It’s an old, grim axiom of neuroscience: After an injury, the nerves in your hand, arm or leg may grow back, but neurons in the brain and the spinal cord will not.

Part of the reason is a molecule called proteoglycan — a biological insulation that separates tissues. During gestation, for example, proteoglycans prevent the placenta from growing too deeply into the uterus. “The proteoglycan molecule has been known as nature’s own barrier molecule,” says Jerry Silver, a professor of neuroscience at Case Western Reserve University.

Proteoglycan strongly inhibits the growth and movement of cells, and explains why cartilage has neither nerves nor a blood supply.

In the spinal cord, proteoglycan serves to lock the nerves into position, preventing unwanted growth. Unfortunately, when the spinal cord is injured, a new burst of proteoglycan “walls off the injury site, but also blocks nerve regeneration,” says Silver.

A bacterial balm?

Now, using an enzyme made by a deadly bacterium, Silver and his colleagues have learned to restore normal breathing in rats with a damaged spinal cord. The study, published in Nature yesterday, shows that a combination of grafting and a proteoglycan-eating enzyme called chondroitinase may sidestep the proteoglycan’s growth-deadening effect – and open a path to the holy Grail of partial repair to the spinal cord.

As scientists continue trying to rebuild the spinal cord with stem cells, the new study shows an alternative route to healing.

The technique is rooted in evolution, Silver says. “Proteoglycans are boundary molecules that have evolved over millennia. One bacterium, proteus vulgaris knows that, and has figured out how to release this enzyme to eat through our defenses.”

That ability allows the bacterium to cause deadly septic shock.

What they did

To demonstrate that grafts plus chondroitinase enzyme could restore function, Warren Alilain, the paper’s first author:

It’s important to realize that when the graft was first connected to the spinal cord, it no longer contained neurons. The graft serves as a tunnel lined with cells that supply growth factors and nutrients to nerves that are growing from the upper part of the spinal cord.

The wait for recovery seemed interminable, Silver admits. “Warren Alilain, my genius post-doc, had given up, he saw no substantial return of function at two months … but at 10 weeks, he ran into my office, he saw some activity coming back.”

After another two weeks, the disconnected nerves had regained at least 80 percent of their normal electrical output in 9 of the 11 animals that got grafts and enzyme.

Spinal cord: A brainy organ?

Just getting neurons to grow in the central nervous system is not enough: the nerves must connect to the motor nerves that activate the diaphragm. After all, the spinal cord contains more than ten thousand nerve cells, and neurosurgeons cannot hope to connect them individually; and instead want to coax a process of self-connection.

The coaxing worked: among about 3,000 spinal-cord neurons that grew through the graft tube, 400 to 500 linked to the neurons that used to control the diaphragm. In other words, the growing neurons seem to be “looking” for precisely those nerve cells that must be reconnected so the diaphragm can return to work. The spinal cord, Silver says, is “smart, and that’s encouraging news. I am more optimistic than I have ever been: The gain in function is really high.”

Yet despite the crying need for better treatments for spinal cord injury, at best this technique will not be available for some years.

The technique seems unlikely to restore the complicated connections needed for walking or typing, but severe paralysis would be eased just by activating a single muscle, Silver says. Bladder control is a major issue after a lower spinal injury, and many quadriplegics require a ventilator, which can fail or cause deadly infection. Learning to reactivate the diaphragm – and to breathe — could produce huge gains in quality of life.

Courtesy Jerry Silver, Case Western Reserve University

Enzyme and graft treatment each restored nerve function in most of the rats, but the best response came from a combined treatment.

“This is an interesting study,” says Daniel Resnick, associate professor of neurosurgery at University of Wisconsin-Madison. “It’s a fairly vigorous model, measuring the diaphragm motion is a fairly clean measure.” Not only did the grafting process restore fairly normal breathing, but when the researchers cut the nerve graft at the end of the experiment, that removed the improvement in breathing. “That’s pretty convincing evidence that you have got neurons growing through the graft.”

