New high definition fiber tracking reveals damage caused by traumatic brain injury

A powerful new imaging technique called High Definition Fiber Tracking (HDFT) will allow doctors to clearly see for the first time neural connections broken by traumatic brain injury (TBI) and other disorders, much like X-rays show a fractured bone, according to researchers from the University of Pittsburgh in a report published online today in the Journal of Neurosurgery.

In the report, the researchers describe the case of a 32-year-old man who wasn't wearing a helmet when his all-terrain vehicle crashed. Initially, his CT scans showed bleeding and swelling on the right side of the brain, which controls left-sided body movement. A week later, while the man was still in a coma, a conventional MRI scan showed brain bruising and swelling in the same area. When he awoke three weeks later, the man couldn't move his left leg, arm and hand.

"There are about 1.7 million cases of TBI in the country each year, and all too often conventional scans show no injury or show improvement over time even though the patient continues to struggle," said co-senior author and UPMC neurosurgeon David O. Okonkwo, M.D., Ph.D., associate professor, Department of Neurological Surgery, Pitt School of Medicine. "Until now, we have had no objective way of identifying how the injury damaged the patient's brain tissue, predicting how the patient would fare, or planning rehabilitation to maximize the recovery."

HDFT might be able to provide those answers, said co-senior author Walter Schneider, Ph.D., professor of psychology at Pitt's Learning Research and Development Center (LRDC), who led the team that developed the technology. Data from sophisticated MRI scanners is processed through computer algorithms to reveal the wiring of the brain in vivid detail and to pinpoint breaks in the cables, called fiber tracts. Each tract contains millions of neuronal connections.

"In our experiments, HDFT has been able to identify disruptions in neural pathways with a clarity that no other method can see," Dr. Schneider said. "With it, we can virtually dissect 40 major fiber tracts in the brain to find damaged areas and quantify the proportion of fibers lost relative to the uninjured side of the brain or to the brains of healthy individuals. Now, we can clearly see breaks and identify which parts of the brain have lost connections."

HDFT scans of the study patient's brain were performed four and 10 months after he was injured; he also had another scan performed with current state-of the-art diffusion tensor imaging (DTI), an imaging modality that collects data points from 51 directions, while HDFT is based on data from 257 directions. For the latter, the injury site was compared to the healthy side of his brain, as well as to HDFT brain scans from six healthy individuals.

Only the HDFT scan identified a lesion in a motor fiber pathway of the brain that correlated with the patient's symptoms of left-sided weakness, including mostly intact fibers in the region controlling his left leg and extensive breaks in the region controlling his left hand. The patient eventually recovered movement in his left leg and arm by six months after the accident, but still could not use his wrist and fingers effectively 10 months later.

Memory loss, language problems, personality changes and other brain changes occur with TBI, which the researchers are exploring with HDFT in other research protocols.

UPMC neurosurgeons also have used the technology to supplement conventional imaging, noted Robert Friedlander, M.D., professor and chair, Department of Neurological Surgery, Pitt School of Medicine, and UPMC Endowed Professor of Neurosurgery and Neurobiology. He is not a member of this research study.

"I have used HDFT scans to map my approach to removing certain tumors and vascular abnormalities that lie in areas of the brain that cannot be reached without going through normal tissue," he said. "It shows me where significant functional pathways are relative to the lesion, so that I can make better decisions about which fiber tracts must be avoided and what might be an acceptable sacrifice to maintain the patient's best quality of life after surgery."

Dr. Okonkwo noted that the patient and his family were relieved to learn that there was evidence of brain damage to explain his ongoing difficulties. The team continues to evaluate and validate HDFT's utility as a brain imaging tool, so it is not yet routinely available.

"We have been wowed by the detailed, meaningful images we can get with this technology," Dr. Okonkwo said. "HDFT has the potential to be a game-changer in the way we handle TBI and other brain disorders."

