department of Anesthesiology.

"We demonstrate that anesthesia-induced cell death in neurons is not limited to the immature brain, as previously believed," said Loepke. "Instead, vulnerability seems to target neurons of a certain age and maturational stage. This finding brings us a step closer to understanding the phenomenon's underlying mechanism"

New neurons are generated abundantly in most regions of the very young brain, explaining why previous research has focused on that developmental stage. In a mature brain, neuron formation slows considerably, but extends into later life in dentate gyrus and olfactory bulb.

The dentate gyrus, which helps control learning and memory, is the region Loepke and his research colleagues paid particular attention to in their study. Also collaborating were researchers from the University of Cincinnati College of Medicine and the Children's Hospital of Fudan University, Shanghai, China.

Researchers exposed newborn, juvenile and young adult mice to a widely used anesthetic called isoflurane in doses approximating those used in surgical practice. Newborn mice exhibited widespread neuronal loss in forebrain structures -- confirming previous research -- with no significant impact on the dentate gyrus. However, the effect in juvenile mice was reversed, with minimal neuronal impact in the forebrain regions and significant cell death in the dentate gyrus.

The team then performed extensive studies to discover that age and maturational stage of the affected neurons were the defining characteristics for vulnerability to anesthesia-induced neuronal cell death. The researchers observed similar results in young adult mice as well.

Research over the past 10 years has made it increasingly clear that commonly used anesthetics increase brain cell death in developing animals, raising concerns from the Food and Drug Administration, clinicians, neuroscientists and the public. As well, several follow-up studies in children and adults who have undergone surgical anesthesia show a link to learning and memory impairment.

Cautioning against immediate application of the current study's findings to children and adults undergoing anesthesia, Loepke said his research team is trying to learn enough about anesthesia's impact on brain chemistry to develop protective therapeutic strategies, in case they are needed. To this end, their next step is to identify specific molecular processes triggered by anesthesia that lead to brain cell death.

"Surgery is often vital to save lives or maintain quality of life and usually cannot be performed without general anesthesia," Loepke said. "Physicians should carefully discuss with patients, parents and caretakers the risks and benefits of procedures requiring anesthetics, as well as the known risks of not treating certain conditions."

About 1 percent of U.S. adults suffer from OCD, and patients usually receive antianxiety drugs or antidepressants, behavioral therapy, or a combination of therapy and medication. For those who do not respond to those treatments, a new alternative is deep brain stimulation, which delivers electrical impulses via a pacemaker implanted in the brain.

For this study, the MIT team used optogenetics to control neuron activity with light. This technique is not yet ready for use in human patients, but studies such as this one could help researchers identify brain activity patterns that signal the onset of compulsive behavior, allowing them to more precisely time the delivery of deep brain stimulation.

"You don't have to stimulate all the time. You can do it in a very nuanced way," says Ann Graybiel, an Institute Professor at MIT, a member of MIT's McGovern Institute for Brain Research and the senior author of a Science paper describing the study.

The paper's lead author is Eric Burguière, a former postdoc in Graybiel's lab who is now at the Brain and Spine Institute in Paris. Other authors are Patricia Monteiro, a research affiliate at the McGovern Institute, and Guoping Feng, the James W. and Patricia T. Poitras Professor of Brain and Cognitive Sciences and a member of the McGovern Institute.

Controlling compulsion

In earlier studies, Graybiel has focused on how to break normal habits; in the current work, she turned to a mouse model developed by Feng to try to block a compulsive behavior. The model mice lack a particular gene, known as Sapap3, that codes for a protein found in the synapses of neurons in the striatum -- a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward.

For this study, the researchers trained mice whose Sapap3 gene was knocked out to groom compulsively at a specific time, allowing the researchers to try to interrupt the compulsion. To do this, they used a Pavlovian conditioning strategy in which a neutral event (a tone) is paired with a stimulus that provokes the desired behavior -- in this case, a drop of water on the mouse's nose, which triggers the mouse to groom. This strategy was based on therapeutic work with OCD patients, which uses this kind of conditioning.

After several hundred trials, both normal and knockout mice became conditioned to groom upon hearing the tone, which always occurred just over a second before the water drop fell. However, after a certain point their behaviors diverged: The normal mice began waiting until just before the water drop fell to begin grooming. This type of behavior is known as optimization, because it prevents the mice from wasting unnecessary effort.

This behavior optimization never appeared in the knockout mice, which continued to groom as soon as they heard the tone, suggesting that their ability to suppress compulsive behavior was impaired.

