Stroke

The third leading cause of death in the United States, stroke is also the number one cause of severe neurological disability, accounting for more than $50 billion annually in related costs. Now, research from Stanford neuroscientists and colleagues offers hope of a potential drug treatment to increase the number of new nerve cells in areas of the brain damaged during stroke and enhance patients’ recovery.

In the animal study (subscription required), researchers focused on a compound called LM22A-4, a small molecule whose bulk is less than one-seventieth that of the brain protein it mimics: brain-derived neurotrophic factor (BDNF), a powerful and long-studied nerve growth factor. Critical during the development of the nervous system, BDNF is known to be involved in important brain functions including memory and learning. As my colleague describes in a release:

[The research] team induced severe strokes on one side of the brain in adult laboratory mice that had been previously trained in several distinct athletic tasks. Three days afterward, the researchers administered once-daily intranasal doses of LM22A-4 in a solution to one group of the mice, while giving another group (who had suffered strokes as severe as those in the first group) a similar dose of the same solution without any LM22A-4 in it. Delaying the first dose for three days better tests the ability of this treatment to help stroke patients in the real world, [senior author, Marion Buckwalter, MD, PhD,] said.

Dosing proceeded for 10 weeks, while the scientists monitored both the animals’ recovery of their motor skills and the numbers of new nerve cells in areas of the mice’s brains that had been damaged by strokes.

Mice receiving LM22A-4 regained their athletic prowess considerably more quickly than those given the dummy solution: both the accuracy of their foot placement and the swing speed of the limb on the side of their bodies affected by the stroke improved more rapidly. Moreover, analysis revealed twice as many new nerve cells in these mice’s stroke-affected brain areas, at six and 10 weeks after the event, than in those of their LM22A-4-denied counterparts.

For recovering patients, walking speed is critical, said Buckwalter. “A major factor in their ability to retain their independence and regain their self-confidence lies in their recovering the ability to get around on their feet,” she said.

The results are promising because the compound wasn’t administered to the animals until a full three days after they had suffered strokes, noted Buckwalter. As such, the treatment – if proven effective in humans – could be particularly useful for patients who suffer strokes while sleeping or don’t readily recognize the symptoms and don’t get to the hospital fast enough for existing therapeutic agents to be administered.

Previously: Brain sponge: Stroke treatment may extend time to prevent brain damage, Every second matters for stroke survival, recovery and Newly approved drug appears to provide more cost-effective stroke prevention than warfarin

There are at least three big problems with the early medical treatment from stroke: First, the only approved drug, tissue plasminogen activator or tPA, has to be infused within a few hours of the stroke. Second, the patient must first be scanned to rule out a type of stroke for which tPA would be precisely the wrong thing to infuse. And third, while tPA does break up the clotting that is responsible for most strokes, it doesn’t actually do anything to stimulate recovery in affected brain regions – or even to prevent the stroke from continuing to spread beyond the initial lesion for a time due to inflammatory processes that ensue.

But with the infusion of some venture capital and a bit of patience, a whole new approach – one that may actually help the brain recover and replace its damaged circuitry - could see the light of day.

In a collaboration (reported today in the journal Neuron) between the labs of neuroscience experts Carla Shatz, PhD, and Rona Giffard, MD, PhD, mice missing the gene for one or another of a particular set of molecules were able to recover their athletic ability much better than mice carrying those genes, which are ordinarily present in their genomes – and ours.

Interestingly, the molecules in question are associated with crucial tasks performed by the immune system. But that’s just their day-job. It was only a few years ago that Shatz demonstrated that these molecules are moonlighting in brain, where they do something entirely different: They serve as “brakes” on the formation, enhancement, diminution, and destruction of connections between nerve cells. In other words, they limit the brain’s propensity to alter these connections in response to experiences.

Ordinarily, one might think that the more amenable the brain is to experience-driven modulation, the better. But as noted in my release concerning the new study:

This very flexibility, if it becomes excessive, is thought to put the brain at risk for conditions such as epilepsy or schizophrenia. The molecules Shatz has been exploring can be seen as providing a measure of stablizing ballast.

