Much Touted “Depression Risk Gene” May Not Add to Risk After All

June 16, 2009

New Look at Data Confirms Strong Association between Depression and Stressful Life Events
computer generated image of DNA

Stressful life events are strongly associated with a person's risk for major depression, but a certain gene variation long thought to increase risk in conjunction with stressful life events actually may have no effect, according to researchers funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. The study, published in the June 17, 2009, issue of the Journal of the American Medical Association, challenges a widely accepted approach to studying risk factors for depression.

"Rigorous re-evaluations of published studies provide the checks and balances necessary for scientific progress," said Thomas R. Insel, M.D., director of NIMH. "We are still in the early days of understanding how genes and environment interact to increase the risk for depression."

Most mental disorders are thought to be caused by a combination of many genetic risk factors interacting with environmental triggers. However, finding the exact combinations continues to present significant challenges to research.

Advances in scientific understanding and technologies during the past decade have led to powerful tools for studying how genetic and environmental factors can affect a person's risk for disease. Such advances allowed mental health researchers in 2003 to show that a gene involved in serotonin activity increased the risk of major depression in people who had a number of stressful life events over a five-year period (see "More About the Science" below for more information about this gene and serotonin). Coming at a time of heightened research interest in these gene-environment interactions and the relative lack of progress in the field for mental disorders, this study received wide acclaim and had a far-reaching influence. Not only have considerable resources been invested in subsequent studies that built on this finding, but also some researchers have proposed marketing the gene test to the public, claiming to be able to predict a person's risk for depression.

However, efforts to replicate the 2003 study's findings—a key step in scientific progress that helps show whether a particular finding was a chance event—have had inconsistent results.

To examine whether the 2003 study's finding had been confirmed, a group of scientists from NIMH and six universities with expertise in epidemiology, biostatistics, genetics, and psychiatry reviewed the status of relevant replication studies. Led by Kathleen Merikangas, Ph.D., of the NIMH Intramural Research Program, the workgroup did a meta-analysis, re-analyzing data on 14,250 participants in 14 studies published from 2003 through March 2009. Of these, the researchers also re-analyzed original data, including unpublished information, on 10,943 participants from 10 studies published before 2008. The workgroup analyzed these original data to see whether there were gender differences in the associations between the serotonin genotype, stressful life events, and depression.

By applying the same definitions of study variables and data analysis methods used in the 2003 study, the workgroup found a strong association between the number of stressful life events and risk of depression across the studies. However, the presumed high-risk version of the serotonin transporter gene did not show a relationship to increased risk for major depression, alone or in interaction with stressful life events, in the analysis of the 14 studies. Their findings were the same in men and women alone in the analysis of original data from 10 studies.

The workgroup noted that their analysis had some limitations. Individual level data were available for only 10 of the 14 studies published before 2008. However, these limitations would have had little effect on the overall findings because the number of participants in the studies not included was only a small proportion of the total sample.

These findings may account for the difficulty many researchers have faced in attempting to replicate the 2003 study. This analysis confirms some earlier reviews that had also questioned the validity of the gene's effect on depression risk. However, the workgroup emphasized that the intent of its analysis was not to deter research on gene-environment interactions for mental disorders.

"Identifying gene-environment interactions is most successful when studies can focus on a single gene with a major effect, or when the environmental exposure has a strong effect," said lead author Neil Risch, Ph.D., University of California, San Francisco and Kaiser Permanente Northern California. "In the case of modest gene effects or environmental impacts, the statistical power to detect an interaction will be low, and thus weak positive results should be interpreted carefully."

The authors concluded that incorporating environmental exposures in candidate gene studies (those that study a particular gene) may be as likely to yield false positive findings as the candidate gene studies themselves. Therefore, the results of other studies using the same approach as the 2003 study also deserve thorough review and meta-analysis.

"Even though our re-analysis did not confirm an association between the serotonin gene and depression, the finding that the environmental factor was strongly associated with depression in several studies reminds us that environmental factors are also involved in the complex pathways leading to mental disorders," noted Merikangas. "Future progress will require thoughtful integration of the tools of genetics, epidemiology, and clinical and behavioral sciences."

