Substance in Humans is Effective Fighting Stroke Damage

A molecular substance that occurs naturally in humans and rats was found to “substantially reduce” brain damage after an acute stroke and contribute to a better recovery, according to a newly released animal study by researchers at Henry Ford Hospital.

The study, published online before print in Stroke, the journal of the American Heart Association, was the first ever to show that the peptide AcSDKP provides neurological protection when administered one to four hours after the onset of an ischemic stroke.

This type of stroke occurs when an artery to the brain is blocked by a blood clot, cutting off oxygen and killing brain tissue with crippling or fatal results.

“Stroke is a leading cause of death and disability worldwide,” said Li Zhang, M.D., a researcher at Henry Ford and lead author of the study. “Our data showed that treatment of acute stroke with AcSDKP alone or in combination with tPA substantially reduced neurovascular damage and improved neurological outcome.”

Commonly called a “clot-buster,” tPA, or tissue plasminogen activator, is the only FDA-approved treatment for acute stroke.

However, tPA must be given shortly after the onset of stroke to provide the best results. It also has the potential to cause a brain hemorrhage.

The Henry Ford study found that this narrow “therapeutic window” is extended for up to four hours after stroke and the therapeutic benefit of tPA is amplified when tPA is combined with AcSDKP. Further, the researchers discovered that AcSDKP alone is an effective treatment if given up to one hour after the brain attack.

The researchers tested the actions of both substances on laboratory rats in which acute stroke had been induced. It was already known that the peptide AcSDKP provides anti-inflammatory effects and helps protect the heart when used to treat a variety of cardiovascular diseases. The Henry Ford scientists reasoned that the peptide may have similar neurological benefits.

Significantly, they found that AcSDKP can readily cross the so-called “blood brain barrier” that blocks other neuroprotective substances.

A battery of behavioral tests was given to the lab rats both before and after stroke was induced to measure the effects of AcSDKP administered alone one hour after onset and combined with tPA four hours after stroke.

Besides finding that both methods “robustly” decreased neurological damage associated with stroke, they did so without increasing the incidence of brain hemorrhage or the formation of additional blood clots.

“With the increased use of clot-busting therapy in patients with acute stroke, both the safety and effectiveness of the combined treatment shown in our study should encourage the development of clinical trials of AcSDKP with tPA,” Dr. Zhang says.

Gesturing with hands is a powerful tool for children’s math learning

Children who use their hands to gesture during a math lesson gain a deep understanding of the problems they are taught, according to new research from University of Chicago’s Department of Psychology.

Previous research has found that gestures can help children learn. This study in particular was designed to answer whether abstract gesture can support generalization beyond a particular problem and whether abstract gesture is a more effective teaching tool than concrete action.

“We found that acting gave children a relatively shallow understanding of a novel math concept, whereas gesturing led to deeper and more flexible learning,” explained the study’s lead author, Miriam A. Novack, a PhD student in psychology.

The study, “From action to abstraction: Using the hands to learn math,” is published online by Psychological Science.

The researchers taught third-grade children a strategy for solving one type of mathematical equivalence problem, for example, 4 + 2 + 6 = ____ + 6. They then tested the students on similar mathematical equivalence problems to determine how well they understood the underlying principle.

The researchers randomly assigned 90 children to conditions in which they learned using different kinds of physical interaction with the material. In one group, children picked up magnetic number tiles and put them in the proper place in the formula. For example, for the problem 4 + 2 + 6 = ___ + 6, they picked up the 4 and 2 and placed them on a magnetic whiteboard. Another group mimed that action without actually touching the tiles, and a third group was taught to use abstract gestures with their hands to solve the equations. In the abstract gesture group, children were taught to produce a V-point gesture with their fingers under two of the numbers, metaphorically grouping them, followed by pointing a finger at the blank in the equation.

The children were tested before and after solving each problem in the lesson, including problems that required children to generalize beyond what they had learned in grouping the numbers. For example, they were given problems that were similar to the original one, but had different numbers on both sides of the equation.

Children in all three groups learned the problems they had been taught during the lesson. But only children who gestured during the lesson were successful on the generalization problems.

“Abstract gesture was most effective in encouraging learners to generalize the knowledge they had gained during instruction, action least effective, and concrete gesture somewhere in between,” said senior author Susan Goldin-Meadow, the Beardsley Ruml Distinguished Service Professor in Psychology. “Our findings provide the first evidence that gesture not only supports learning a task at hand but, more importantly, leads to generalization beyond the task. Children appear to learn underlying principles from their actions only insofar as those actions can be interpreted symbolically.”

Researchers Model a Key Breaking Point Involved in Traumatic Brain Injury

Even the mildest form of a traumatic brain injury, better known as a concussion, can deal permanent, irreparable damage. Now, an interdisciplinary team of researchers at the University of Pennsylvania is using mathematical modeling to better understand the mechanisms at play in this kind of injury, with an eye toward protecting the brain from its long-term consequences.

