Averting the Devastating Effects of Stroke

Researchers at the University of Connecticut Health Center are studying ways to prevent the devastating injuries to the body caused by stroke, a leading cause of serious long-term disability.

One American dies from stroke, sometimes called a “brain attack,” every four minutes. More than five times that many people survive a stroke, and for them, the physical damage it causes can be enormous.

“Stroke often doesn’t kill you, but some patients say they would have rather died than be left with severe disability and not be able to care for themselves,” says Dr. Louise D. McCullough, professor of neurology and neuroscience and director of stroke research. “People can often be disabled from their stroke. They need assistance with feeding and sometimes can’t get out of bed. Many can’t speak or communicate, and this is very isolating. And now we’re seeing an increasing number of stroke survivors as our population ages.”

There are two types of stroke. Ischemic strokes, which account for the vast majority, happen when clots block the blood vessels to the brain and cut off blood flow. Hemorrhagic strokes happen when the wall of a blood vessel breaks and blood leaks into the surrounding brain. Signs of either type of stroke include sudden numbness or weakness of the face or arm or leg, especially on one side of the body, as well as sudden confusion, difficulty speaking or understanding, trouble seeing or walking, dizziness or loss of balance, and/or a sudden severe headache.

McCullough’s research focuses on ischemic stroke. This type of stroke can be treated in an emergency room with “clot-busting” medication called tissue plasminogen activator (tPA), which helps reduce damage to the brain. But tPA can be effective only if given within a few hours of a stroke, and many people don’t immediately realize they are having a stroke and don’t seek help right away. In addition, some people can’t receive tPA because of other health issues.

“Nationwide, only 5 to 8 percent of people who have a stroke get tPA effectively,” she says. “So we’ve been limited in treatment. We’ve never been able to find a drug to protect the brain after stroke. Reperfusion (restoring the blood flow using tPA) is less useful because the brain is already damaged.”

So McCullough’s research involves studying factors such as what contributes to brain injury after a stroke and how it might be reversed. Because women tend to do worse than men in terms of survival and disability, she also is studying the role that hormones play in stroke risk and recovery.

Much of the understanding about stroke and its treatment has stemmed from research in men, but not all of those findings can benefit women, she points out. “Stroke is different in women – how we present, how we respond to drugs, how we recover. Women have a higher risk of stroke, a slower recovery and more cognitive problems. We need to understand the sex differences on a cellular level. For example, cell death occurs by different pathways in the two sexes. We’re trying to figure out why the biology is different and whether that’s important to therapy.”

In addition, women and men respond differently to different types of drugs. McCullough points to basic aspirin as an example of this. In women, a daily dose of aspirin can help prevent stroke but seems to have no impact in preventing heart disease. In men, the opposite is true.

Interestingly, McCullough also has found a correlation between social factors and stroke. In a study funded by the National Institutes of Health (NIH), McCullough is using mouse models to understand the role that social isolation might play in ischemic stroke.

“We’ve found that isolation is as big a risk factor for having a stroke as hypertension (high blood pressure),” she explains. “We also found that if we induce a stroke in a mouse that is isolated from others, the stroke is 40 percent bigger. And three days after a stroke, a mouse that is placed with others does better than a mouse that is alone. So now we’re saying that with hospitalized patients, maybe we should put someone who has had a stroke in a room with, say, someone who has had a hip replacement.”

McCullough earned her medical degree and Ph.D. from UConn’s School of Medicine. She completed an internship, residency and fellowship at Johns Hopkins University in Baltimore before returning to Connecticut after her father, a physicist, suffered a disabling stroke. She hopes her research will help people like her father as well as future generations, including her four children ranging in age from 7 to 13, whose framed artwork covers larger portions of the walls in her office than do the smaller certificates honoring her with Best Doctor awards and Outstanding Teacher recognition.

In a nearby office, Dr. Lauren Hachmann Sansing, assistant professor of neurology, is looking at stroke in another way. Her research focuses on hemorrhagic stroke, the type that results from a ruptured blood vessel in the brain. “This type of stroke is devastating,” she explains. “It affects two million patients a year, and only 50 percent survive it. People may become paralyzed, unable to speak and unconscious due to the mass of blood within the brain.”