The repair was not a true replacement for the spinal cord, Resnick adds. “They are not regenerating across the injury itself, but are by-passing it, going directly to the muscle. It’s not a cure for a spinal cord injury, but is a means to promote focal re-enervation, but for a high spinal cord injury, if you could get them off a ventilator, that is a big deal.”

Silver says the data also suggest that the bacterial enzyme may in some cases be effective enough to avoid grafting. “I am enthusiastic about using just the enzyme, in spinal cord injury and stroke rehabilitation,” Silver says. “Given the success to date – in our lab and others — it’s simple to do and seems to carry almost no risk — it’s just putting in a shot of enzyme as a way of stimulating neural plasticity.”

– David J. Tenenbaum

Talk about going to extremes: In 2004, an anonymous American man with ulcerative colitis chose to eat parasitic worms instead of having his diseased colon removed. He hoped that whipworms would provide a last-ditch biological balm for painful, bloody and frequent diarrhea, and more serious complications of colitis.

If his symptoms had not improved, you would not be reading about his sojourn through planet parasite. “It did work with this individual, he seemed to get better, not just once but twice,” says P’ng Loke, a parasite immunologist at New York University who studied the case.

Photo: Delorieux for Johann Gottfried Bremser

Imagine swallowing 2000 of these guys. You just might, if you were plagued with an inflammatory bowel disease.

In the same year that Mr. A swallowed those worm eggs, two other biological treatments gained Food and Drug Administration blessing as “medical devices”: leeches for removing excess blood after surgery, and maggots for cleaning difficult wounds.

Live organisms once played a bigger role in medicine, observes Ronald Sherman, a California doctor and maggot maven. “Before we had a good method for controlling syphilis, the bacterium was killed by inducing a fever, and one of the best methods was through malaria, carried by mosquitoes.”

Ready for some greatest hits from the ancient-but-modern realm of medicinal vermin?

Wondrous whipworms

Ulcerative colitis is a chronic bowel disease that afflicts up to one American in a thousand, apparently caused by some combination of inflammation and heredity. There is no cure. To prevent holes in the colon and other nasty outcomes, the bowel is often removed — a treatment that is also used for Crohn’s, the other major inflammatory bowel disease.

Photo: Uma Mahadevan, UCSF

Mr. Anonymous’s colon has a heavy infestation with whipworms, which are damaging the intestinal walls. Could that bleeding be a good thing?

In 2003, Mr. Anonymous was diagnosed with ulcerative colitis, and in 2004, he went to Thailand and ate 500 eggs of Trichuris trichiura, a parasitic helminth worm, and then 1,000 more.

The symptoms abated, and when they returned in 2008, Mr. A, who’s now 35, slurped 2,000 more whipworm eggs, and again his symptoms receded.

There is some support for the idea that parasitic worms can help with ulcerative colitis. Whipworms infest almost a billion people around the world, and colitis is scarce in infected regions. Animal tests, and one human trial¹ suggest that parasitic worms can help with ulcerative colitis.

This story of salvation courtesy of planet parasite might be dismissed as another tall tale told over a tall goblet of organic wheat-grass at the Health-4-All-Spa, except that Mr. A came under the scrutiny of medical experts² eager to explore the effect of parasites on one ulcerated colon.

Although eating worm eggs twice reduced the symptoms, one person does not constitute scientific proof, says Loke, a parasite expert. “The question is whether it would work for everyone, and for whom it would do more harm than good; that’s what we worry about.”

Image: Kimberley Evason, UCSF

Stained Trichuris trichiura eggs inside a worm from the ulcerative colitis patient who infected himself with these whipworms.

Whipped into shape?

The study did pinpoint a mechanism of help, and surprisingly, it was not, as expected, via a dampening the immune system. “When we analyzed this patient, we started thinking that the protection may be more related to restoring mucus production,” Loke says.