Provided by University of Pittsburgh

"New high definition fiber tracking reveals damage caused by traumatic brain injury." March 2nd, 2012. http://medicalxpress.com/news/2012-03-high-definition-fiber-tracking-reveals.html

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Finding unseen damage of traumatic brain injury

March 2nd, 2012 in Neuroscience 
This undated handout artist rendering provided by the Schneider Lab, University of Pittsburgh shows an experimental type of scan showing damage to the brain’s nerve fibers after a traumatic brain injury. The yellow shows missing fibers on one side of the brain, as compared to the uninjured side in green, in a man left with limited use of his left arm and hand. The soldier on the fringes of an explosion. The survivor of a car wreck. The football player who took yet another skull-rattling hit. Too often, only time can tell when a traumatic brain injury will leave lasting harm _ there's no good way to diagnose the damage. Now scientists are testing a tool that promises to light up breaks that these injuries leave in the brain's wiring, much like X-rays show broken bones. (AP Photo/Schneider Lab, University of Pittsburgh)

The soldier on the fringes of an explosion. The survivor of a car wreck. The football player who took yet another skull-rattling hit. Too often, only time can tell when a traumatic brain injury will leave lasting harm - there's no good way to diagnose the damage.

Now scientists are testing a tool that lights up the breaks these injuries leave deep in the brain's wiring, much like X-rays show broken bones.

Research is just beginning in civilian and military patients to learn if this new kind of MRI-based test really could pinpoint their injuries and one day guide rehabilitation. It's an example of the hunt for better brain scans, maybe even a blood test, to finally tell when a blow to the head causes damage that today's standard testing simply can't see.

"We now have, for the first time, the ability to make visible these previously invisible wounds," says Walter Schneider of the University of Pittsburgh, who is leading development of the experimental scan. "If you cannot see or quantify the damage, it is hard to treat it."

About 1.7 million people suffer a traumatic brain injury, or TBI, in the U.S. each year. Some survivors suffer obvious disability, but most TBIs are concussions or other milder injuries that generally heal on their own. TBI also is a signature injury of the wars in Iraq and Afghanistan, affecting more than 200,000 soldiers by military estimates.

Not being able to see underlying damage leads to frustration for patients and doctors alike, says Dr. Walter Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke.

Some people experience memory loss, mood changes or other problems after what was deemed a mild concussion, only to have CT scans indicate nothing's wrong.

Repeated concussions raise the risk of developing permanent neurologic problems later in life, a concern highlighted when some retired football players sued the National Football League. But Koroshetz says there's no way to tell how much damage someone is accumulating, if the next blow "is really going to cause big trouble."

And with more serious head injuries, standard scans cannot see beyond bleeding or swelling to tell if the brain's connections are broken in a way it can't repair on its own.

"You can have a patient with severe swelling who goes on to have a normal recovery, and patients with severe swelling who go on to die," says Dr. David Okonkwo, a University of Pittsburgh Medical Center neurosurgeon who is part of the research. Current testing "doesn't tell you what the consequence of that head injury is going to be."

Hence the increasing research into new options for diagnosing TBI. In a report published Friday in the Journal of Neurosurgery, Schneider's team describes one potential candidate, called high-definition fiber tracking.

Brain cells communicate with each other through a system of axons, or nerve fibers, that acts like a telephone network. They make up what's called the white matter of the brain, and run along fiber tracts, cable-like highways containing millions of connections.

The new scan processes high-powered MRIs through a special computer program to map major fiber tracts, painting them in vivid greens, yellows and purples that designate their different functions. Researchers look for breaks in the fibers that could slow, even stop, those nerve connections from doing their assigned job.

Daniel Stunkard of New Castle, Pa., is among the first 50 TBI patients in Pitt's testing. The 32-year-old spent three weeks in a coma after his all-terrain vehicle crashed in late 2010. CT and regular MRI scans showed only some bruising and swelling, unable to predict if he'd wake up and in what shape.

When Stunkard did awaken, he couldn't move his left leg, arm or hand. Doctors started rehabilitation in hopes of stimulating healing, and Okonkwo says the high-def fiber tracking predicted what happened. The scan found partial breaks in nerve fibers that control the leg and arm, and extensive damage to those controlling the hand. In six months, Stunkard was walking. He now has some arm motion. But he still can't use his hand, his fingers curled tightly into a ball. Okonkwo says those nerve fibers were too far gone for repair.

"They pretty much knew right off the bat that I was going to have problems," Stunkard says. "I'm glad they did tell me. I just wish the number (of missing fibers) had been a little better."