This intracerebral bleeding induces an immune reaction in the body in which white blood cells (leukocytes) travel to the brain in response to the injury. Unfortunately, this does further harm by causing brain swelling and actually worsens the cell death caused by the stroke. Sansing has obtained an NIH K08 grant – funds awarded to support the research of new physician-scientists – to study how this immune reaction can be prevented.

“Using a mouse model, we are measuring and quantifying how many leukocytes travel to the brain and how we could block them using certain anti-inflammatory drugs, such as arthritis drugs that target this cell population,” Sansing says. “We are working to determine which pathways are active in patients after a stroke, and we think we are onto something. We’re using drugs already tested in humans, with good safety data, and so we already know the dosing. If we find efficacy in animal models, we can go right to safety in human studies.”

Working to understand and treat this secondary wave of injury after a stroke is an interesting mix of the neurology and immunology courses that Sansing enjoyed as a student. She completed undergraduate studies at Cornell University, her medical degree at SUNY Stony Brook School of Medicine, and a master’s in translational research (which involves converting scientific discovery into health improvement) at the University of Pennsylvania, where she also completed an internship, residency and fellowships in vascular neurology and translational medicine.

“We’re hopeful about our work,” Sansing says. “But there have been many, many treatments for stroke that have worked in animal models but failed to improve outcomes in patients. With the evolution of biomarkers studies and the ability to study proteins and activation in patients, we have a lot of insights into what we should go after as potential targets. Dr. McCullough and I have a large biobank of samples from stroke patients who have donated blood samples to help us study the disease. These samples help ensure that what we study in our animal models is important in our patients.”

Both McCullough and Sansing are involved in active research while also seeing patients, and they say their studies are greatly benefitted by doing both. “It’s like a big puzzle,” Sansing explains. “We create a model, study it, go back to patients, then go back to research. Our overall goal is to someday say we have a new treatment that can make a difference in people’s lives.”

New Early Warning System for the Brain Development of Babies

A new research technique, pioneered by Dr. Maria Angela Franceschini, was published in JoVE (Journal of Visualized Experiments) on March 14th. Researchers at Massachusetts General Hospital and Harvard Medical School have developed a non-invasive optical measurement system to monitor neonatal brain activity via cerebral metabolism and blood flow.

Of the nearly four million children born in the United States each year, 12% are born preterm, 8% are born with low birth weight, and 1-2% of infants are at risk for death associated with respiratory distress. The result is an average infant mortality rate of 6 deaths per 1,000 live births. These statistics, though low compared to those of 50 or even 20 years ago, are troubling both to parents and to clinicians. Until recently there were no effective bedside methods to screen for brain injury or monitor injury progression that can contribute to developmental abnormalities or infant mortality. Dr. Franceschini’s new system does both.

“We want to measure cerebral vascular development and brain health in babies,” Dr. Franceschini tells us. Because neuronal metabolism is hard to measure directly, scientists instead evaluate cerebral oxygen metabolism, which highly corresponds to neuronal metabolism. Dr. Franceschini and her team have developed a near infrared optical system to quantify cerebral oxygen metabolism by measuring blood oxygen saturation and blood flow.

The technology is an improvement on continuous-wave near-infrared spectroscopy (CWNIRS), which measures oxygen saturation but does not provide long-term or real time brain monitoring. Instead, frequency-domain near-infrared spectroscopy (FDNIRS) is used in conjunction with diffuse correlation spectroscopy (DCS) to get a more robust evaluation of infant health. Dr. Franceschini explains, “CWNIRS has been used for many years but it only provides relative measurements of blood oxygen saturation. Our technology allows quantification of multiple vascular parameters and evaluation of oxygen metabolism which gives a more direct picture of infant distress.”

“This technology will let us monitor babies who may be having seizures, cerebral hemorrhages, or other cerebral distresses and may allow us to expedite treatment,” says Dr. Franceschini, who plans to develop and streamline this technology to one that nurses can use clinically. “We chose to publish in JoVE because it is important to show how these measurements can be done and this publication lets us reach early adopters.”