Mucus protects the intestinal lining from bacteria and other dangers, and Loke and his colleagues think the worms accelerated activity in genes involved in producing mucus, through a stimulating chemical called IL 22.

A second benefit probably came from faster growth of cells lining the intestine, Loke added. “We know from mouse studies of Trichuris that the mechanism of expelling the parasite from the gut involves a combination of turning over epithelial cells so worms will get sloughed off, and an increase in mucus production.”

Immunology still matters, he says, but it may be that the worms are triggering a protective immune response rather than immune suppression.

Before worms could be considered a treatment for ulcerative colitis, “we hope to understand the mechanism a bit better,” says Loke. “In the ideal situation, we’d like to activate this response without using the worms themselves.”

Amen.

Photo: Professor David B. Fankhauser, University of Cincinnati Clermont College.

Goblet cells (arrow) in the intestinal lining create protective mucus. Increased mucus production could explain how whipworms treat ulcerative colitis.

Worms v. asthma

There’s been some hope that regulating the immune system could help with asthma, but the improvements in patients in a clinical trial³ of hookworms were, disappointingly, not statistically significant.

But 13 of the 16 patients who swallowed hookworms decided not to get de-wormed afterwards, which suggests some perceived benefit, admits study author John Britton, in the division of epidemiology and public health at the University of Nottingham (United Kingdom). “We weren’t able to measure anything objective; hence the implication that larger, longer (and simpler) trials are needed.”

If you are tempted by do-it-yourself worm treatment for asthma, Britton has simple advice: “Don’t. There’s no evidence that it works.”

Both the benefits and the risk remain to be documented, says Loke, who tracked Mr. Anonymous, “and we don’t understand that fully. Worms can cause symptoms of colitis” and in the case of Mr. A, “are causing damage to the gut. But we think the gut is activating a healing response against the worms, and one benefit of that is the side effect of helping colitis.”

Marvelous maggots

While people have long used live organisms for medical purposes, many trace the scientific foundations of maggot therapy to World War I, when surgeon William Baer observed that maggot-infested wounds were often the cleanest and quickest to heal.

Photo: Alvesgaspar

Baby animals usually are cuter than the adults, but nobody told the green bottle fly!

In 1929, Baer reported complete success after treating 21 bone infections with maggots, and fly larvae quickly gained acceptance for wound treatment. But when antibiotics became widespread in the 1940s, healing became simply a matter of sprinkling a magic powder, and maggots were forgotten.

With diabetes becoming epidemic, and with so many bacteria immune to antibiotics, maggot use is again on the upswing. One key use is treating foot ulcers: slow-healing sores that affect about 15 percent of people with diabetes, and force 70,000 amputations each year in the United States.

Since Baer’s time, the common green-bottle fly, Phaenicia sericata, has been the preferred medical maggot, because it devours dead tissue, but not living flesh. Flies must be sterilized before use, and because the eggs quickly hatch into larvae (maggots), air-shipment is necessary, says Ronald Sherman, laboratory director of maggot-maker Monarch Labs.

The healing never stops

Sherman says he became interested in blending entomology and medicine when he read about Baer during medical school. “I was always interested in medical entomology, the intersection of health and insects, but usually that was in the context of insects that cause disease. I was also interested in the beneficial uses of insects.”

As investigations in maggot therapy started to ramp up the 1980s, he recalls a “huge wave of resistance [that] was not all due to revulsion” at the thought of hosting insects.

Part of the problem was resistance to change, he says, especially “When that change is associated with these negative, emotional connotations: death, flies, an unhygienic environment.”

Some resistance, he says, came from doctors “who saw that patients were lining up for [maggot] treatment. People … were canceling amputation surgeries … just to give maggot therapy a try!” According to Sherman⁷, some studies show that maggots can “salvage” 40 to 50 percent of limbs and digits scheduled for amputation.

One study⁸ found that although 43 percent of patients had flies escaping from their wounds, and 19 percent eventually needed amputation, 89 percent would use maggots again.

