Tag Archives: Neurosurgery

Study provides new treatment targets for deadly brain swelling

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High-efficiency transporters that work like a shuttle system to constantly move ions into and out of neurons appear to slam into reverse following a stroke or other injury and start delivering instead too much water, scientists have found.

It’s called spreading depolarization, a wave of death that can follow a stroke or traumatic brain injury, as neurons and their extensions, called dendrites, become bloated, dysfunctional and vulnerable, said Dr. Sergei Kirov, neuroscientist in the Department of Neurosurgery and director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.

While swelling is clearly a result of trauma to the brain, just how water gets into neurons was largely a mystery.

In a study published in The Journal of Neuroscience, Kirov and his colleagues report that a handful of these ion transporters – known to tote some combination of sodium, potassium and chloride – appear to be a missing link in how excess water gets inside.

“They act as molecular water pumps. This is a new way of thinking,” said Kirov. He and Dr. Nanna MacAulay, associate professor in the Department of Cellular and Molecular Medicine at the University of Copenhagen, are co-corresponding authors on the study, which is highlighted in the journal. These transporters also provide new drug targets for treating deadly edema.

Some water is routinely needed by neurons to carry out basic metabolic functions, but despite what some medical textbooks say, neurons are not freely permeable to water, Kirov said. “You need some molecular mechanism for water to enter or leave,” he said. The transporters, which are known to snatch up water and ions from outside the neuron, appeared a plausible option to Kirov.

At rest, neurons have a lot of potassium inside and a lot of sodium outside. This differential distribution of ions polarizes the neuron, creating a negative electrical charge inside. The unequal amount of sodium and potassium inside and outside is actively maintained through the operation of sodium-potassium pumps.

The differential distribution of sodium and potassium also is essential for neurons to generate electrical signals, called action potential, and communicate with other neurons or cells so humans and animals can think or move or otherwise function.

When action potential is generated, a neuron goes through a process called depolarization, which alters its electrical charge so it becomes positive inside. Sodium channels open and small amounts of sodium move inside and channels rapidly close. The whole thing happens mega-rapidly.

During the repolarization that follows, the opposite happens: potassium channels open and small amounts of potassium move out of the neuron and those channels close. Once again, the sodium-potassium pumps push the ions back in their correct location. It’s a continuous, efficient process in the healthy brain.

But a traumatic brain injury, stroke, brain bleed or even a migraine can result in unrelenting, pathological spreading depolarization in which large amounts of sodium move inside and large amounts of potassium move out of neurons. Sodium-potassium pumps quickly get overwhelmed trying to straighten things out and neurons and their extensions, called dendrites rapidly find themselves in trouble.

While a swollen ankle may be uncomfortable, a swelling brain can quickly become deadly in the closed confines of the skull. “The normal balance of potassium and sodium during spreading depolarization is almost completely off so the normal function of the cell is off and it is at increased risk of dying,” Kirov said.

Kirov’s team used powerful two-photon laser scanning microscopy to study the function of transporters in slices of mouse brain and in mice. They watched the spreading depolarization and resulting swelling and documented how the edema was dramatically diminished by drugs that blocked the action of the transporters.

He notes that drugs he used in the lab can’t be used in humans, but like the transporters, they provide direction. “We need to develop better agents that will be safe in human patients that we can give for a short period of time and reduce swelling,” Kirov said of next steps in the research. Today, in severe cases of brain swelling, neurosurgeons will remove a piece of the skull to give the brain more room and ideally reduce permanent damage.

Kirov notes that astrocytes, another brain cell type that support neurons, have natural water channels, called aquaporins, so that water typically can more easily move in and out, but neurons don’t have these well-defined channels. “That was the puzzle,” Kirov said.

The research was supported by the National Institutes of Health, the American Heart Association and the Thorberg’s Foundation.

Study looks at whether daily limb compressions reduce dementia

A new study is looking at whether short, daily bouts of reduced blood flow to an arm or leg can reduce the ravages of dementia.

It’s called remote conditioning, and researchers say it activates natural protective mechanisms in the brain that should help about half of dementia patients.

The approach uses a blood pressure cuff-like device to temporarily restrict blood flow to an appendage repeatedly for a few minutes each day, which increases blood flow to other body areas, including the brain, said Dr. David Hess, Chairman of the Department of Neurology at the Medical College of Georgia at Georgia Regents University.

Increased flow activates endothelial cells lining blood vessels, calling to action a series of natural protective mechanisms that can be effective wherever blood travels, Hess said. Interestingly, the mechanisms seem most active in areas of impaired flow, such as those deep inside the brain, where most dementia has its roots.

“The most powerful way to protect the brain is to cut off blood flow to it for a short period of time to condition it,” said Hess. “What it does is elicit these protective pathways so when potentially lethal ischemia comes, you can survive it.” What it also appears to do is help permanently improve blood flow to these deep regions of the brain.