Their recent findings, published in the Biophysical Journal, shed new light on the mechanical properties of a critical brain protein and its role in the elasticity of axons, the long, tendril-like part of brain cells. This protein, known as tau, helps explain the apparent contradiction this elasticity presents. If axons are so stretchy, why do they break under the strain of a traumatic brain injury?    

Tau’s own elastic properties reveal why rapid impacts deal permanent damage to structures within axons, when applying the same force more slowly causes them to safely stretch. This understanding can now be used to make computer models of the brain more realistic and potentially can be applied toward tau-related diseases, such as Alzheimer’s.

The team consists of Vivek Shenoy, professor of materials science and engineering in the School of Engineering and Applied Science, Hossein Ahmadzadeh, a member of Shenoy’s lab, and Douglas Smith, professor of neurosurgery in Penn’s Perelman School of Medicine and director of the Penn Center for Brain Injury and Repair. 

“One of the main things you see in the brains of patients who have died because of a TBI is swellings along the axons,” Shenoy said. “Inside axons are microtubules, which act like tracks for transporting molecular cargo along the axon. When they break, there’s an interruption in the flow of this cargo and it starts to accumulate, which is why you get these swellings.”  

Smith had previously studied the mechanical properties of axons as a whole. By patterning axons in culture in parallel tracts, Smith and his colleagues could apply a stretch to the axons at different forces and speeds and measure how they responded.

“What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage,” Smith said. “But at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretch at fast rates. So the rate at which stretch is applied is the important component, such as occurs during rapid movement of the brain and stretching of axons due to head impact from a fall, assault or automobile crash.”

This observation still did not explain to researchers why microtubules, the stiffest part of the axon, were the parts that were breaking. To solve that puzzle, the researchers had to delve even deeper into their structure.

Microtubules are closely packed together inside axons, somewhat like a bundle of straws. Binding the individual straws together is the protein tau. Other biophysical modelers had previously accounted for the geometry and elastic properties of the axon during a stretching injury based on Smith’s work but did not have good data for representing tau’s role in the overall behavior of the system when it is loaded with stress over different lengths of time. 

“You need to know the elastic properties of tau,” Shenoy said, “because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole.”

Shenoy and his colleagues had a sense of tau’s elastic properties but did not have hard numbers until a 2011 experiment from a Swiss and German research team physically stretched out lengths of tau by plucking it with the tip of an atomic force microscope.

“This experiment demonstrated that tau is viscoelastic,” Shenoy said. “Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks.”

This behavior is because the strands of tau protein are coiled up and bonded to themselves in different places. Pulled slowly, those bonds can come undone, lengthening the strand without breaking it. 

“The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far,” Shenoy said. “If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break.”

With a comprehensive model of the tau-microtubule system, the researchers were able to boil down the outcome of rapid stress loading to equations with only a handful of variables. This mathematical understanding allowed the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus safe and reversible loading and unloading of stress.

“Predicting what kind of impacts will cause these strain rates is still a complicated problem,” Shenoy said. “I might be able to measure the force of the impact when it hits someone’s head, but that force then has to make its way down to the axons, which depends on a lot of different things.

“You need a multiscale model, and our work will be an input to those models on the smallest scale.”

In the longer term, knowing the parameters that lead to irreversible damage could lead to better understanding of brain injuries and diseases and to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury; Smith’s group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after stretch injury.    

“Intriguingly, it may be no coincidence that tau is also the same protein that forms neurofibrillary tangles, one of the hallmark brain pathologies of chronic traumatic encephalopathy, or CTE, which is linked to a history of concussions and higher levels of TBI,” said Smith. “Uncovering the role of tau at the time of trauma may provide insight into how it is involved in long-term degenerative processes.”

Shedding a light on pain: A technique developed by Stanford bioengineers could lead to new treatments

The mice in Scott Delp’s lab, unlike their human counterparts, can get pain relief from the glow of a yellow light.

Right now these mice are helping scientists to study pain – how and why it occurs and why some people feel it so intensely without any obvious injury. But Delp, a professor of bioengineering and mechanical engineering, hopes one day the work he does with these mice can also help people who are in chronic, debilitating pain.

"This is an entirely new approach to study a huge public health issue," Delp said. "It’s a completely new tool that is now available to neuroscientists everywhere." He is the senior author of a research paper published Feb. 16 in Nature Biotechnology.

A switch for pain

The mice are modified with gene therapy to have pain-sensing nerves that can be controlled by light. One color of light makes the mice more sensitive to pain. Another reduces pain. The scientists shone a light on the paws of mice through the Plexiglas bottom of the cage.

Graduate students Shrivats Iyer and Kate Montgomery, who led the study, say it opens the door to future experiments to understand the nature of pain and also touch and other sensations that are part of our daily lives but little understood.

"The fact that we can give a mouse an injection and two weeks later shine a light on its paw to change the way it senses pain is very powerful," Iyer said.

For example, increasing or decreasing the sensation of pain in these mice could help scientists understand why pain seems to continue in people after an injury has healed. Does persistent pain change those nerves in some way? If so, how can they be changed back to a state where, in the absence of an injury, they stop sending searing messages of pain to the brain?