However, after a stroke, when re-establishing lost or damaged brain functions is paramount and time is of the essence, what could be more important than restoring lost nerve connections or quickly forming new ones? Might easing up on the brake pedal under those circumstances possibly be a good idea?

The Shatz/Giffard study suggests the answer might be yes. But demonstrating this in a way that will lead to stroke recovery in our species, or at least to clinical trials in humans - will require an agent a bit more subtle than deleting a gene. A small molecule that could get into the brain quickly and impede the molecular brakes – the MHC molecules and their receptor – from engaging for a finite period of time instead of permanently would be just what the doctor ordered.

But that will have to await the beneficent intervention of a pharmaceutical company, a biotech, or an academic molecule manipulator. “We’re not pharmacologists,” says Shatz.

Any takers?

Get thee to a gallery: Art lovers may have an edge on happiness among people who are recovering from a stroke.

A study by researchers at the University Tor Vergata School of Nursing in Rome compared quality of life for stroke survivors who had appreciated art, music, and theater before their injury, and those who didn’t. Healthland reports:

Overall, art lovers reported a slew of positive physical and mental health benefits. They had more energy, better general health and improved mobility. They were also happier, less anxious or depressed and had better memory and communication skills.

“Stroke survivors who saw art as an integrated part of their former lifestyle, by expressing appreciation towards music, painting and theater, showed better recovery skills than those who did not,” lead author Dr. Ercole Vellone, assistant professor in nursing science at the University Tor Vergata, said in a statement.

The research, presented during the 12th Annual Spring Meeting on Cardiovascular Nursing, in Copenhagen, Denmark, follows other studies on music’s effect on the brain in stroke recovery.

Previously: Study could lead to new class of stroke drugs, Brain sponge: Stroke treatment may extend time to prevent brain damage, Recovering from a stroke, recovering from war: Two conversations about survival
Photo by vertigonoir

Stroke is the third-leading cause of death in the United States and the number-one cause of severe neurological disability, accounting for about $75 billion per year in related costs.

Meanwhile, the closest we’ve got to an approved drug for stroke is actually a clot-buster that, if given very soon after the stroke, can at least dissolve the obstruction that’s cutting off the blood supply to the brain. But it doesn’t address the severe inflammatory damage that occurs after the stroke.

A new study led by Stanford’s Katrin Andreasson, MD, has identified a new target: a receptor found both on nerve cells and on endothelial cells that line the copious capillaries crisscrossing the brain. When stimulated, this receptor both strengthens nerve cells’ ability to survive after a stroke and causes blood vessels to dilate, allowing increased blood flow to both the damaged core area and the at-risk region around it.

I go into more detail in a release on the study. And I also describe how Andreasson’s findings may help explain why a much-heralded class of anti-inflammatory drugs that included the now-withdrawn Vioxx turned out to have some unanticipated cardio- and cerebrovascular side effects.

A new study in mice reports that admistering pharmacological doses of a “sponge-like” molecule that occurs naturally in the human body may stave off brain damage from stroke. 

One of the study’s two senior co-authors, neuroimmunologist Larry Steinman, MD, has published several articles in the past few years on the substance’s anti-inflammatory properties and possible therapeutic benefits in indications ranging from multiple sclerosis (his specialty) to heart attack.

Strokes – there’s a new one every 40 seconds in North America alone – are caused by a sudden drop in the flow of blood to the brain resulting from a clot or, less often, bleeding. Here are the grim statistics:

The largest single cause of severe neurological disability and the third-leading cause of death in the United States, stroke accounts for an estimated $74 billion annually in related costs, including treatment and additional assistance for the three of every four stroke patients whose ability to perform the activities of daily life is impaired. One of every three stroke patients is under the age of 65. In all, there are 5.4 million stroke survivors in the United States and 15 million worldwide.

The only currently approved treatment, tissue plasminogen activator or tPA, is not only costly, but must be given within 4.5 hours of the incident to be effective. That’s already tough, given the initial denial that often prevents those experiencing a stroke from immediately getting help. Further complicating the logistics is the fact that before administering tPA to a patient, doctors have to first run a brain scan to make sure the patient’s stroke was caused by a clot, not by bleeding. (If it’s the latter, tPA, which works by dissolving clots, would make it even worse.)