Study Explains Why Fainting Can Result From Blood Pressure Drug Used In Conjunction With Other Disorders

A new study led by a Canadian research team has identified the reason why prazosin, a drug commonly used to reduce high blood pressure, may cause lightheadedness and possible fainting upon standing in patients with normal blood pressure who take the drug for other reasons, such as the treatment of PTSD and anxiety.

According to University of British Columbia researcher and study team leader Dr. Nia Lewis, the body is in constant motion leading to changes in blood pressure with every activity. For example, when standing, the body copes with the sudden drop in blood pressure by constricting peripheral vessels to concentrate the blood in the areas that help stabilize the body.

This study found that prazosin prevents this process by blocking the α1-adrenoreceptor, a critical pathway that allows the vessels to constrict. This physiological response is dangerous for individuals with normal blood pressure who take prazosin to treat the symptoms of PTSD and anxiety, for the act of standing up can cause light-headedness and/or fainting.

The study, entitled “Initial orthostatic hypotension and cerebral blood flow regulation: effect of α1-adrenoreceptor activity,” is published in the American Journal of Physiology–Regulatory, Integrative and Comparative Physiology.

Methodology

Eight males and four females, with an average age of 25, and all of whom had normal blood pressure, were enrolled in the cross-over trial.  On day one of the study, participants were weighed, measured, and familiarized with the blood pressure monitoring equipment and procedures that would be used.

On the next visit, participants stayed overnight at the research facility in order to control for activity and diet. The following morning they were given either prazosin (1mg/20kg body weight) or a placebo, and instructed to lie down.  After 20 minutes, they were told to rise in one smooth motion from the lying-down position to standing, and their blood pressure and cerebral blood flow was continuously monitored. They were required to remain standing for three minutes or until they felt severe lightheadedness and dizziness, or felt as if they were about to faint.

On their third and final visit the participants underwent the same procedure as on the second visit. At this visit, however, they received the placebo if they had previously been given the medication, and vice versa.

Results

The investigators found that:

• All but one of the 12 participants who took the medication experienced temporary dizziness or lightheadedness upon standing.
• All participants who took the placebo were able to complete the three-minute standing test. By contrast, only 2 of the 12 were able to complete the standing test after taking prazosin.
• After taking prazosin, none of the participants were able to attain normal blood pressure levels after standing. As a result, blood flow to the brain was reduced and subjects were unable to stand for 3 minutes as they began to experience the onset of fainting.
• When the participants had taken prazosin, mean arterial blood pressure and systolic blood pressure was significantly lower—by 15 percent— when lying down compared to when they took the placebo. Mean arterial blood pressure also fell for a longer period (11 seconds versus eight for placebo) after participants stood up following consumption of the medication, resulting in a lower arterial pressure levels.
• Blood flow to the brain, as measured by cerebral blood flow velocity, was not different when lying down. However, brain blood flow in the prazosin trial was reduced by 33 percent more than in than compared with the placebo trial.

Conclusions

“We were able to determine that, because prazosin shuts down a pathway that is critical to regulate blood pressure, the capacity to safely control blood flow to the brain was also reduced to a level that could induce fainting,” said Dr. Lewis. “No study has examined the effects of prazosin on the interaction between blood pressure and blood flow to the brain. The findings derived from this study show a mechanism of how prazosin causes fainting,” she explained.

Importance of the Findings

“This study highlights the importance of a key pathway in the body’s blood pressure system, known as the α1-adrenergic sympathetic pathway, in ensuring the recovery of blood pressure following standing and how important this pathway is in ensuring blood flow to the brain is not reduced to a level where fainting may occur,” said Dr. Lewis.

Additionally, this study provides a cautionary alert to those who are prescribed prazosin, for other conditions besides hypertension. 

Stanford psychologists uncover brain-imaging inaccuracies

Pictures of brain regions “activating” are by now a familiar accompaniment to any neurological news story. With functional magnetic resonance imaging, or fMRI, you can see specific brain regions light up, standing out against the background like night owls’ apartment windows.