The authors on the paper include Neil Risch, Ph.D., University of California at San Francisco and Kaiser Permanente Northern California; Richard Herrell, Ph.D., NIMH; Thomas Lehner, Ph.D., NIMH; Kung-Yee Liang, Ph.D., Johns Hopkins University; Lindon Eaves, Ph.D., Virginia Commonwealth University; Josephine Hoh, Ph.D., Yale University; Andrea Griem, NIMH; Maria Kovacs, Ph.D., University of Pittsburgh; Jurg Ott, Ph.D., Rockefeller University; Kathleen Ries Merikangas, Ph.D., NIMH.
More About the Science

Serotonin is one of several chemical messengers in the brain, or neurotransmitters, which help brain cells communicate with one another. Among many other functions, serotonin is involved in regulating mood. Problems with making or using the right amount of serotonin have been linked to many mental disorders, including depression, bipolar disorder, anxiety disorder, autism, and schizophrenia.

There are many genes that code for serotonin. Some of these genes guide serotonin production and other are involved in its activity. The serotonin transporter gene makes a protein that directs serotonin from the space between brain cells-where most neurotransmitters are relayed from one cell to another-back into cells, where it can be reused. Since the most widely prescribed class of medications for treating major depression acts by blocking this transporter protein, the gene has been a prime suspect in mood and anxiety disorders.

The serotonin transporter gene has many versions. Since everyone inherits a copy of this gene from each parent, a person may have two copies of the same version or one copy each of two different versions. One version of the serotonin transporter gene makes less protein, resulting in decreased transport of serotonin back into cells. This version has also long been the focus of depression research due to its suggested effect on risk.

Read more about NIMH research on depression and genetic risk factors
Reference

Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR. Interaction between the Serotonin Transporter Gene, Stressful Life Events and Risk of Depression: A Meta-Analysis. JAMA. 2009 Jun 17;301(23):2462-71.

Car Exhaust Associated With Premature Births in Southern California

Mothers living near freeways and congested roads are more likely to give birth to premature babies and suffer from preeclampsia

By Marla Cone and Environmental Health News

Women exposed to air pollution from freeways and congested roads are much more likely to give birth to premature babies and suffer from preeclampsia, according to a study by University of California scientists published Wednesday.

The findings, based on pregnant women in the Long Beach/Orange County region of Southern California, add to the growing evidence that car and truck exhaust can jeopardize the health of babies while they are in the womb.

Reviewing the birth records of more than 81,000 infants, researchers found that the risk of having a baby born before 30 weeks of gestation increased 128 percent for women who live near the worst traffic-generated air pollution.

In addition, preeclampsia increased 42 percent for women who lived in those areas, according to the study, published online in the scientific journal Environmental Health Perspectives. Preclampsia, a serious illness that involves high blood pressure, can endanger the baby and the mother.

The team of scientists from UCLA and University of California, Irvine studied babies born in Long Beach, near the Ports of Los Angeles and Long Beach, and in adjacent Orange County. Those areas are traversed by several major freeways used by commuters as well as heavy-duty trucks delivering goods to and from the ports.

The infants’ birth records were matched with their addresses and then compared with traffic patterns and estimates of two pollutants—particulates and nitrogen oxides—from vehicles near the mothers’ homes.

The study was unique in that the researchers constructed a database estimating what the pregnant women breathed in their own neighborhoods--within three kilometers, or less than two miles, of their homes. Previous studies have used general air pollution measurements, which is a less accurate estimate of what people are exposed to.

Only traffic-generated emissions were included in the study, not pollutants from factories and other sources.

Fetuses “are in a very sensitive stage of development” that could be vulnerable to the toxic substances inhaled by their mothers, said Jun Wu, an assistant professor of epidemiology at UC Irvine and the study’s lead author.

Other recent studies have linked air pollutants to preterm births and low birth weights. But until now, “no study has associated air pollution with preeclampsia. This is the first one,” Wu said.

Tracey Woodruff, director of University of California, San Francisco’s Program on Reproductive Health and the Environment, said the research offers a relatively “new twist on air pollution,” since most scientists have focused on respiratory and cardiovascular diseases.

“This is just one more piece of the scientific evidence that air pollution can have effects on adverse pregnancy outcomes,” said Woodruff, who was not involved in the research.

The babies in the study were born between 1997 and 2006 at four hospitals: Long Beach Memorial and three in Orange County--Anaheim Memorial, Orange Coast Memorial in Fountain Valley and Saddleback Memorial in Laguna Hills.

Maria Gugerty, a Long Beach resident, said she always has wondered what might have caused her son, Will, to be born premature, at 31 weeks. Her son was likely one of the preemies reviewed in the study since he was born at Long Beach Memorial in 1997.