Age and being a female are two of the major risk factors for dementia. With nearly 15 percent of the U.S. population age 65 and older and half being female, Hess calls dementia a major health concern. “This is a big epidemic coming. This is a big killer and disabler, and everybody is concerned about this.”

A two-year, $750,000 translational grant from the National Institute of Neurological Disorders and Stroke should help Hess and his research team do the additional animal studies needed to move this safe and inexpensive technique for dementia to human studies.

“We think reduced cerebral blood flow, particularly in the deep white matter, is a major trigger of dementia,” Hess said. The white matter is primarily composed of axons, which connect neurons and different areas of the brain to each other and enable the brain to communicate with the body. The white protective coating on the axon is why this deep brain area is called white matter.

Hess, who is also a stroke specialist, says this area is particularly vulnerable to ischemia because the blood vessels that feed it are small and have long, tortuous routes. Strokes and/or impaired blood flow can lead to classic dementia symptoms such as forgetfulness and an unsteady gait.

By age 70, essentially everyone has some white matter disease, but in some it can be devastating. “You cannot go out in a car and find where you are going. You may not even be able to find your car. You can’t cook meals without setting the house on fire,” Hess said.

“What we want to do long term is find people who are at risk for dementia – they already have some white matter damage you can see on an MRI – then we condition them chronically with this device in their home,” Hess said. Chronically is a key word because, as with exercise, when this conditioning stops, so do its benefits. In fact, this passive therapy provides blood vessels many of the same benefits as exercise. “If you can exercise, you probably don’t need this,” Hess adds.

Previous studies in their animal model of vascular dementia have shown that just two weeks of daily, short bouts of ischemia to an appendage can improve the health of the important white matter. The new grant is allowing them to use a similar approach for periods of one and four months in older mice of both genders to better understand the mechanisms of action and how long and how often therapy is needed. While they don’t make as much as human, mice do make more amyloid, a protein that deposits in the brains of patients with Alzheimer’s, when brain blood flow is impaired. Mice make less with the conditioning, so the researchers also are looking further at that result.

A small intramural grant is enabling similar studies with a pig model in collaboration with University of Georgia colleagues Dr. Simon R. Platt, professor of neurology and neurosurgery in the College of Veterinary Medicine, and Dr. Franklin D. West, assistant professor in the College of Agricultural and Environmental Sciences.

While he notes that multiple natural mechanisms are activated, Hess and his team are focusing on how the temporary bouts of increased blood flow prompt endothelial cells to make the precursor for the blood vessel dilator nitric oxide.

“The enzyme that makes nitric oxide is upregulated and stimulated quickly,” Hess said. Nitric oxide gas has a short life, but when a lot is dumped in the blood, it’s oxidized into nitrite – the same stuff put in hot dogs – which circulates throughout the bloodstream so it goes wherever blood goes. Although just how this happens is unclear, when the nitrite gets to an area of low blood flow, it is converted back to nitric oxide, which helps improve flow, Hess said.

The MCG researchers are applying for federal funding to do trials in humans who are at high risk for stroke because of small vessel disease deep in the brain. In 2012, they published results of a small study in the journal Stroke indicating that successive, vigorous bouts of leg compressions following a stroke trigger natural protective mechanisms that reduce damage and double the effectiveness of the clot buster tPA. Similar studies have been done by others in patients with heart disease.

Vascular dementia is considered the second most common cause of dementia after Alzheimer’s disease, according to the Alzheimer’s Association. There are currently no drugs approved by the U.S. Food and Drug Administration specifically for vascular dementia.

Collaborators at MCG and GRU include Dr. Mohammad B. Khan, postdoctoral fellow in Dr. Hess’ lab; Dr. Nasrul Hoda, College of Allied Health Sciences; Dr. Philip Wang, Department of Psychiatry and Health Behavior; Dr. Ali Syed Arbab, Department of Biochemistry and Molecular Biology; Dr. Nathan Eugene Yanasak, Department of Radiology and Imaging;  and Dr. Jennifer Waller, Department of Biostatistics and Epidemiology.

Aiken Standard: Barnwell teen heals after removal of rare tumor

Aiken Standard: July 13, 2014

Colton Bolen, a rising Barnwell High School sophomore, was suffering from juvenile nasopharyngeal angiofibroma, a vascular tumor mostly consisting of blood vessels that only occurs in adolescent males. This type of tumor is benign but grows rapidly.

Dr. George Harris, a pediatric otolaryngologist at Children’s Hospital of Georgia, and Dr. Scott Rahimi, a neurosurgeon at Georgia Regents Medical Center, teamed up to remove the tumor.

They were able to successfully do so through Colton’s nose and mouth without leaving any scars, and he is on the road to recovery.