David Goldman for The New York Times
THALAMUS SPECIALIST Dr. Rodolfo Llinás, neuroscience chairman at N.Y.U.
The New York Times, December 2, 2008, by Sandra Blakeslee — Dr. Patrick J. Kelly, the head of neurosurgery at New York University, folded his arms hard against his chest, radiating skepticism.
“I have a neurological problem that I’ve never told anyone about — not a soul,” he recalls saying to his colleague Dr. Rodolfo Llinás before an auditorium packed with neurosurgeons. “You listen to my brain and tell me what it is. If you do, I will believe you.”
So it was that Dr. Kelly allowed his brain to be scanned in a MEG machine, a device that measures tiny magnetic signals reflecting changes in brain rhythms.
After analyzing his colleague’s brain activity, Dr. Llinás announced: “You have tinnitus. Right brain. The phantom sound ringing in your ears must be very loud. It is low frequency, a rumbling noise.”
Dr. Kelly was stunned, he said later. He had been hearing that noise ever since he served at a station hospital in Danang during the Vietnam War. The roar of helicopters dropping off casualties had permanently warped his hearing.
Dr. Llinás, the chairman of neuroscience and physiology at the N.Y.U. School of Medicine, believes that abnormal brain rhythms help account for a variety of serious disorders, including Parkinson’s disease, schizophrenia, tinnitus and depression. His theory may explain why the technique called deep brain stimulation — implanting electrodes into particular regions of the brain — often alleviates the symptoms of movement disorders like Parkinson’s.
The theory is far from widely accepted, and most neurosurgeons say the mechanisms behind deep brain stimulation remain a mystery. Still, surgeons like Dr. Kelly are excited about the research, saying it suggests new targets for treating a variety of disorders.
“It’s a mystery to me why it took me so long to get what Rodolfo was saying,” Dr. Kelly said. “I’d like to latch on to the excuse that I was too busy. In truth, I was too dumb to listen. Now I tell my younger colleagues, ‘Listen to this man.’ He’s on to something that can revolutionize neurosurgery and our understanding of how the brain works.”
Dr. Llinás (pronounced yee-NAHS), born in Colombia 73 years ago, has long followed his own instincts.
Unlike neuroscientists who study the brain’s outer layer, or cortex, he has focused his attention on the thalamus, a paired structure in the midbrain. He has found that each walnut-size thalamus has 30 or more nuclei, each of which specializes in one type of information collected from the senses — sights, sounds, movements, external touches, internal feelings and so on.
Each nucleus sends its message to a specific area of the cortex for initial processing. But then the information is shuttled back down to the thalamus, where it is associated with other senses. And then it is returned to the cortex in a richer, multisensory form that is constantly elaborated, reverberating into a symphony of life experiences.
The thalamus and cortex work dynamically by passing loops of information back and forth, Dr. Llinás said. “If you think of the brain as an orchestra, the thalamus is the conductor. The players are in the cortex. When the conductor makes a move, the players follow. The conductor then hears their sounds and makes new moves, resulting in a continuous dialogue.”
Cells in the thalamus and cortex rely on intrinsic electrical properties to keep the music going. “Groups of neurons, millions strong, act like little hearts beating all their own,” Dr. Llinás said. They can oscillate at multiple frequencies, depending on what is happening in the outside world.
When the brain is awake, neurons in the cortex and thalamus oscillate at the same high frequency, called gamma. “It’s like a Riverdance performance,” Dr. Llinás continued. “Some cells are tapping in harmony and some are silent, creating myriads of patterns that represent the properties of the external world. Cells with the same rhythm form circuits to bind information in time. Such coherent activity allows you to see and hear, to be alert and able to think.”
But at day’s end, cells in the thalamus naturally enter a low-frequency oscillation. They burst slowly instead of firing rapidly. With the thalamus thrumming at a slower rhythm, the cortex follows along. You fall asleep. Your brain is still tapping out slow rhythms, but consciousness is suspended.