The new tool promises a much closer look at nerve fibers than is now possible through a technique called diffusion tensor imaging, says Dr. Rocco Armonda, a neurosurgeon at Walter Reed National Military Medical Center.

"It's like comparing your fuzzy screen black-and-white TV with a high-definition TV," he says.

Armonda soon will begin studying the high-def scan on soldiers being treated for TBI at Walter Reed, to see if its findings correlate with their injuries and recovery. It's work that could take years to prove.

Other attempts are in the pipeline. For example, the military is studying whether a souped-up kind of CT scan could help spot TBI by measuring changes in blood flow inside the brain. The National Institutes of Health is funding a search for substances that might leak into the bloodstream after a brain injury, allowing for a blood test that might at least tell "if a kid can go back to sports next week," Koroshetz says.

He cautions that just finding an abnormality doesn't mean it's to blame for someone's symptoms.

And however the hunt for better tests pans out, Walter Reed's Armonda says the bigger message is to take steps to protect your brain.

"What makes the biggest difference is everybody - little kids riding their bicycles, athletes playing sports, soldiers at war - is aware of TBI," he says.

©2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

"Finding unseen damage of traumatic brain injury." March 2nd, 2012. http://medicalxpress.com/news/2012-03-unseen-traumatic-brain-injury.html

Posted by
Robert Karl Stonjek

Pioneering research reveals bacterium’s secrets

 by Biomechanism 

Ground-breaking research by an international team of scientists will help to make one of the most versatile of bacteria even more useful to society and the environment.

Though it lives naturally in the soil, the bacterium Bacillus subtilis is widely used as a model laboratory organism. It is also used as a ‘cell factory‘ to produce vitamins for the food industry and, in biotechnology, to produce enzymes such as those used in washing powders.

The BaSysBio research project, carried out by a consortium of researchers from eight European countries and Australia including the Department of Chemistry at the University of York, is unprecedented in its scope and has given scientists an unrivalled level of understanding of the way the organism can adapt to diverse conditions. Continue reading below….

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Billions of years of evolution have shaped the performance of B. subtilis cells and the research has provided novel insights into the regulatory processes that help them to maintain their metabolism in prime condition.

Published in two papers in the latest edition of Science, the findings will enable scientists to engineer B. subtilis to become an even more effective producer of metabolites for a wide range of industries from pharmaceutical and chemical manufacturing to the agri and food sectors. The work also has medical implications as it will help scientists to understand how bacteria deal with changing conditions during infection.

B. subtilis is able to survive and grow in diverse and changing environments. The research used expertise from different fields ranging from molecular biology to bioinformatics and mathematics to investigate the cell as a system of interacting molecular components and the strategies it uses to adapt to varying conditions.

The researchers acquired and analysed large experimental data sets which were used with mathematical models to capture the complexity of the cellular system. They analysed the genes expressed under more than 100 different conditions that mimic the natural and laboratory environment of the organism.

It was already known that the B. subtilis genome carries around 4,200 genes but the new research identified 512 new potential genes in the bacterium.

The project co-ordinator Dr Philippe Noirot, of the INRA Centre at Jouy-en-Josas, near Paris, says: “Besides their scientific novelty, these two studies also represent a potential blueprint for bacterial systems biology. Our work will potentially make B. subtilis an even more efficient producer of enzymes. The results and approaches used in our studies, suggest it is now possible to design specific experiments to unravel other, previously more intractable, cellular processes.”

Professor Tony Wilkinson, of the York Structural Biology Laboratory, says: “The work has thrown up surprises. In one instance, where we expected that a few simple tweaks would be sufficient to achieve an adaptation, we observed wholesale changes involving almost half the genes in the organism.”

Professor Uwe Sauer, of the Eidgenössische Technische Hochschule, Zürich, says: “The work represents a conceptual step forward in how to assess and understand cellular adaptation to new situations that is fundamental to basic science as well as applications in biotech and medical research.”

Prof Jan Maarten van Dijl, of the University Medical Centre in Groningen, adds: “These studies help us to understand how bacteria deal with changing conditions during infection such as when normally commensal bacteria such as Staphylococcus aureus that live in the nose and throat adapt and invade the body and cause disease. This provides a foundation for research into the development of agents to combat these invasive bacteria.”

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The work has been backed by a €12 million grant from the European Union. 

