Attempts to cool the brain to reduce injury from stroke and other head trauma may face a significant obstacle: current cooling devices can't penetrate very deeply into the brain.
Scientists at Washington University School of Medicine in St. Louis used rats to validate a "cold shielding" effect of blood flow that they previously predicted theoretically. The shielding effect, created by large quantities of warm blood that continually perfuse brain tissue, prevents a drop in temperatures around the head from penetrating beyond a certain depth in the brain.
Many ongoing clinical trials try to reduce brain temperatures through cooling units incorporated into hats or other devices that surround the head. However, the new findings, published online this month in the Journal of Applied Physiology, suggest in most patients such techniques will be unable to defeat the natural temperature regulation built into the brain via the blood system.
"In adult humans, the characteristic length that this kind of cold assault appears to penetrate is approximately a tenth of an inch, leaving the temperature of approximately 6 inches of brain tissue unchanged," says senior author Dmitriy Yablonskiy, Ph.D., professor of radiology at the School of Medicine and of physics in Arts and Sciences. "Our findings suggest that the reason trials of this kind have so far produced inconsistent results is because we're not cooling enough of the brain."
The amount of blood flowing through brain tissue determines the extent of the shielding effect. Young children, infants and in particular newborns have smaller brains with lower blood flow and may be more susceptible to a cooling unit around the head. But for other patients, Yablonskiy asserts, a different approach is needed.
Cold slows down the rate of chemical reactions, potentially slowing the reactions that cause permanent injury in patients with stroke and other head trauma. Attempts to create this effect in animals were successful enough to inspire efforts to adapt the approach for human trials.
"The problem has been that we have no idea what the temperature of the human brain is and no way to measure it short of surgery, which just isn't the same as measuring temperature in an intact brain," explains Yablonskiy, who is also an adjunct professor of physics in the School of Arts and Sciences.
Alex Sukstanskii, Ph.D., a senior research scientist in Yablonskiy's lab, used mathematics and physics to develop a theory of how far cold would penetrate into the brain. Sukstanskii and his colleagues hypothesized that the hair, skin, bone and cerebrospinal fluid surrounding the brain would not substantially impede the penetration of cold. But they thought the tremendous volumes of blood flowing through the brain would prove much more resistant. While the brain only accounts for about 2 percent of the body's mass, it uses 20 percent of the total oxygen intake, all of which is delivered by blood flow.
The chemical reactions between brain cells that underlie thought are also significant generators of heat. Yablonskiy has previously speculated that blood flow may increase to active areas of the brain in part to carry away that heat.
Sukstanskii's theory, published in 2004, suggested that the distance to which cold could reach into the brain, which they called the characteristic length, dropped off as the amount of blood flowing in the brain increased.
"Mathematically speaking, the characteristic length is inversely proportional to the square root of blood flow," Yablonskiy says.
To validate the theory, lead author Mingming Zhu, a graduate research assistant, inserted tiny temperature-measuring devices known as thermocouples into rat brains and measured brain tissue temperature at various depths.
In a second group of rats, Zhu used microspheres, tiny balls of polystyrene labeled with radioactive isotopes, to assess blood flow. He injected the microspheres, which were just large enough to get stuck in the capillaries of the brain, into the rat's hearts. He then counted the number of microspheres in key brain regions to assess blood flow.
By matching a detailed inventory of physiological characteristics between the two groups of rats, including heart rate, blood pressure, pH and concentration of oxygen and carbon dioxide, Zhu could estimate brain blood flow in the group whose brain temperatures he had assessed. His results closely matched the predictions of Sukstankii's theory.
"Now that we know our theory is valid, we can use what we know about blood flow in various types of patients, calculate the characteristic length of this cold shield and make predictions on what the temperature distribution in the brain will be like," Yablonskiy says.
"We now also understand why attempts to use hypothermia for brain injury treatment in rats were encouraging," he adds. "Rats have quicker metabolism and higher blood flow, making their characteristic shielding length proportionally smaller. But the rat brain is already so much smaller that this still leaves room for cooling to penetrate throughout its brain."
Yablonskiy and colleagues including co-author Joseph J.H. Ackerman, Ph.D., the William Greenleaf Eliot Professor and chair of chemistry in the School of Arts and Sciences, have been developing a way to use magnetic resonance imaging units to assess temperature non-invasively in the human brain. Yablonskiy, Ackerman, who is also professor of radiology and research professor of chemistry in medicine, and their colleagues hope to apply this approach soon to further validate their theories.
Yablonskiy anticipates that his research group will have further opportunities to help fine-tune attempts to use hypothermia to reduce brain injury. He notes that other approaches to induce hypothermia currently under consideration include cooling the entire body all at once and inserting cooling devices into the arteries that supply the brain with blood.
Zhu M, Ackerman JJH, Sukstanskii AL, Yablonskiy DA. How the body controls brain temperature: the temperature shielding effect of cerebral blood flow. Journal of Applied Physiology, online publication.
Funding from the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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