So if a small part of the thalamus gets permanently stuck at a low frequency, or part of the cortex fails to respond to the wake-up call, Dr. Llinás said, an abnormal rhythm is generated, a so-called thalamocortical dysrhythmia.
“Neurosurgeons think in terms of anatomical changes — holes in the brain, growths, tumors,” he said. “But a maintained, abnormal low frequency in a part of the brain can generate what is called an attractor. Think about a tornado. It’s just wind that is turning on itself. In doing so, it becomes a thing that, while made out of air, has a life of its own.
“A thalamocortical dysrhythmia also has a structure. It is a thing. And it leads to the symptoms seen in a wide variety of brain diseases.”
Dr. Llinás believes that these disrupted rhythms can be set off by a variety of causes — faulty genes, brain injury, chemical imbalance. In the case of his colleague Dr. Kelly, a small portion of the auditory cortex was damaged by helicopter noise. Dr. Llinás spotted it in the MEG machine — a spot oscillating as if in light sleep.
Tinnitus and other dysrhythmias can be treated with deep brain stimulation, drugs or tiny surgical lesions that return brain oscillations to normal, he said. The goal is to wake up parts of the brain that have fallen into low-frequency sleep mode.
In Parkinson’s, chemical changes send bits of the thalamus into a low-frequency mode. If the affected part of the thalamus connects to the brain’s primary motor center, a slow tremor, at four cycles per second, appears. The patients shake at the same frequency as the oscillating motor thalamus.
If the abnormal bit of thalamus connects to a region that plans movements, the patients cannot initiate movement.
And if the piece of thalamus is involved in making smooth movements, the patients experience increased muscle tone. They become rigid.
Dr. Llinás says a patient can experience several of these symptoms or only one, depending on the site of the abnormal rhythm. By the same token, he says, normal function can be restored by acting on the right spot.
Deep brain stimulation, in which slender electrodes are implanted directly into the cortex or thalamus, has been used in 40,000 patients around the world, mostly for movement disorders, and is now being tried for schizophrenia, epilepsy, Tourette’s syndrome, dystonia, chronic pain, depression, phantom pain and traumatic brain injury.
Dr. Llinás says that even if the treatments work, they should be regarded not as a cure but as a way to alleviate symptoms. And he acknowledges that many things can go wrong: the electrode needs to be placed in exactly the right spot, and because there are individual differences in brain structures, surgeons may need to make an educated guess. Also, wires break. Tissues become infected.
“Then you have to choose a frequency,” he said. “If it’s too high, the stimulation can produce hallucinations or other psychiatric problems. One woman could not stop crying.”
Fortunately, he said, deep brain stimulation is reversible: pull out the electrodes, and the side effects subside.
Dr. Alan Greene and his son Austin retrieving organic potatoes from their home garden.
The New York Times, December 1, 2008, by Tara Parker-Pope — Last year pediatrician Dr. Alan Greene visited my office, but after a quick check of the company cafeteria, he raced out to forage for lunch elsewhere. The reason? He was determined to eat only organic foods, and nothing in The Times’s cafeteria was labeled as such.
I was taken aback, but Dr. Greene explained he was in the midst of his own personal experiment — to determine if a person can eat organic foods exclusively — just as breeding livestock must do to be certified organic by the U.S. Department of Agriculture. He has finally achieved his goal — three years of eating all organic all the time.
Dr. Greene’s organic diet, including the challenges he faced sticking to it, is chronicled in the Well column in Tuesday’s Science Times. Whether eating organic makes a difference for health is a matter of debate. A University of Copenhagen study of peas, kale and other organic foods says it doesn’t. But last year, a 10-year study from the University of California at Davis showed organic tomatoes have nearly double the level of certain nutrients than tomatoes grown the conventional way.