The Patient of the Future

Internet pioneer Larry Smarr's quest to quantify everything about his health led him to a startling discovery, an unusual partnership with his doctor, and more control over his life.

• BY JON COHEN

Gym rat: In his quest to optimize his health, Larry Smarr recently underwent tests to measure his peak oxygen consumption, maximum heart rate, and other physiological indicators. Credit: Michael Kelley

Back in 2000, when Larry Smarr left his job as head of a celebrated supercomputer center in Illinois to start a new institute at the University of California, San Diego, and the University of California, Irvine, he rarely paid attention to his bathroom scale. He regularly drank Coke, added sugar to his coffee, and enjoyed Big Mac Combo Meals with his kids at McDonald's. Exercise consisted of an occasional hike or a ride on a stationary bike. "In Illinois they said, 'We know what's going to happen when you go out to California. You're going to start eating organic food and get a blonde trainer and get a hot tub,' " recalls Smarr, who laughed off the predictions. "Of course, I did all three."

Smarr, who directs the California Institute for Telecommunications and Information Technology in La Jolla, dropped from 205 to 184 pounds and is now a fit 63-year-old. But his transformation transcends his regular exercise program and carefully managed diet: he has become a poster man for the medical strategy of the future. Over the past decade, he has gathered as much data as he can about his body and then used that information to improve his health. And he has accomplished something that few people at the forefront of the "quantified self" movement have had the opportunity to do: he helped diagnose the emergence of a chronic disease in his body.

Like many "self-quanters," Smarr wears a Fitbit to count his every step, a Zeo to track his sleep patterns, and a Polar WearLink that lets him regulate his maximum heart rate during exercise. He paid 23andMe to analyze his DNA for disease susceptibility. He regularly uses a service provided by Your Future Health to have blood and stool samples analyzed for biochemicals that most interest him. But a critical skill separates Smarr from the growing pack of digitized patients who show up at the doctor's office with megabytes of their own biofluctuations: he has an extraordinary ability to fish signal from noise in complex data sets.

On top of his pioneering computer science work—he advocated for the adoption of ARPAnet, an early version of the Internet, and students at his University of Illinois center developed Mosaic, the first widely used browser—Smarr spent 25 years as an astrophysicist focused on relativity theory. That gave him the expertise to chart several of his biomarkers over time and then overlay the longitudinal graphs to monitor everything from the immune status of his gut and blood to the function of his heart and the thickness of his arteries. His meticulously collected and organized data helped doctors discover that he has Crohn's, an inflammatory bowel disease.

I have ulcerative colitis, a cousin of Crohn's, and I am intrigued by what Smarr calls his "detective story." His investigation of his body has evolved into a novel collaboration with a leading gastroenterologist to better understand and treat his disease, and maybe even to help others like me. But I am also a disease-weary skeptic. After 22 years of seeing specialists, enduring a battery of tests, unscrambling the complex medical literature, and trying a hodgepodge of interventions, I have had no luck staving off flares and only modest success controlling them with blunt-force drugs. Like others who have chronic illnesses, I am acutely sensitive to false hope. I have been repeatedly baffled by the course my disease takes and thoroughly confused by tests meant to clarify my condition.

When I first meet Smarr and he gives me a tour of his institute, commonly known as Calit2, I tell him that I find it difficult to separate promise from hype, noting that his endeavor has all the pitfalls of any "n = 1" experiment—a test in which only one person is the subject. "Every disruption begins with an n of 1," he replies.

Smarr has a standard-issue office on the side of a sleek six-story building, but much of his floor resembles a hip architectural firm. Workstations zigzag across a vast space that features exposed venting pipes and electrical conduits on the naked ceiling. His chief assistant, who lives near San Francisco, talks to coworkers via Skype and a dedicated computer monitor. Across the room, chairs are arranged before a wall of 30-inch displays stacked five high and 14 wide, with a total of 286.7 million pixels that can simultaneously show dozens of brain scans or the stars in a galaxy.

Though he has no laboratory of his own, he shows off the projects at Calit2 as though each were one of his children. The labs investigate everything from machine perception and game culture to integrated nanosensors and 3-D virtual reality. One, which Smarr recently tapped to determine his peak oxygen consumption and maximum heart rate, studies ways to improve individual and population health. Another researches digitally enabled genomic medicine—a blend of self-quantification devices with wireless technology and DNA data.