Courtesy Ronald Sherman

A bottle of chemically sterilized maggots costs about $100, plus shipping. Because the adult flies can be infectious, they must be restrained with cheesecloth or a special-purpose dressing.

Flies on trial

Other studies are less definitive. For example, in a randomized trial⁹ of wounds published in 2009, larvae-infested leg wounds were more painful, and while maggots were better at cleaning, they did not hasten healing or reduce bacterial infections.

A review¹⁰ of randomized treatments for diabetic foot ulcers found that “one small trial suggested that larvae resulted in a more than 50 percent reduction in wound area compared with hydrogel.” (Hydrogels are new dressings that keep wounds moist.)

Why only “one small trial” for the common diabetic foot ulcers? Because the gold standard for selecting therapies requires that neither doctor nor patient know which treatment was used — but this “double-blind” is doubly difficult when the medical device is a mess of growing flies!

Sherman, who is a maggot entrepreneur as well as medical doctor, says maggot therapy ought no longer be considered a last resort. “Most clinicians come to it either because their patients, or they themselves, are at a dead end. Facing amputation, they’ve run out of options. Once they see what maggots can do, and recognize how simple, inexpensive, and relatively safe they are, they recognize that they don’t have to wait so long, and in the future will think about maggot therapy … before the wound has progressed, before the infection has progressed.”

Image: Rsabbatini

Leeching was standard practice until the mid-1800s. Leech saliva contains anesthetics, which could also explain why this lady is so cool, calm and collected with her slithery pals!

Maggot therapy is occurring “throughout the world,” Sherman says. “Twenty-four labs are producing medical grade maggots and providing them in 40 countries. In the United States alone, about 2,000 centers are regularly using maggot therapy. The treatments are included in textbooks, review articles on wound care and conferences.”

Leapin’ Leeches!

Leeches — bloodsucking aquatic worms — have been a part of medicine for at least 2,000 years. The Encyclopedia Britannica tells us that “Throughout most of Western history, leeching-or leechcraft-became such a common practice that a physician was commonly referred to as a ‘leech.’”

Modern-day “leeches” use leeches to drain excess blood after surgery. “The classic use is when a finger is reattached surgically,” says Kosta Mumcuoglu, a parasitologist at Hebrew University in Jerusalem. “Even if the surgeon succeeds nicely in reattaching the arteries, they often have problems with the veins, so blood can enter the finger but not return to the body. Then it’s a short time until the blood in the finger coagulates and the patient loses the finger.”

Surgeons may try to improve circulation with further surgery or anti-coagulants like heparin, says Mumcuoglu, president of the International Biotherapy Society. But if circulation is still stuck, “The skin may start to turn brown or violet, and any time now, the finger is going to be lost.”

Courtesy Kosta Mumcuoglu, Hebrew University¹¹

After finger-reattachment surgery, leeches excess blood that would otherwise clot and kill the finger. Those white objects are holding the surgery tight. Children whose fingers have been caught in doors are major beneficiaries of this surgery, but snowblowers can also amputate fingers.

Evolution plays two contrasting roles in our story: To avoid bleeding to death, mammals have evolved a powerful “coagulation cascade” that clots blood outside blood vessels. Because clotting could be deadly to leeches, they, like their bloodsucking brethren the ticks, mosquitoes and vampire bats, have evolved anti-coagulants.

One chemical in leech saliva, for example, blocks thrombin, which helps platelets clump to start a blood clot.

Not only do leeches produce prodigious amounts of clot-blockers, but they also have chemicals that relax blood vessels, which contributes to their utility in surgery. In 2004, leeches garnered FDA approval as a “medical device.”

The chemicals in leech saliva, aided by some manual clot removal, ensure that the skin around a surgery will bleed for hours or days after leeching. Even though the patient may need a blood transfusion, after a few days, “new blood vessels are growing in the area, and the circulation becomes normal, and we have a good feeling that we have saved the finger,” Mumcuoglu says.