The substance tested in the study, alpha-B-crystallin, is produced in healthy tissues as well as in the brain in response to a stroke – but, according to neurosurgeon Gary Steinberg, MD, PhD, the study’s other senior co-author, not in sufficient amounts to fully quench the inflammatory mayhem that follows. Indeed, much of the damage caused by stroke is due not to the initial blockage of blood flow to affected brain areas, but to the ensuing storm of inflammatory activity brought about by a scream of molecular sirens, an ensuing police riot of trigger-happy immune cells squirting brain-cell-breaking oxidants.

Alpha-B-crystalline seems to act like a sponge, soaking up all these crazed inflammatory hotheads, shrinking the ultimate size of the stroke lesion, and apparently reducing the resulting behavioral deficits even when given 12 hours after the stroke. At least in mice. (Stay tuned.)

Photo by Pobre.ch

Before I head to the beach, I wanted to mention two 1:2:1 podcasts that complement articles in the latest issue of Stanford Medicine magazine.

Jill Bolte Taylor, PhD, is a brain scientist who wrote about her stroke in the New York Times best-seller, My Stroke of Insight. At the beginning of the book, she describes her stroke in remarkable detail. It felt like she was sort of looking at herself inside out: living and feeling the stroke on the one hand and on the other, observing her body and motor skills as they crash. It’s all rather unnerving in its clarity. She describes her neurological breakdown with such granularity that it makes you wonder who was taking the notes.

In our conversation for the Stanford Medicine article, she couldn’t talk about the day of her stroke (she’s muzzled by a movie deal in the works), but she does talk about the eight years it took to recover. You can hear the full conversation in the podcast, and if her story captures your imagination, take a look at her TED talk. It’s the second-most viewed presentation over the program’s past five years, with more than 8 million online viewers.

Another podcast pertains to survivors of extreme psychological and physical trauma. And it makes you ask, can the residue from unspeakable abuse at the hands of a terrorist government ever be diminished? That’s one of the questions posed by a United Nations-backed tribunal trying Khmer Rouge war criminals in Phnom Penh, Cambodia. For the first time and to an unprecedented degree, the trial is including victims’ testimonies as a central component of the proceedings. Thousands of survivors from Pol Pot’s reign of terror live in the Bay Area, and mental health workers here, some of whom are affiliated with Stanford, are helping these survivors with critical mental health issues like PTSD.

I talked with Daryn Reicherter, MD, a psychiatrist at Stanford, who works with Cambodian immigrants in San Jose, Calif. He’s seen survivors of some of the worst human crisis of the 20th century – not only Cambodian immigrants but also asylum seekers from Darfur, Congo, and the Middle East, along with refugees from Vietnam, and Central and South America. Tracie White has written an amazing story for Stanford Medicine asking the question: Can the testimony at the tribunal ever bring a sense of justice and help heal the psychological scars for the victims of the terror campaign? The horror of the physical and psychological abuse thrust upon the nation by their fellow citizens won’t leave your mind very easily.

Previously: Surviving survival: The new Stanford Medicine magazine is out

In a straight-out-of-sci-fi experiment, University of Florida researchers grew neurons on a computer chip – and the neurons started to think. That is to say, they started to show signs of brain activity. By the time the brain cells had been left to grow for 30 days, researchers measured levels of neural activity approaching those present in a real, live, developing mammal brain. IT’S ALIIIIVE!

Well, sort of alive, anyway. The computer-chip model that researchers designed cannot, by itself, retain information or demonstrate intellectual capacity.  The success of this synthetic brain does, however, suggest the possibility of future treatments for brain trauma or for brain-matter replacement in the wake of disorders like strokes.

This is not the first synthetic brain to show promise, though it is the most tangibly biological (Stanford researcher Kwabena Boahen, PhD, for example, has developed a computer chip theoretically capable of powering a computer with the intelligence of the human mind). One can only imagine the evil cackling that would ensue if these technologies ever wound up in the wrong hands.