The place makes my imagination dance. So, too, does Smarr's medical sleuthing of his own body. Not only does he want to convince others that they can fundamentally alter the patient-doctor relationship and transform physicians into partners, but he's also going public with his biodata, hoping to crowdsource information that will lead to new insights about the elusive links between DNA sequences, biomarkers, and disease. I soon buy into his vision, embarking on a closer examination of my own disease that, at the very least, scuttles my resignation to it.

MYSTERY SOLVED

Larry Smarr stumbled into his role as a proselytizer for digitizing and then crowdsourcing medicine; he stresses that by nature he is a reserved and private person. He was born and raised in Columbia, Missouri, where his parents ran a flower shop from the home basement. One of his greatest passions is the quiet, solitary cultivation of that most finicky and delicate of plants, the orchid. Yet he has no regrets about going public in writings and talks with extremely intimate details about his body. "Most people think I'm crazy," he says. But as a result of his candor, many people have contacted him, he says, and he shows me how a Google search on his name now pulls up articles about his quantified-health quest before everything else he has published in his distinguished career.

Smarr says he "got outed as a quantified self" after he spoke at a technology summit in May 2010. A session titled "Bio­NanoInfo Technology: The Big Challenges" featured him on a panel with Leroy Hood, a cofounder of the Institute for Systems Biology in Seattle and one of the inventors of the first automated DNA sequencer. Hood discussed his push for technology that he hopes will introduce an era of medicine he calls P4: predictive, preventive, personalized, and participatory. Smarr told his own story of using self-quantification to lose weight. A reporter interviewed him after the session, seeking more details, and in the wake of that article, speaking requests started to pour in.

Hood envisions a day when devices using nanotechnology will measure 2,500 markers in blood to track fluctuations in what he estimates are about 50 proteins in 50 of the body's organs. But that is not yet practical, so Smarr settled on about 100 biomarkers to understand how his dietary changes were affecting his body. Levels of one of the markers, C-reactive protein, or CRP,  stood out as higher than normal.

CRP triggers an immune response by binding to the surface of ailing cells, and the level of it should be less than one milligram per liter of blood. Smarr's level in November 2007 was 6.1. More alarming still, over the next seven months it steadily climbed to 11.8. He felt fine, but he decided to seek a doctor's advice, worried that something was amiss. The doctor dismissed Smarr's self-charted longitudinal CRP data, telling him to return if he had symptoms. "Doctors are the gatekeepers, and they're worried about getting disintermediated," he says, comparing them to the bank tellers who initially bad-mouthed ATMs.

Within a few months, a sharp, persistent pain in the left side of his abdomen sent him to the doctor's office, and he was diagnosed with acute diverticulitis, an infection of pockets in the wall of the colon. A blood test showed that his CRP had climbed to 14.5 during the attack. He took antibiotics, the symptoms resolved, and his CRP dropped to 4.9—but that was still unusually high. Concerned that these readings might, as he had read, indicate a plaque buildup that could lead to a heart attack, he had doctors do ultrasounds of his carotid artery and found that it was indeed thickening.

To better understand the attack, he had his stool analyzed for, among other things, lactoferrin, a marker of inflammation. His lactoferrin, too, rose several times to sky-high levels—200, whereas the normal count is less than 7.3. When he overlaid his results on a graph with his CRP fluctuations, he noticed that the two roller-coastered in tandem. A colonoscopy in December 2010 revealed extensive diverticulitis, but Smarr, who had trolled the medical literature online, remained unconvinced that this was his underlying disorder. He became particularly intrigued by studies that linked high lactoferrin levels to inflammatory bowel disease.

At this point, Smarr discovered that UCSD had recently hired a new head of gastroenterology, William Sandborn, who had published a compelling study that charted rises in lactoferrin levels during flares of inflammatory bowel disease. The two met and decided to do yet another colonoscopy. By then, Smarr's lactoferrin level had risen to a whopping 900. Sandborn reviewed the results and concluded that his new patient might have Crohn's disease. Smarr now thinks his diverticulitis attack was actually a Crohn's flare.