“My pregnancy was completely fine, but all of a sudden my water broke. It seemed completely random and the doctors were never able to determine any physical reason for it,” she said. “I was so careful during my pregnancy. No alcohol, no smoking and a good diet. So I’ve always wondered if it was something in the environment, not necessarily air pollution but the environment in general.”

Another Long Beach mother, Susan Taylor, said her doctor thought a gum infection most likely was the cause of her daughter, Maddy, being born early, also at 31 weeks. But, she said, “we did live near a very busy, noisy intersection.”

Like most women, Gugerty and Taylor didn't know there was a connection between air pollution and pregnancies. But Gugerty said that she “absolutely” worries about the potential health effects of the pollution around her home in Long Beach. Her son, now 12, has asthma.

About half of the babies included in the study were born in Long Beach. Air pollution experts have said that people living in that area faced a variety of increased health risks, including cancer and reduced lung function, due to heavy traffic and other sources of air pollution related to the ports and freeways.

Every year, more than half a million infants are born prematurely in the United States. In the study, 8 percent of the 81,186 babies were preterm, including 1 percent that were “very preterm,” or under 30 weeks of gestation.

The link to air pollution was strongest for the “very preterm” babies, who often weigh less than three pounds and have the greatest risk of serious health problems. The researchers compared women who lived in areas with the most traffic-related pollution with women who lived in areas with the least traffic pollution. Those in the polluted areas were 128 percent more likely to deliver “very preterm” babies.

The risk of less severe preterm babies—those born between 30 and 37 weeks--was about 30 percent higher for women living in the areas with a lot of traffic emissions.

About 3 percent of the study’s pregnant women had preeclampsia, which can result in premature babies. Its causes are unknown, although doctors think it is related to abnormal growth of the placenta.

The new study focused on “an important area of research, since there are a lot of reasons to believe that there is something happening with environmental chemicals and preeclampsia,” Woodruff said. “Women with preeclampsia have high blood pressure, and some air pollutants can increase blood pressure. This is a serious condition, and these women are at risk of adverse pregnancy outcomes.”

Scientists are uncertain how air pollutants might trigger premature babies. The chemicals may interfere with placental development, which would impair the nutrients and oxygen delivered to the fetus. Or they could trigger oxidative stress—when cells are overwhelmed and DNA is damaged by reactive compounds in the environment called free radicals.

Wu said it is likely that other pollutants are to blame, not the fine particles and nitrogen oxides. Instead, those two pollutants could be an indicator of other toxic compounds in vehicle exhaust, such as polycyclic aromatic compounds. A recent study of babies in New York City linked those compounds, called PAHs, to preterm and low-weight babies.

Wu said doctors should warn pregnant women about air pollution because “they should be aware of these issues.” While most can’t move to avoid traffic emissions, Wu said they might be able to take precautions, such as reducing their commutes or closing their windows in cars and homes.

But avoiding air pollution is virtually impossible, Woodruff said, so “pregnant women should be aware of the risks and advocate for the kinds of [government] actions that reduce overall exposure to air pollution.”

The authors said a major limitation of their research is that it only looked at where the women lived when their babies were born, not where they lived or worked during their pregnancies, or whether they had long commutes in heavily polluted areas. Still, they said by using neighborhood data, they were probably more accurate in estimating the women’s exposures than past researchers have been.

Beate Ritz, an epidemiology professor at UCLA’s School of Public Health, was the study’s senior author. Her research has focused on using geographic information to map people’s exposure to pollutants and chemicals and search for links to chronic diseases such as Parkinson's and cancer.

Woodruff said many researchers are starting to use such data, which only has been available in recent years, because it can provide “reasonable estimates of what people are exposed to.”

Plug and Play

Plug and Play: Researchers Expand Clinical Study of Neural Interface Brain Implant
BrainGate moves to phase II testing as scientists search for a way to return life to paralyzed limbs

By Larry Greenemeier

Having proved in 2004 that plugging a sensor into the human brain's motor cortex could turn the thoughts of paralysis victims into action, a team of Brown University scientists now has the green light from the U.S. Food and Drug Administration (FDA) and the Massachusetts General Hospital (MGH) institutional review board to expand its efforts developing technology that reconnects the brain to lifeless limbs.