Leaders at the National Institutes of Health agree that the work could have important implications for treating pain. “This powerful approach shows great potential for helping the millions who suffer pain from nerve damage,” said Linda Porter, the pain policy adviser at the National Institute of Neurological Disorders and Stroke and a leader of the NIH’s Pain Consortium.

"Now, with a flick of a switch, scientists may be able to rapidly test new pain-relieving medications and, one day, doctors may be able to use light to relieve pain," she said.

Accidental discovery

The researchers took advantage of a technique called optogenetics, which involves light-sensitive proteins called opsins that are inserted into the nerves. Optogenetics was developed by Delp’s colleague Karl Deisseroth, a co-author of the journal article. He has used the technique as a way of activating precise regions of the brain to better understand how the brain functions. Deisseroth is a professor of bioengineering, psychiatry and behavioral sciences.

Delp, who has an interest in muscles and movement, saw the potential for using optogenetics not just for studying the brain – interesting though those studies may be – but also for studying the many nerves outside the brain. These are the nerves that control movement, pain, touch and other sensations throughout our body, and that are involved in diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease.

A few years ago Stanford Bio-X, which encourages interdisciplinary projects such as this one, supported Delp and Deisseroth in their efforts to use optogenetics to control the nerves that excite muscles. In the process of doing that work, Delp said, his student at the time, Michael Llewellyn, occasionally found that he had placed the opsins into nerves that signal pain rather than those that control muscle.

That accident sparked a new line of research. Delp said, “We thought, ‘Wow, we’re getting pain neurons; that could be really important.’” He suggested that Montgomery and Iyer focus on those pain nerves that had been a byproduct of the muscle work.

A faster approach

A key component of the work was a new approach to quickly incorporate opsins into the nerves of mice. The researchers started with a virus that had been engineered to contain the DNA that produces the opsin. Then they injected those modified viruses directly into mouse nerves. Weeks later, only the nerves that control pain had incorporated the opsin proteins and would fire, or be less likely to fire, in response to different colors of light.

The speed of the viral approach makes it very flexible, both for this pain work and for future studies. Researchers are developing newer forms of opsins with different properties, such as responding to different colors of light. “Because we used a viral approach we could, in the future, quickly turn around and use newer opsins,” said Montgomery, who is a Stanford Bio-X fellow.

This entire project, which spans bioengineering, neuroscience and psychiatry, is one Delp says could never have happened without the environment at Stanford that supports collaboration across departments. The pain portion of the research came out of support from NeuroVentures, which was a project incubated within Bio-X to support the intersection of neuroscience and engineering or other disciplines. That project was so successful it has spun off into the Stanford Neurosciences Institute, of which Delp is now a deputy director.

Delp said that many challenges must be met before results of these experiments – either new drugs based on what they learn, or optogenetics directly – could become available to people but that he always has that as a goal.

"Developing a new therapy from the ground up would be incredibly rewarding," he said. "Most people don’t get to do that in their careers."

Delp and Deisseroth have started a company called Circuit Therapeutics to develop therapies based on optogenetics.

Study debunks alcohol consumption assertions

ALCOHOL consumption is not a direct cause of cognitive impairment in older men later in life, a study conducted by the University of Western Australia has found. 

The study, published in the Journal of Neurology, used Mendelian randomisation to analyse the genetic data from 3,542 men between the ages of 65 and 83 years. 

The scientists measured the participants’ cognitive function three to eight years after recording their alcohol consumption. 

Lead author, Western Australian Centre for Health and Ageing Director and UWA Professor Osvaldo Almeida says the team investigated the triangular association between alcohol consumption, cognitive impairment and a genetic polymorphism that modulates the efficiency of a critical enzyme of alcohol metabolism. 

“We found a genetic variation that increases absenteeism and decreases the total amount of alcohol consumed,” Prof Almeida says.

“If alcohol were a cause of cognitive impairment, one would expect that this genetic variation would be associated with lower risk of cognitive impairment in later life [because people with this genetic variation drink less or not at all]. 

“That was not the case. Hence, we concluded that the association between alcohol use and cognitive impairment is not due to a direct effect of alcohol.”

The study also presented results that are consistent with the possibility, but do not necessarily prove, that regular moderate drinking decreases the risk of cognitive impairment in older men.

Prof Almeida says the reasons for these results were unclear.

“But evidence from a randomised trial looking at the effect of the Mediterranean diet [which includes nuts, olive oil, vegetables and wine] on health outcomes is supportive of this hypothesis,” he says. 

“One may argue that people who drink in moderation have a lifestyle where, in general, things are done in moderation. 

“This approach to life may decrease health hazards in general.”

Prof Almeida says that although the results didn’t show alcohol affecting cognitive impairment, other studies have found excessive alcohol use to be associated with worse physical health, widowhood and poor social support. 

“[These studies] led to the assumption that alcohol must directly damage the brain and cause cognitive impairment,” he says. 

“This study shows that such an assumption is wrong. 

“It also suggests that alcohol may have a small protective effect that we need to understand better in order to develop new interventions that might contribute to prevent dementia without all the bad outcomes associated with alcohol.”