Via SmartPlanet
Photo by Hatchibombotar

A very lucky stroke survivor tells his story in this month’s Stanford Health Notes and in the video above.

Minutes after slumping over, paralyzed in mid-conversation, Chris McLachlin was taken to the hospital and given life-saving blood clot-busting medicine. A fellow stroke survivor in the room had recognized the signs and called 911.

Strokes, which are the number one cause of adult disability, starve parts of the brain of blood and oxygen. The quicker blood flow can be restored, the less permanent damage occurs. “Time is brain,” according to physicians who treat strokes.

McLachlin’s speedy treatment made all the difference for him. He’s now back working as an assistant coach for Stanford University’s men’s volleyball team. His youngest son, Spencer McLachlin, captains the team.

Stroke hospitalizations among men and women ages 15 to 44 have increased notably in the past decade. Now findings from a new survey suggest the rise in stroke among young people could be because they are dangerously naive about how lifestyle choices influence disease risk.

In a survey conducted by the American Stroke Association, 1,248 Americans ages 18-44 were asked about their attitudes regarding health, including influences of and beliefs about health behaviors and their risks for stroke. Results showed nine out of 10 respondents between ages 18-24 believed they make healthy choices yet most consumed too much fast food, drank alcoholic or sugar-sweetened beverages and engaged in other behaviors that could increase their risk of stroke, according to a release.

Other findings included:

• Among 35-44 year olds, only 22 percent said they were not concerned about cardiovascular diseases and conditions, including heart disease/heart attack; high blood pressure; obesity; high cholesterol; diabetes; and stroke. Yet, about half (48 percent) of them are more likely to have health concerns they struggle with today.

• Most 18-24 year olds said they want to live long and maintain quality health throughout their life. Yet, one-third of those surveyed don’t believe engaging in healthy behaviors now could affect their risk of stroke in the future.

• All groups said that they’re least worried about stroke as a personal health threat.

Previously: Stroke Awareness Month begins today. What’s your risk?
Photo by Ernesto Andrade

Nature Methods has picked optogenetics, a biological-research technology largely pioneered at Stanford, as its designated “method of the year” for 2010. Karl Deisseroth, MD, PhD, who’s also written a commentary appearing in the same issue, was and is the leading force in this new tool’s development.

If there’s anyone who understands the meaning of the admonition, “Get the right tool for the job,” it’s neuroscientists. Trying to make sense of the 100 billion neurons and 250 trillion nerve-cell-to-nerve-cell connections that dot the human brain is a huge headache.

But the payoff is big, too: Understanding exactly which circuits in the brain go awry in autism, schizophrenia, depression and other mental diseases – not to mention Parkinson’s disease and stroke, which are brain disorders, too – is the surefire way to developing treatments and perhaps cures.

Until recently, though, the only tools researchers had available for dissecting the brain’s circuitry were pretty rusty knives.

There’s electrophysiology, in which investigators place an electrode near a nerve cluster of interest, flip on the juice, and observe the change in an experimental animal’s (or in some surgical procedures, a person’s) behavior. That can cause a nerve to fire, but it can’t keep it from firing, which is sometimes what you’d like to do. And it may excite other nerves in the vicinity that the investigator didn’t intend to affect and doesn’t even know have been affected.

And there’s drugs. They tend to ooze all over (at least in terms of the microscopic scale you’re working at). They also can be pretty imprecise as to which circuits they affect as well as with respect to both how and how much they affect those circuits, and in any case they do whatever they do rather slowly compared with the speed an impulse of information moves along a nerve.

And there’s genetic approaches – mutate a particular gene, see what happens. These approaches have the advantages of working in a very specific way and in a highly reproducible manner. But genetic manipulations are tedious, take a ton of time and mouse food, and are usually irreversible. No quick-and-easy on/off switch here.