For his part, Dr. Greene says he feels healthier. To learn more, read For 3 Never-Easy Years, Every Bite Organic
Ten-year comparison of the influence of organic and conventional crop management practices on the content of flavonoids in tomatoes.
Mitchell AE, Hong YJ, Koh E, Barrett DM, Bryant DE, Denison RF, Kaffka S.
Department of Food Science and Technology and Department of Plant Sciences, One Shields Avenue, University of California-Davis, Davis, California 95616, USA. firstname.lastname@example.org
Understanding how environment, crop management, and other factors, particularly soil fertility, influence the composition and quality of food crops is necessary for the production of high-quality nutritious foods. The flavonoid aglycones quercetin and kaempferol were measured in dried tomato samples (Lycopersicon esculentum L. cv. Halley 3155) that had been archived over the period from 1994 to 2004 from the Long-Term Research on Agricultural Systems project (LTRAS) at the University of California-Davis, which began in 1993. Conventional and organic processing tomato production systems are part of the set of systems compared at LTRAS. Comparisons of analyses of archived samples from conventional and organic production systems demonstrated statistically higher levels (P < 0.05) of quercetin and kaempferol aglycones in organic tomatoes. Ten-year mean levels of quercetin and kaempferol in organic tomatoes [115.5 and 63.3 mg g(-1) of dry matter (DM)] were 79 and 97% higher than those in conventional tomatoes (64.6 and 32.06 mg g(-1) of DM), respectively. The levels of flavonoids increased over time in samples from organic treatments, whereas the levels of flavonoids did not vary significantly in conventional treatments. This increase corresponds not only with increasing amounts of soil organic matter accumulating in organic plots but also with reduced manure application rates once soils in the organic systems had reached equilibrium levels of organic matter. Well-quantified changes in tomato nutrients over years in organic farming systems have not been reported previously. PMID: 17590007 [PubMed - indexed for MEDLINE] …………………………………………………………………………………………………. For Three Years, Every Bite Organic
The New York Times, December 2, 2008, by Tara Parker-Pope — Fruits, vegetables and animals can be 100 percent organic. What about people?
In a fascinating experiment — on himself — Dr. Alan Greene, a pediatrician and author in Danville, Calif., decided to find out. For the last three years, Dr. Greene has eaten nothing but organic foods, whether he’s cooking at home, dining out or snacking on the road.
He chose three years as a goal because that was the amount of time it took to have a breeding animal certified organic by the Department of Agriculture. While food growers comply with organic regulations every day, Dr. Greene wondered whether a person could meet the same standards.
It hasn’t been easy.
“This isn’t a way of eating I could recommend to anybody else because it’s so far off the beaten food grid,” said Dr. Greene, 49, the founder of a popular Web site about children’s health, drgreene.com. “It was much more challenging than I thought it would be, and I thought it would be tough. There were definitely days where there was nothing I could find that was organic.”
Other writers have ventured off the traditional food grid, notably Barbara Kingsolver in “Animal, Vegetable, Mineral” and Michael Pollan in “The Omnivore’s Dilemma.” But what makes Dr. Greene’s experiment remarkable is the length of time he devoted to it, and his effort to incorporate organic eating into the routines of everyday living. His findings offer new insight into the challenges facing the organic food industry and those of us who want to patronize it.
Organic farmers don’t use conventional methods to fertilize the soil, control weeds and pests, or prevent disease in livestock.
Organic methods often lead to higher costs, and consumers can pay twice as much for organic foods as for conventional products. Last week, the financial advice Web site SmartMoney.com reported that to feed eight people an organic meal of traditional Thanksgiving foods, a shopper would pay $295.36 — a premium of $126.35, or 75 percent, over a nonorganic holiday spread.
To cut back on the cost of an organic diet, Dr. Greene said he had to cut back on meat. “Whenever you go up the food chain, the costs pile up,” he said. “If you don’t eat meat at every meal, if meat becomes more of a side dish than a centerpiece, you can fill the plate with healthy organic food for about the same price.”