Leeches also secrete anti-inflammatory compounds that are being tested against diseases linked to inflammation. In a randomized trial¹³ in Germany, four to six leeches, which attached for an average of 70 minutes, led to a significant decrease in pain of osteoarthritis of the knee after seven days, compared to the anti-inflammatory drug diclofenac. Leech treatment also significantly improved stiffness, function and general arthritis symptoms, for the entire 91-day study.

In 2008, the same researchers¹⁴ found that leeches. when compared to diclofenac, produced significant benefits in pain, mobility and quality of life for osteoarthritis of the thumb.

Solution: Outsourcing?

Still, leeches may never regain their former medical prominence. In London, in 1846, “at least tens of millions of leeches” were imported each year. A reservoir in Norwich, one author¹⁵ wrote, “might at least aid in supplying the quantity needed for our own consumption, instead of being almost entirely dependant, as we at present are, on a foreign supply.”

However, this last finding may be key to further progress, says Mark Siddall of the American Museum of Natural History, who led the group that identified three species. “This raises the tantalizing prospect of three times the number of anti-coagulants, and three times as many [other] biomedically important developments…”

Did we forget what parasitologists call the “Yuck! factor”? Do patients squirm at the thought of attaching primitive bloodsuckers to their wounds? Generally not, says Mumcuoglu. “We have less problem with leeches than with maggots. We explain, ‘This is your last chance, if you don’t want to lose the finger, we have to try this.’ … Nobody has rejected the treatment.”

Strokes — bleeding or blocked blood vessels in the brain — are a major cause of disability, and most neuroscientists say the brain has little or no ability to repair itself afterwards: Dead neurons do not spring to life. They are not replaced, and losing the ability to talk to each other is irrevocable.

Photo: University of Cincinnati

Relearning the activities of daily life can be a struggle after a stroke. The University of Cincinnati has tested a robotic brace to aid recovery. A drug that restores brain cells could reduce the need for this kind of retraining.

When a stroke cannot be prevented, damage is irreversible. Or so went the neuroscientific dogma.

But a mouse study being published today in Nature shows that suppressing a common brain chemical can boost neuronal repair after a stroke. The treatment focuses not on restoring neurons, but rather on restoring connections, so neurons located at the edge of the dead zone can talk to each other and go back to work.

Based on tests of walking ability, the mice regained 30 to 50 percent of their motor coordination. If this result can be repeated, it could represent a major step forward, as no drug is approved for helping restore communication between nerve cells after a stroke.

“Basically, we are upsetting a lot of dogma that says the brain does not repair itself or recover, that there is no formation of new connections,” says study leader S. Thomas Carmichael, a professor of neurology and stroke specialist at the University of California at Los Angeles. “My lab is one of those that has showed that this is not true, and that has opened interesting molecular and cellular questions about what happens to regenerate the brain.”

Begging for an explanation

The research was rooted in some facts that did not jibe with the “no repair” dogma, Carmichael says. “Most strokes get a little better, and some get quite a bit better, in the weeks after the stroke. So our question is what events lead to this repair and recovery in the brain, and why they are limited.”

Several processes could explain these small recoveries, Carmichael says:

Brain cells are under both positive and negative controls; some chemicals make them more excitable, and others dampen their excitation. The study reported today was designed to test whether blocking a major inhibitory chemical would help neurons return to work after a stroke.

Just as two negatives make a positive, blocking an inhibitory chemical can stimulate a nerve cell.

The study concerned GABA, the major inhibitory compound in the brain. GABA released at a synapse, where neurons connect with each other, causes other neurons to briefly be less excitable. In the 1990s, an “extra-synaptic” receptor for the same compound, GABA, was found elsewhere on the nerve cell. “This is a whole separate group of GABA receptors that are on the cell body,” says Carmichael. “They don’t respond to GABA released into the synapse, but to GABA that spills over.”

Because these receptors are built differently, they can be blocked without affecting the synaptic GABA, says Carmichael.