And then, wham!! Along came optogenetics, which as the name implies is a blend of optics and genetics (but also of several other disciplines from microbiology to animal care). Deisseroth and his colleagues succeeded in bioengineering mice so that long-known photosensitive molecules called opsins, ordinarily found only in various one-celled creatures, would turn up on the surfaces of mice’s nerve cells. And not just any nerve cells, only the nerve cells forming the circuits that researchers want to manipulate.

Once they figured out how to do that, Deisseroth and his team figured out how to deliver laser bursts of light, at just the right frequency, via a long, flexible optical fiber, to just the right place in a mouse’s brain, then at the flick of a switch turn the circuits on, turn them off, or deliver patterns of on/off repetitions to see how the circuits respond to waves of impulses coming in at various frequencies.

Armed with optogenetics, Deisseroth and his collaborators both at Stanford and elsewhere have identified circuits whose defective operation may be behind sleep disorders, schizophrenia, cocaine addiction, and Parkinson’s disease. This experimental technique has now spread to some 800 labs (and climbing) around the world, and holds promise for understanding how not just the brain but the heart, pancreas, and immune system do what they do, and what’s going on when they’re not doing well.

From December 20 to January 3, Scope will be on a limited holiday publishing schedule. During that time, you may also notice a delay in comment moderation. We will return to our regular schedule on January 3.

As if sleep interruptions weren’t bad enough, now women also have to worry about their jobs taking a toll on their heart health. New findings presented this week at the American Heart Association conference in Chicago show that women with high levels of stress at work face increased risks of heart attacks.

The Women’s Health Study analyzed data from 17,415 healthy women and found a 40 percent increase overall in cardiovascular disease, and an 88 percent increase in risk for heart attacks alone:

“Our study indicates that there are both immediate and long-term clinically documented cardiovascular health effects of job strain in women,” said Michelle A. Albert, M.D., M.P.H., the study’s senior author and associate physician at Brigham and Women’s Hospital, Boston, Mass. “Your job can positively and negatively affect health, making it important to pay attention to the stresses of your job as part of your total health package.”

While it may be difficult to get rid of stress, the researchers suggested ways to manage it through exercising, spending time with friends and family and limiting bringing work home.

As a new mom who recently returned to work, I feel lucky to have both a baby who sleeps through the night and a low-stress job. Now if I could only figure out what to do about my snoring husband.

Photo by Joshua Hoffman

The Los Angeles Times‘ Health Section has a feature today on the drug dabigatran, the first new drug in two decades to be approved to prevent stroke in patients with atrial fibrillation. As I blogged about earlier this month, a recent study showed that the drug was as effective as, but less likely to cause certain side effects than, its alternative, warfarin. And a separate analysis, conducted by researchers here, showed that the drug also appears to be more cost-effective.

“It’s a potential game-changer,” Mintu Turakhia, MD, MAS, a cardiac electrophysiologist with Stanford and the Veterans Affairs Palo Alto Health Care System, says of dabigatran in the piece. Turakhia was senior author on the cost-effectiveness study, which appeared in the Nov. 2 issue of the Annals of Internal Medicine.

Previously: Newly approved drug appears to provide more cost-effective stroke prevention than warfarin

I’ve written before - in fact more than once – about statistics purporting to show that the U.S. health care system stinks compared with those of, say, Canada or Europe. It appears these apples-and-oranges comparisons may be full of beans.

The evidence keeps piling up. In a just-out Rand Corporation study, investigators compared older American versus older English citizens’ death rates from various aging-associated diseases. Older Americans are almost twice as likely to be diagnosed with such increasingly common conditions as type 2 diabetes, high blood pressure, and the like. Is this evidence of an inferior U.S. health care system?

Probably not. Those suffering from these syndromes in the U.S. are only half as likely to die from them as their British counterparts. As a result, the afflicted Americans live at least as long as the afflicted British. Overall, 65-year-old Americans can expect to outlive their like-aged friends across the pond by about three months, despite their higher likelihood of having or getting an aging-associated illness.

The researchers note two possible explanations for why sick elders live longer in America than in England:

One is that the illnesses studied result in higher mortality in England than in the United States. The second is that the English are diagnosed at a later stage in the disease process than Americans.