Questions remain about whether organic foods are really better for you. The data are mixed. This fall, researchers from the University of Copenhagen reported on a two-year experiment in which they grew carrots, kale, peas, potatoes and apples using both organic and conventional growing methods. The researchers found that the growing methods made no difference in the nutrients in the crops or the levels of nutrients retained by rats that ate them, according to the study, published in The Journal of the Science of Food and Agriculture.
But other research suggests that organic foods do contain more of certain nutrients — almost twice as many, in the case of organic tomatoes studied for a 2007 report in The Journal of Agricultural and Food Chemistry.
Dr. Greene said he was inspired to go all-organic after talking to a dairy farmer who noted that livestock got sick less after a switch to organic practices. He wondered if becoming 100 percent organic might improve his own health.
Three years later, he says he has more energy and wakes up earlier. As a pediatrician regularly exposed to sick children, he was accustomed to several illnesses a year. Now, he says, he is rarely ill. His urine is a brighter yellow, a sign that he is ingesting more vitamins and nutrients.
At home, he said, the organic routine was relatively easy. Organic food is widely available, not just at stores like Whole Foods but at traditional supermarkets. He also shopped at farmer’s markets and joined a local community-supported agriculture group, or C.S.A. Because he bought less meat, the costs tended to balance out. And his family (two of his four children still live at home) largely went along with the experiment.
On the road, though, life was more challenging. In corporate cafeterias and convenience stores, he looked for stickers that began with the number 9 to signify organic; stickers on conventionally grown produce begin with 4.
When dining out, he called ahead; high-end restaurants were willing to accommodate his all-organic request. He also found a few lines of organic backpacking food that he could carry with him.
Dr. Greene reached the three-year milestone in October, but his diet is still organic. He hasn’t decided whether to keep going full tilt or to ease up in the interest of cost and convenience. In his latest book, “Raising Baby Green: The Earth-Friendly Guide to Pregnancy, Childbirth and Baby Care” (Jossey-Bass), he advocates a “strategic” approach, urging parents to insist on organic versions of a few main foods, like milk, potatoes, apples and baby food.
The biggest surprise of the whole experience, he says, was that many people still don’t know what “organic” means.
“It’s surprising to me how few people know that organic means without pesticides, antibiotics or hormones,” he said. “In stores or restaurants around the country, I would ask, ‘Do you have anything organic?’ Half the time they would say, ‘Do you mean vegetarian?’ ”
The New York Times, December 2, 2008, by Gina Kolata — Bone formation appears to be controlled by serotonin, a chemical previously known mainly for its entirely separate role in the brain, researchers are reporting.
The discovery could have enormous implications, osteoporosis experts say, because there is an urgent need for osteoporosis treatments that actually build bone.
Osteoporosis affects 10 million Americans over age 50. It results in bone loss, and its hallmark is fragile bones that break easily. With one exception, current treatments only slow further bone loss rather than increase bone formation. And the exception, parathyroid hormone, given by injection, is recommended only for short-term use and costs about $6,700 a year.
But in a paper published online Wednesday in the journal Cell, a team led by Dr. Gerard Karsenty, chairman of the department of genetics and development at the Columbia University College of Physicians and Surgeons, reports the discovery of an unexpected system that appears to control bone formation.
At its heart is serotonin made by the gut rather than the brain, whose role outside the brain had been a mystery. Ninety-five percent of the body’s serotonin is made by the gut, but gut serotonin cannot enter the brain because it is barred by a membrane, the so-called blood-brain barrier.
Dr. Karsenty reports, though, that gut serotonin can directly control bone formation. It is released into the blood, and the more serotonin that reaches bone, the more bone is lost. Conversely, the less serotonin, the denser and stronger bones become. Dr. Karsenty was even able to prevent menopause-induced osteoporosis in mice by slowing serotonin production.
Osteoporosis researchers were dumbfounded by the report.