It’s easy to forget that these brain images aren’t real snapshots of brain activity. Instead, each picture is the result of many layers of analysis and interpretation, far removed from raw data.

"It’s just one representation of brain activity," said Matthew Sacchet, a PhD student in the Neurosciences Program at the Stanford School of Medicine. "As you process the data, it can change."

Sacchet works in the lab of Stanford psychology Associate Professor Brian Knutson, who studies reward processing in a small area of the brain known as the nucleus accumbens. Precisely how that structure activates is at the heart of an ongoing debate about reward circuits – a subject that holds relevance for our understanding of everything from addiction to financial risk-taking.

Unfortunately, according to a paper from Knutson and Sacchet, hundreds of research papers on this circuit may be unintentionally biased. When the labs processed their fMRI findings, many used a one-size-fits-all strategy that skewed which regions of the brain appeared to be activating.

"I honestly think most people want good data," said Knutson. "I’m excited that we can make this kind of research more rigorous."

The paper appeared in the journal NeuroImage.

Too much smoothing

Functional magnetic resonance imaging measures changes in blood flow in the brain. It’s a powerful tool, but the signal fMRI actually detects – the result of the magnetic differences between oxygenated and deoxygenated blood – is noisy.

Researchers need to statistically process the data in order to make the resulting data interpretable. One of the most common approaches is known as “spatial smoothing,” which involves averaging the activity of each brain region with that of its neighbors.

But fMRI has only been in use since the mid-1990s. Many of the most common analyses in use today are holdovers from older, lower-resolution types of imaging and seem to have some undesired effects on the finer-grained signals fMRI can provide.

Knutson and Sacchet found that when researchers process fMRI data with a traditional “smoothing kernel” of 8mm, they end up averaging their images over too large an area. Activity in smaller brain structures can then be overlooked, or even shifted to areas that receive more blood flow and where the blood oxygenation level-dependent signal is stronger.

"It might seem strange that a systematic bias like that could bias the whole field," Knutson said. "But if half the people use 8mm and half use 4mm, you might end up with very different results, and it could add up."

Reward structure

These statistical pitfalls are particularly glaring when studying the small, structurally complex nucleus accumbens.

Findings from the Knutson Lab, which has been using the smaller, 4mm smoothing kernel for years, suggest that different parts of the nucleus accumbens have different functions. The forward portion seems to distinguish between positive or negative stimuli, reacting specifically to rewards. Meanwhile, the rear section responds more to the intensity of the motivation.

While some other labs have corroborated this finding, others only found activation in the rear half of the structure.

These contradictory findings now appear to have been skewed. Because the back of the nucleus accumbens is larger and surrounded by more blood-infused gray matter than the front, the smoothing step made it appear as if all the nucleus accumbens’ activity originated far to the rear.

A collaborator in Germany already has taken the paper’s advice, Sacchet said. “She had a colleague reanalyze her data and found the same thing we found.”

Knutson emphasized that the research paper doesn’t mean “the methods are bunk.” Simply improving the way scientists process signals can enhance their ability to locate specific brain functions.

"There may be a debate, but you can resolve that debate with data," he said.

Even mild traumatic brain injuries can kill brain tissue

Scientists have watched a mild traumatic brain injury play out in the living brain, prompting swelling that reduces blood flow and connections between neurons to die.

“Even with a mild trauma, we found we still have these ischemic blood vessels and, if blood flow is not returned to normal, synapses start to die,” said Dr. Sergei Kirov, neuroscientist and Director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.

They also found that subsequent waves of depolarization – when brain cells lose their normal positive and negative charge – quickly and dramatically increase the losses.

Researchers hope the increased understanding of this secondary damage in the hours following an injury will point toward better therapy for the 1.7 million Americans annually experiencing traumatic brain injuries from falls, automobile accidents, sports, combat and the like.  While strategies can minimize impact, no true neuroprotective drugs exist, likely because of inadequate understanding about how damage unfolds after the immediate impact.