The researchers suspected that failed communication between the striatum, which is related to habits, and the neocortex, the seat of higher functions that can override simpler behaviors, might be to blame for the mice's compulsive behavior. To test this idea, they used optogenetics, which allows them to control cell activity with light by engineering cells to express light-sensitive proteins.

When the researchers stimulated light-sensitive cortical cells that send messages to the striatum at the same time that the tone went off, the knockout mice stopped their compulsive grooming almost totally, yet they could still groom when the water drop came. The researchers suggest that this cure resulted from signals sent from the cortical neurons to a very small group of inhibitory neurons in the striatum, which silence the activity of neighboring striatal cells and cut off the compulsive behavior.

"Through the activation of this pathway, we could elicit behavior inhibition, which appears to be dysfunctional in our animals," Burguière says.

The researchers also tested the optogenetic intervention in mice as they groomed in their cages, with no conditioning cues. During three-minute periods of light stimulation, the knockout mice groomed much less than they did without the stimulation.

Scott Rauch, president and psychiatrist-in-chief of McLean Hospital in Belmont, Mass., says the MIT study "opens the door to a universe of new possibilities by identifying a cellular and circuitry target for future interventions."

"This represents a major leap forward, both in terms of delineating the brain basis of pathological compulsive behavior and in offering potential avenues for new treatment approaches," adds Rauch, who was not involved in this study.

Graybiel and Burguière are now seeking markers of brain activity that could reveal when a compulsive behavior is about to start, to help guide the further development of deep brain stimulation treatments for OCD patients.

Now, University of Washington researchers have demonstrated that when humans use this technology -- called a brain-computer interface -- the brain behaves much like it does when completing simple motor skills such as kicking a ball, typing or waving a hand. Learning to control a robotic arm or a prosthetic limb could become second nature for people who are paralyzed.

"What we're seeing is that practice makes perfect with these tasks," said Rajesh Rao, a UW professor of computer science and engineering and a senior researcher involved in the study. "There's a lot of engagement of the brain's cognitive resources at the very beginning, but as you get better at the task, those resources aren't needed anymore and the brain is freed up."

Rao and UW collaborators Jeffrey Ojemann, a professor of neurological surgery, and Jeremiah Wander, a doctoral student in bioengineering, published their results online June 10 in theProceedings of the National Academy of Sciences.

In this study, seven people with severe epilepsy were hospitalized for a monitoring procedure that tries to identify where in the brain seizures originate. Physicians cut through the scalp, drilled into the skull and placed a thin sheet of electrodes directly on top of the brain. While they were watching for seizure signals, the researchers also conducted this study.

The patients were asked to move a mouse cursor on a computer screen by using only their thoughts to control the cursor's movement. Electrodes on their brains picked up the signals directing the cursor to move, sending them to an amplifier and then a laptop to be analyzed. Within 40 milliseconds, the computer calculated the intentions transmitted through the signal and updated the movement of the cursor on the screen.

Researchers found that when patients started the task, a lot of brain activity was centered in the prefrontal cortex, an area associated with learning a new skill. But after often as little as 10 minutes, frontal brain activity lessened, and the brain signals transitioned to patterns similar to those seen during more automatic actions.

"Now we have a brain marker that shows a patient has actually learned a task," Ojemann said. "Once the signal has turned off, you can assume the person has learned it."

While researchers have demonstrated success in using brain-computer interfaces in monkeys and humans, this is the first study that clearly maps the neurological signals throughout the brain. The researchers were surprised at how many parts of the brain were involved.

"We now have a larger-scale view of what's happening in the brain of a subject as he or she is learning a task," Rao said. "The surprising result is that even though only a very localized population of cells is used in the brain-computer interface, the brain recruits many other areas that aren't directly involved to get the job done."

Several types of brain-computer interfaces are being developed and tested. The least invasive is a device placed on a person's head that can detect weak electrical signatures of brain activity. Basic commercial gaming products are on the market, but this technology isn't very reliable yet because signals from eye blinking and other muscle movements interfere too much.

A more invasive alternative is to surgically place electrodes inside the brain tissue itself to record the activity of individual neurons. Researchers at Brown University and the University of Pittsburgh have demonstrated this in humans as patients, unable to move their arms or legs, have learned to control robotic arms using the signal directly from their brain.