During the experiment, Carmichael and colleagues used chemical or genetic mechanisms to block extra-synaptic GABA, and found that the mice recovered 30 to 50 percent of their motor coordination in various tests.

Neurons in the area around the injury started conversing once again, but only if they had been treated with the GABA inhibitor.

Courtesy S. Thomas Carmichael, UCLA

After a stroke, mice received three treatments. “Foot faults” measured their coordination; mice that got the experimental drug L655,708 were more coordinated than untreated mice.

Red: Stroke alone.

Blue: Stroke + GABA-inhibiting compound

Green: GABA-inhibiting compound (no stroke)

A promising drug?

Many drugs cannot enter the brain, but Carmichael says the oddly-named L655,708 can do so. And since it’s in early-stage human trials, it has already satisfied preliminary safety standards. More important, no other drug treatment has been able to put intact, but “stunned,” neurons back to work following a stroke, Carmichael says.

In essence, the treatment seems to “change the set point of neurons,” Carmichael says, making them more excitable — without affecting the synapse. “Inhibiting or blocking all inhibition of synaptic signaling would put you to sleep or give you a seizure, and neither is desirable after a stroke. The nice thing about this receptor is that it is involved in a completely different situation.”

“The research is both important and relevant,” commented Matthew B. Jensen, an assistant professor in the Comprehensive Stroke Program at the University of Wisconsin-Madison. “Post-stroke disability is a major public health problem, and we need to better understand the limitations for recovery of the nervous system after injury to be able to design effective treatments.”

“The study matters because it suggests a new target for treatments to improve stroke recovery,” Jensen added, although it is not completely clear that the drug acted solely in the area near the stroke, or also elsewhere in the nervous system.

The 30 to 50 percent improvement is “dramatic, an impressive recovery,” says Carmichael. Treatment for strokes focuses on restoring blocked blood flow, but “If you look at stroke literature, there are no drugs that promote recovery” of lost function.

But this is only one study, as Carmichael admits. “We have done this in one lab, and somebody has to replicate these findings.”

Once that happens, it should be time to test the drugs in stroke patients. Although mice are not people, “At that point, we will have done all we can with a non-human model.”

– David J. Tenenbaum

It’s been a bad month for brains, and particularly for traumatic brain injury:

In national security, the national sport, and on the national highways, brains are getting banged. Some estimates say 5 million Americans have some permanent damage from a traumatic brain injury which is due to impact rather than bleeding or loss of blood flow — the causes of stroke.

2006, Centers for Disease Control

The causes of brain injuries in the United States during six years.

Eighty two years after dementia pugilistica was diagnosed in boxers, we should not be surprised that impacts in war, car accidents and high-intensity sports are taking a toll on the thinking organ, says Robert John Dempsey, chair of neurological surgery at the University of Wisconsin-Madison. “As we have improved our ability to image brains, and to diagnose dysfunction to include cognition, we have discovered deficits that may have been obvious to family members and physicians.”

Dempsey says autopsies of people who have had multiple concussions, “suggest there was a permanent injury, a disruption of axons and loss of brain substance.”

The brain shrinkage seen in autopsies of former football players after multiple concussions is called chronic traumatic encephalopathy. This disturbing shrinkage of the brain is linked to severe, deadly brain abnormalities, including memory loss, confusion, paranoia, depression, dementia and Parkinsonism.

Images: WBUR, Boston’s NPR Station

Chronic traumatic encephalopathy is marked by concentrations of tau protein, shown here as brown spots. More tau equals more damage. Left: a normal, 65-year-old brain. Right: The brain of former NFL linebacker John Grimsley, who died of a gunshot at age 45 after nine concussions.

Striking younger

After the growing concern about traumatic brain injury among middle-aged football veterans who were paid to endure thousands of blows to the head, the discovery of such damage in the 21-year-old Penn player raised questions for young athletes and their parents, as Robert Stern, a professor of neurology at Boston University, explained to the New York Times. “We don’t know if it’s a specific age, we don’t know if it’s a cumulative number of years of exposure to head trauma, we don’t know what combination of hits to the head set this disease in motion. These are critical issues that need to be answered in order to help guide any dramatic policy changes and individual decisions down the road.”