"It's a paradigm for what will happen in the future," Hood says of Smarr's story. "With P4 medicine, consumers are going to be the driving force—it isn't going to be physicians. They're going to demand to quantize themselves about their own wellness and what can be done."

Cardiologist Eric Topol, author of The Creative Destruction of Medicine (see "Technological Healing" ) and head of the Scripps Translational Science Institute down the street from UCSD, supports the self-quantification movement but says it has the most to offer people who, like Smarr, zoom in on specific issues. "My colleagues have a doctors-know-best attitude," says Topol. "Individuals like Larry have much more invested here, and they're going to put in time and resources to gather as much information as possible. Those clinicians who have the plasticity to adapt to this will be better doctors in the future."

Smarr recognizes that many people do not have his skills at amassing and analyzing data, nor do they have his resources—he estimates that his "burn rate" for tests and other expenses his health insurance would not pay for has ranged from $5,000 to $10,000 per year. Still, he thinks medical quests like his will become more common with the emergence of technologies that more easily and cheaply test biomarkers and sequence DNA. "My particular story is a good example of an early victory," he says. "I'm not saying we need to get rid of doctors. But imagine if you go in to the doctor and little widgets have been recording data to the cloud and the doctor can look at it. That's going to be a vastly more productive visit. There'll be a liberating effect on them."

GUT CHECK

Unlike the doctors who deemed Smarr's data mining a clinically useless "academic" exercise by an amateur, Sandborn welcomes his input. "I've learned an enormous amount from listening to patients over the years and just being open-minded about the journey that they go through with their illness," says the gastroenterologist. Yet Smarr's unusual project and personality have clearly encouraged Sandborn to explore a patient-doctor relationship of a kind he might have avoided with others. Sandborn notes that in many cases, overtesting wastes money, sends patients on tangents, and can lead to false positive results that actually cause harm. "None of those things apply in Larry's case," he says.

Sandborn has agreed to accompany Smarr on an expedition into another medical frontier: the microbiome. In 2010, Nature published a study that sifted through fecal samples from 124 people, plucking out the microbial genes in healthy individuals and those with Crohn's or ulcerative colitis. In the healthy group, the researchers found an average of 3.3 million microbial genes—about 150 times the number of genes in the human genome. People who had an inflammatory bowel disease harbored 25 percent fewer microbial genes, and the species of bacteria that were depleted differed in people with Crohn's and those with ulcerative colitis.

Smarr being Smarr, he decided to have his microbiome sequenced at the J. Craig Venter Institute. Sandborn, in turn, plans to work with researchers at the Venter Institute to assess whether they can pull something meaningful out of this most basic data, coupled with Smarr's biomarkers and the evolution of his disease. Future treatments, for example, might specifically repopulate the gut with the bacteria that people with the disease are lacking. Smarr also plans to have his entire genome sequenced by George Church, the Harvard University geneticist whose Personal Genome Project recruits people willing to share medical records and DNA sequences. "Larry and a few others are becoming very well-­measured individuals," says Church. "What we're trying to do is gather together such individuals and turn it into more of a collective process. If you keep data to yourself, it's hard to interpret."

Larry Smarr has not convinced me that I can manage my ulcerative colitis more effectively by following his lead. But his experience has prodded me to consider options I previously discounted or didn't know about. I had 23andMe analyze my single-­nucleotide polymorphisms, which spotlighted a mutant immune-system gene I carry that almost doubles my risk for ulcerative colitis. I joined the Personal Genome Project—which will also sequence my micro­biome—and agreed to make all my DNA and medical records public. I saw Sandborn as a patient, and we plan to monitor my CRP and lactoferrin during a flare and on medication. If I can find immune-modulating drugs on the market that specifically counteract the effects of my mutant gene and do not have serious side effects, ­Sandborn says, he's willing to try those on me too.

At the end of my consultation with Sandborn, it becomes clear that we share a sense of skepticism and hope about the new medical world that Larry Smarr has encouraged each of us to enter. "I have no doubt this is the future of medicine, but I have no idea how to get there from here," he says. "Then again, when you find the right patients, you can start to figure out how to move forward."

TR contributing editor Jon Cohen is a correspondent with Science. His latest book is Almost Chimpanzee: Redrawing the Lines that Separate Us From Them.