“I am very excited by this paper,” said Dr. J. Christopher Gallagher, an osteoporosis specialist and professor of medicine at Creighton University. “It is a groundbreaking paper. One is completely surprised.”
Dr. Ronald N. Margolis, senior adviser for molecular endocrinology at the National Institute of Diabetes and Digestive and Kidney Diseases, said: “I was astonished. My jaw was dropping.”
Dr. Clifford J. Rosen, a senior scientist at the Maine Medical Center Research Institute, was no less impressed. “This is amazing science,” Dr. Rosen said. “Amazing. The science is spectacular.”
Dr. Ethel S. Siris, who directs the Toni Stabile Osteoporosis Center at Columbia, cautioned that the work was not with humans but instead involved mice that were engineered to have human genes. “This stuff is really exciting basic — underscore basic — research,” Dr. Siris said.
The story of the serotonin-bone connection began with reports of a rare inherited condition causing fragile bones and blindness. Children with the condition had bones so weak that they needed wheelchairs or devices to assist them in walking.
The problem turned out to be a mutation that inactivated a gene called LRP5.
A few years later, another mutation was found in LRP5 that produced the opposite effect: extremely dense bones and resistance to osteoporosis. In this case, LRP5 was overactive. People with this gene mutation, Dr. Karsenty said, had jawbones so dense that it was difficult to extract their teeth.
Osteoporosis researchers jumped on those findings, realizing that LRP5 could hold clues to the disease. But most assumed that LRP5’s role was in bone itself.
With Dr. Karsenty’s work, said Dr. Bjorn R. Olsen, a bone growth researcher at Harvard Medical School, “that has now been proven completely wrong.”
Instead, Dr. Karsenty discovered that LRP5 acts on serotonin-producing cells in the gut. It blocks an enzyme that converts the amino acid tryptophan to serotonin. The more LRP5, the more the enzyme is blocked, and the less serotonin is made. The gene has no effect, apparently, on brain cells that make serotonin.
After the gut releases serotonin into blood, serotonin travels to bone-forming cells and inhibits their growth.
“We made mice with the inactivated gene,” Dr. Karsenty said, in which “the bone-forming cells are on strike.” The cells simply would not grow, and the mice developed severe osteoporosis.
But the bone cells themselves were fine. When Dr. Karsenty grew them in the lab, where they were not exposed to serotonin, they developed normally.
That told him that the problem was not in the bone cells but in some molecule in the mice’s circulation. And that, Dr. Karsenty says, led him to serotonin. The mice had four to five times more serotonin in their blood than mice without the mutation.
He tested the idea by adding serotonin to normal mouse bone cells in the laboratory. The cells stopped growing.
He could even control bone formation in the mice with the mutated gene by giving them a diet deficient in tryptophan, the precursor of serotonin. Without much tryptophan, the mice could not make much serotonin. And their bones grew denser. (But animals with a normal version of the gene did not grow denser bones when they ate a tryptophan-deficient diet.)
Dr. Karsenty and his colleagues also did the reverse experiment, making mice with the mutation that causes superdense bones in humans. Those animals, he said, had “amazing bones” that were hard to break, and they did not develop osteoporosis.
When Dr. Karsenty looked at patients with the dense-bones mutation, they had low levels of serotonin in their blood.
Osteoporosis patients, though, tend to have normal serotonin levels, Dr. Karsenty said. Their disease involves not impaired bone formation but accelerated bone loss.
Bone is constantly being formed and absorbed, but when the balance shifts toward loss more than formation, the result can be osteoporosis. Dr. Karsenty’s hope is to find a drug that depresses the gut’s serotonin synthesis and stimulates bone growth in these patients.
Dr. T. John Martin, an emeritus professor of medicine at the University of Melbourne in Australia, cautions that all this will take years. He is enthusiastic, though.
“This will really change thinking in the field,” Dr. Martin said. “It will have a big impact. I’m certain of that.”