Photo: Jayme Pastoric/U.S. Navy

A 2007 study by University of North Carolina scientists suggests that concussions can follow almost any type of head impact in football, regardless of its strength and location.

A changed picture of brain injury

Until recently, impact was considered less serious than contusions — brain injuries with obvious damage like bleeding and swelling, says Dempsey. “It was considered possible you would not make a full recovery [of movement, speech and vision] from a contusion.”

Until a decade or two ago, Dempsey says, “concussion without a structural disruption was considered a source of transient loss of function, consciousness, confusion, but one where recovery was felt to be complete.”

But when the brains of former pro football players were examined after death, massive damage was blamed for serious problems like depression, confusion and movement disorders.

Today, concussion and contusion seem less like distinct things and more like stages of a continuum of brain injury, Dempsey says. “There is a wave of increasing realization that any injury to the brain should be taken seriously, and that repeated minor injury is cumulative.”

Searching for succor

What can be done in the face of a wave of traumatic brain injuries? The obvious measure, protection and prevention, seems, well, obvious. But ironically, better protection is part of the reason why so many soldiers are returning with brain injuries — body and vehicle armor keeps them alive without always protecting the head.

So what is medicine learning about treating traumatic brain injury? Nobody has a recipe for repairing damage once it’s complete — but traumatic brain injury is not always sudden, and researchers are hot on the trail of techniques that can interrupt the damage process and preserve brain tissue and function.

Photo: 2008, Kamryn Jaroszewski/U.S. Navy

Hospital corpsman Anthony Thompson gets a medal while being treated for a traumatic brain injury caused by an improvised bomb in Iraq.

What do some promising recent studies say about halting or treating traumatic brain injury in animals or people?

Glucose — a sweet solution?

Doctors have long worried that an injured brain often contains too much energy in the form of blood sugar, says David Hovda, a professor of neurosurgery and director of Brain Injury Research Center at the University of California at Los Angeles. In stroke victims, a high level glucose in the blood is known to be “really bad because it promotes more damage, and we thought the same thing was true in traumatic brain injuries, so the standard of care became to reduce plasma glucose down to normal.”

Photo: biblicone

Car accidents account for 20 percent of traumatic brain injuries.

But Hovda questions the wisdom of reducing fuel to the brain after trauma. “In animal studies, we began to manipulate serum glucose and found that if we dropped it, brain cells began to show all the signs of being killed by not having enough fuel. When we began to use the same sort of measures in human patients, we discovered the same thing: If we deprive the brain of more glucose, brain cells start to die.”

Hovda says his studies in rodents suggest the brain has complicated fuel needs during recovery. “We believe, but don’t know, that the fuel characteristics are also going to be different, given age, gender, stage of recovery and perhaps the type of injury.”

Photo: U.S. Air Force Tech. Sgt. Cecilio M. Ricardo Jr.

With improved safety gear, more U.S. soldiers are surviving attacks, but then must live with brain injuries.

Hovda says UCLA is in the second year of a five-year project to test the optimum level of plasma glucose after a traumatic brain injury in 20 to 25 patients. Beyond glucose, he will also test other fuels that might support recovery while reducing harm in other parts of the brain. “We’re going to see if we can change their outcome; it’s an efficacy trial, and it’s funded by National Institutes of Health for $5 million.”

If the new approach has promise, Hovda hopes to start a larger trial that would treat traumatic brain injury patients with a variety of intravenous fuels.

Supreme supplements?

Brain injuries can affect small structures like the hippocampus, which is critical to memory and other higher thought processes. In a mouse model of brain injury, Akiva Cohen, an associate professor of pediatrics and neurology at the University of Pennsylvania School of Medicine, has found that dietary supplements may help the hippocampus work after injury.