Either explanation, they add, implies a more responsive health care system in the U.S. – at least for older people, who have nearly universal access to it. The fault appears to lie not in the health care system we Americans frequent (if you ignore its expense), but in our own lifestyle choices and, perhaps, other factors outside the control of both our health-care system and ourselves.

The blood-thinner warfarin isn’t the most universally loved medication in the world. The drug, which is commonly prescribed to people with certain heart conditions, can be quite effective at preventing blood clots. But it also carries risks (too little and it could fail to be effective, too much and it could lead to serious or fatal hemorrhage), and people taking the medication face constant blood testing and dose adjustment.

“Among my patients, I get asked about alternatives to warfarin a dozen times a week,” Mintu Turakhia, MD, MAS, a cardiac electrophysiologist with Stanford and the Veterans Affairs Palo Alto Health Care System, recently told me. “Many of them are just unhappy with the need for regular, often lifelong blood testing.”

Last month the FDA approved an alternative – the drug dabigatran, marketed as Pradaxa – to prevent stroke in patients with an irregular heart rhythm. (This followed a large study showing the drug, which requires no blood testing, was about as effective as warfarin in preventing strokes but less likely to cause hemorrhages.) And now there is more potentially promising news about the therapy: According to a study led by Turakhia, using the drug to prevent stroke appears to be cost-effective, depending on pricing, and dabigatran may also offer patients better health outcomes than warfarin.

To come to this conclusion, Turakhia and colleagues developed a mathematical model that simulated 10,000 older patients with atrial fibrillation and risk factors for stroke, and compared outcomes and costs of warfarin and two different doses of dabigatran. They found that the high-dose dabigatran yielded an additional 0.56 quality-adjusted-life-year – a common metric that takes into account quality of life as well as length of survival – and came at an incremental cost over warfarin of $45,372 per quality-adjusted-life-year – well below the commonly accepted cost-effective threshold of $50,000.

Dabigatran is the first new drug in two decades to be approved for stroke prevention in atrial fibrillation, and Turakhia said it was exciting that it appears to be both therapeutically effective and cost-effective. His hope is that the findings, which appear in the Annals of Internal Medicine, will help guide decisions by physicians, insurance payers and policy-makers about the medication.

Did you ever think photosynthetic algae would throw light on the problem of helping paraplegics walk before they run? A new study in Nature Medicine illustrates basic science’s potential to lead to medically valuable results.

Optogenetics, invented at Stanford by psychiatrist and bioengineer Karl Deisseroth, MD, PhD, is a research technology in which the gene for a light-sensitive protein found in algae is inserted into the genome of experimental animals (mice).

The result is that the surfaces of nerve fibers in those otherwise normal mice’s brains wind up dotted with this protein. In turn, the protein responds to certain wavelengths of light by triggering electrical impulses in the nerve fibers on which they sit.

The technique allows scientists such as Deisseroth to use light to precisely probe the functions of very specific groups of nerve cells in the brain, leading to all kinds of insights about the nature of syndromes such as Parkinson’s disease.

Now, for the first time, optogenetics has been adapted for use with the skeletal musculature. It turns out that, in the same experimental mice, the motor nerves that exit the spinal cord and make contact with muscle fibers are also coated with the light-sensitive, impulse-triggering protein.

The problem of restoring physiologically normal movement in paraplegics is something bioengineer Scott Delp, PhD, has been working on for some time. Attempts to do this using electrical impulses to trigger the firing of motor nerves have met with partial success. But electrical stimulation triggers nerve firing in the wrong sequence: powerful fast-twitch muscle fibers first, fine-movement-coordinating slow-twitch muscle fibers last. The result: extremely jerky motion, and rapid fatigue.

Mike Llewellyn, PhD, of Delp’s lab designed a tiny optical cuff that beamed intense LED light at the mice’s sciatic nerves. This activated nerves in such a way that slow-twitch muscle fibers contracted first, just as they do in normal muscles.

A big obstacle to moving this work rapidly into the clinic is the need to demonstrate the safety of gene therapy on humans. But that ought to be easier to accomplish in an experiment involving arms and legs than in one involving brains.