Kirov is corresponding author of a study in the journal Brain describing the use of two-photon laser scanning microscopy to provide real-time viewing of submicroscopic neurons, their branches and more at the time of impact and in the following hours.

Scientists watched as astrocytes – smaller cells that supply neurons with nutrients and help maintain normal electrical activity and blood flow – in the vicinity of the injury swelled quickly and significantly. Each neuron is surrounded by several astrocytes that ballooned up about 25 percent, smothering the neurons and connective branches they once supported.

“We saw every branch, every small wire and how it gets cut,” Kirov said. “We saw how it destroys networks. It really goes downhill. It’s the first time we know of that someone has watched this type of minor injury play out over the course of 24 hours.”

Stressed neurons ran out of energy and became silent but could still survive for hours, potentially giving physicians time to intervene, unless depolarization follows. Without sufficient oxygen and energy, internal pumps that ensure proper polarity by removing sodium and pulling potassium into neurons, can stop working and dramatically accelerate brain-cell death.

“Like the plus and minus ends of a battery, neurons must have a negative charge inside and a positive charge outside to fire,” Kirov said. Firing enables communication, including the release of chemical messengers called neurotransmitters.

“If you have six hours to save tissue when you have just lost part of your blood flow, with this spreading depolarization, you lose tissue within minutes,” he said.

While common in head trauma, spreading depolarization would not typically occur in less-traumatic injuries, like his model. His model was chemically induced to reveal more about how this collateral damage occurs and whether neurons could still be saved. Interestingly, researchers found that without the initial injury, brain cells completely recovered after re-polarization but only partially recovered in the injury model.

While very brief episodes of depolarization occur as part of the healthy firing of neurons, spreading depolarization exacerbates the initial traumatic brain injury in more than half of patients and results in poor prognosis, previous research has shown. However, a 2011 review in the journal Nature Medicine indicated that short-lived waves can actually protect surrounding brain tissue. Kirov and his colleagues wrote that more study is needed to determine when to intervene.

One of Kirov’s many next steps is exploring the controversy about whether astrocytes’ swelling in response to physical trauma is a protective response or puts the cells in destruct mode. He also wants to explore better ways to protect the brain from the growing damage that can follow even a slight head injury.

Currently, drugs such as diuretics and anti-seizure medication may be used to help reduce secondary damage of traumatic brain injury. Astrocytes can survive without neurons but the opposite is not true, Kirov said. The ratio of astrocytes to neurons is higher in humans and human astrocytes are more complex, Kirov said.

Shedding New Light on Infant Brain Development

A new study by Columbia Engineering researchers finds that the infant brain does not control its blood flow in the same way as the adult brain. The findings, which the scientists say could change the way researchers study brain development in infants and children, are published in the February 18 Early Online edition of Proceedings of the National Academy of Sciences (PNAS).

“The control of blood flow in the brain is very important,” says Elizabeth Hillman, associate professor of biomedical engineering and of radiology, who led the research study in her Laboratory for Functional Optical Imaging at Columbia. “Not only are regionally specific increases in blood flow necessary for normal brain function, but these blood-flow increases form the basis of signals measured in fMRI, a critical imaging tool used widely in adults and children to assess brain function. Many prior fMRI studies have overlooked the possibility that the infant brain controls blood flow differently.”

“Our results are fascinating,” says Mariel Kozberg, a neurobiology MD-PhD candidate who works under Hillman and is the lead author of the PNAS paper. “We found that the immature brain does not generate localized blood-flow increases in response to stimuli. By tracking changes in blood-flow control with increasing age, we observed the brain gradually developing its ability to increase local blood flow and, by adulthood, generate a large blood-flow response.”

The study results suggest that fMRI experiments in infants and children should be carefully designed to ensure that maturation of blood-flow control can be delineated from changes in neuronal development. “On the other hand,” says Hillman, “our findings also suggest that vascular development may be an important new factor to consider in normal and abnormal brain development, so our findings could represent new markers of normal and abnormal brain development that could potentially be related to a range of neurological or even psychological conditions.”