The UW team tested electrodes on the surface of the brain, underneath the skull. This allows researchers to record brain signals at higher frequencies and with less interference than measurements from the scalp. A future wireless device could be built to remain inside a person's head for a longer time to be able to control computer cursors or robotic limbs at home.

"This is one push as to how we can improve the devices and make them more useful to people," Wander said. "If we have an understanding of how someone learns to use these devices, we can build them to respond accordingly."

At the suburban Chicago laboratory, a group of scientists has seemingly defied the laws of physics and found a way to apply pressure to make a material expand instead of compress/contract.

"It's like squeezing a stone and forming a giant sponge," said Karena Chapman, a chemist at the U.S. Department of Energy laboratory. "Materials are supposed to become denser and more compact under pressure. We are seeing the exact opposite. The pressure-treated material has half the density of the original state. This is counterintuitive to the laws of physics."

Because this behavior seems impossible, Chapman and her colleagues spent several years testing and retesting the material until they believed the unbelievable and understood how the impossible could be possible. For every experiment, they got the same mind-bending results.

"The bonds in the material completely rearrange," Chapman said. "This just blows my mind."

This discovery will do more than rewrite the science text books; it could double the variety of porous framework materials available for manufacturing, health care and environmental sustainability.

Scientists use these framework materials, which have sponge-like holes in their structure, to trap, store and filter materials. The shape of the sponge-like holes makes them selectable for specific molecules, allowing their use aswater filters, chemical sensors and compressible storage for carbon dioxide sequestration of hydrogen fuel cells. By tailoring release rates, scientists can adapt these frameworks to deliver drugs and initiate chemical reactions for the production of everything from plastics to foods.

"This could not only open up new materials to being porous, but it could also give us access to new structures for selectability and new release rates," said Peter Chupas, an Argonne chemist who helped discover the new materials.

The team published the details of their work in the May 22 issue of the Journal of the American Chemical Society in an article titled "Exploiting High Pressures to Generate Porosity, Polymorphism, And Lattice Expansion in the Nonporous Molecular Framework Zn(CN)₂ ."

The scientists put zinc cyanide, a material used in electoplating,  in a diamond-anvil cell at the Advanced Photon Source (APS) at Argonne and applied high pressures of 0.9 to 1.8 gigapascals, or about 9,000 to 18,000 times the pressure of the atmosphere at sea level. This high pressure is within the range affordably reproducible by industry for bulk storage systems. By using different fluids around the material as it was squeezed, the scientists were able to create five new phases of material, two of which retained their new porous ability at normal pressure. The type of fluid used determined the shape of the sponge-like pores. This is the first time that hydrostatic pressure has been able to make dense materials with interpenetrated atomic frameworks into novel porous materials. Several series of in situ high-pressure X-ray powder diffraction experiments were performed at the 1-BM, 11-ID-B, and 17-BM beamlines of the APS to study the material transitions.

"By applying pressure, we were able to transform a normally dense, nonporous material into a range of new porous materials that can hold twice as much stuff," Chapman said. "This counterintuitive discovery will likely double the amount of available porous framework materials, which will greatly expand their use in pharmaceutical delivery, sequestration, material separation and catalysis."

The study was led by University of Adelaide Public Health researchers, who analysed data from more than 13,800 children who were born full-term.

The results, published in the international journal Pediatrics, show that babies who put on 40% of their birthweight in the first four weeks had an IQ 1.5 points higher by the time they were six years of age, compared with babies who only put on 15% of their birthweight.

Those with the biggest growth in head circumference also had the highest IQs.

"Head circumference is an indicator of brain volume, so a greater increase in head circumference in a newborn baby suggests more rapid brain growth," says the lead author of the study, Dr Lisa Smithers from the University of Adelaide's School of Population Health.

"Overall, newborn children who grew faster in the first four weeks had higher IQ scores later in life," she says.

"Those children who gained the most weight scored especially high on verbal IQ at age 6. This may be because the neural structures for verbal IQ develop earlier in life, which means the rapid weight gain during that neonatal period could be having a direct cognitive benefit for the child."

Previous studies have shown the association between early postnatal diet and IQ, but this is the first study of its kind to focus on the IQ benefits of rapid weight gain in the first month of life for healthy newborn babies.

Dr Smithers says the study further highlights the need for successful feeding of newborn babies.

"We know that many mothers have difficulty establishing breastfeeding in the first weeks of their baby's life," Dr Smithers says.

"The findings of our study suggest that if infants are having feeding problems, there needs to be early intervention in the management of that feeding."