“We have shown in an animal model that dietary intervention can restore a proper balance of neurochemicals in the injured part of the brain, and simultaneously improves cognitive performance,” says Cohen, who is also a neuroscientist at Children’s Hospital of Philadelphia.

Photo: Buckeye Surgeon

A 2007 study found that football impacts could reach more than 100 Gs (100 times the acceleration of gravity). That’s equivalent to slamming against a brick wall at 25 mph.

Like many biological processes, the transmission of nerve impulses is tightly controlled. One major neurotransmitter, glutamate, excites neurons, while another, GABA, calms them. An imbalance in these compounds can cause the hippocampus to malfunction, Cohen says.

The imbalance has been concealed because the hippocampus has two pools of the neurotransmitters, and only the smaller pools at synapses (where two brain cells make contact) appear to be altered after injury.

If you study the hippocampus as a whole, Cohen says, “you can’t see the change in smaller, synaptic pool because it’s concealed by a larger pool of the neurotransmitters used for other cellular functions.”

In a study with mice, Cohen found that feeding the mice with branched chain amino acids that are precursors — raw materials — for the two transmitters returned their level at the synapses to normal.

“Once we saw that through feeding, we could bring the concentration back to the level of the control animal, we asked if we could bring back memory, and memory did come back to normal,” Cohen told us. “Memory is a hippocampus-dependent task, and it was only restored because we restored precursors to those two neurotransmitters.”

The team performed electrical tests on brain slices and got normal results if the amino-acid supplements were present.

Even though the supplements “are not really fixing the problem — there are still things wrong in the pathway — we are synthesizing enough new glutamate, and subsequently enough GABA, to restore the synaptic pools, allowing the hippocampus function to return to normal,” Cohen says.

As Cohen searches for funding for a human trial, he notes that the mice received leucine, isoleucine and valine. “These are essential amino acids, you have to eat them, but if you don’t need them, you will just get rid of them. There are athletes who take these supplements for strength training.”

A visionary idea

It sounds too good to be true, but a Michigan research group has published a study showing that simple corrective lenses can reduce headache, neck ache, and dizziness — common symptoms of traumatic brain injury. “We came into this backward,” says Mark Rosner, an adjunct clinical instructor in emergency medicine at the University of Michigan, who worked with optometrists who were treating the same symptoms in people without brain injury.

Image: Jmh649

A CT scan of the head after a traumatic brain injury. Arrow shows a damaged, empty space.

“We found that the post-concussion visual symptoms pretty much crossed over with the symptoms we were already treating in headachy, dizzy people,” Rosner says.

The problem seems to be rooted in a brain malfunction that prevents the eyes from converging, so one eye aims slightly above or below the other. The misalignment can cause words to bounce around on the page.

The working hypothesis, Rosner says, is that “There’s a faulty signal from the brain that is trying to vertically diverge the eyes, and that makes them double the image, but other parts of the brain say ‘You can’t do that! You are giving us double imagery!’”

The resulting tug of war between the muscles that raises and lower the eyes causes tension and headaches, Rosner says.

The divergence is subtle, but detectable, and in many cases, it can be cured with prismatic eyeglasses, Rosner contends. Many patients even notice their headache and neck ache start to subside during a 20-minute trial period in the office.

Like regular eyeglasses, the lenses are used continually; the goal is not to retrain the brain but to correct the misalignment.

A published study of 43 patients¹, for whom Rosner and his colleagues had complete records, found a 72 percent reduction in several symptoms of traumatic brain injury, based on a subjective scale.

The majority of the patients had had a motor vehicle accident, Rosner says, but falls, strokes or and blast injuries to veterans were also represented.

As Rosner and colleagues struggle to get the word out on their simple treatment, he says prism glasses are helpful, but not a panacea. “These people do have other injuries. I would love to tell you this would fix all traumatic brain injuries. It cannot do that, but it does do a lot.”