Brown's BrainGate Neural Interface System—conceived in 2000 with the help of a $4.25-million U.S. Defense Department grant—includes a baby aspirin–size brain sensor containing 100 electrodes, each thinner than a human hair, that connects to the surface of the motor cortex (the part of the brain that enables voluntary movement), registers electrical signals from nearby neurons, and transmits them through gold wires to a set of computers, processors and monitors. (ScientificAmerican.com in 2006 wrote about one patient's experience using BrainGate during its first phase of trials.)

The researchers designed BrainGate to assist those suffering from spinal cord injuries, muscular dystrophy, brain stem stroke, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease), and other motor neuron diseases. During the initial testing five years ago, patients suffering from paralysis demonstrated their ability to use brain signals sent from their motor cortex to control external devices such as computer screen cursors and robotic arms just by thinking about them. "The signals may have been disconnected from the (participant's) limb, but they were still there," says Leigh Hochberg, a Brown associate professor of engineering and a vascular and critical care neurologist at MGH who is helping lead the research.

Due to the high risk of plugging a device directly into the brain, the FDA in 2004 granted the BrainGate system an investigational device exemption so that researchers could begin testing the unit in patients and collect data about its safety and effectiveness. Thanks to the success of those early tests, the researchers last week kicked off a pilot clinical trial, dubbed BrainGate2. Although the technology is similar to what was used in the original testing, the researchers are looking to enlist up to 15 patients this time and gather more information that will help them better understand brain signals as well as "the method by which we decode them," Hochberg says. Since the initial four-person clinical trial launched five years ago, "we have a better appreciation for things that we need to learn."

A successful BrainGate2 trial could open up a number of new possibilities, including the use of a second sensor to stimulate both sides of the motor cortex, says John Donoghue, a Brown neuroscience professor and director of the Brown Institute for Brain Science. Researchers thus far have implanted the sensor in the side of the brain that controls a patient's dominant side—the left cortex for righties and the right cortex for lefties.

BrainGate2 is part of a larger mission to help paralysis victims regain control of their bodies. "We want to reconnect the brain back to the muscles and eventually back to the entire limb," Donoghue says. "We are attempting to recreate parts of the nervous system that have been disconnected from the brain."

Hochberg expects this second phase to last for several years, "depending on what we learn and how quickly we learn it." The research project has received about $8 million in funding over the past three years from a number of organizations, including the National Institutes of Health (NIH) and the U.S. Department of Veterans Affairs.

D-Day

June 6, 1944, 160,000 Allied troops landed along a 50-mile stretch of heavily-fortified French coastline to fight Nazi Germany on the beaches of Normandy, France. General Dwight D. Eisenhower called the operation a crusade in which “we will accept nothing less than full victory.” More than 5,000 Ships and 13,000 aircraft supported the D-Day invasion, and by day’s end on June 6, the Allies gained a foot- hold in Normandy. The D-Day cost was high -more than 9,000 Allied Soldiers were killed or wounded -- but more than 100,000 Soldiers began the march across Europe to defeat Hitler.

00:00:00 Erik M. Juleen - During those five days leading up to the invasion, why... we were mostly all prepared at that time -- there wasn't much to do except that, and um, we were ready to move out to a bidwack area. We were in this area and it was unbelievable. For myself it was the anxiety, the thing we were waiting for for a long time.

00:00:31 Joseph Dragotto - Over the loudspeaker, I heard the words "Attention!" I with the other troops, snapped to attention and in the corner of my eye, I could see two men -- one wearing an American uniform, the other a British uniform. The American was General Eisenhower and the other was Field Marshall Montgomery. General Eisen said that we were about to embark on a great cause -- the liberation of Europe. God be with you. Montgomery said almost the same thing but added that he was grateful for the help and supplies and troops from America.

00:01:10 Harlod Baumgarten - We left the martianry area with full battle equipment -- about 100 pounds per man. The harbor of Weymuth was crowded with ships of every size, shape and description, most of them flying the stars and stripes. On the evening of June 5th the harbor came alive. I could see one ship signaling to the other that this was it. We would hit the beach the next morning at 6:30 AM, June 6th 1944, to be called "D-Day".

00:01:43 Dragotto - Around 00, 01 hours June the 6th I heard the roar of the aircraft. I got up and looked out into the sky and I noticed airplanes and gliders behind them -- 101st 82nd Airborne were being flown to be dropped out of the plane.

00:02:04 Juleen - I guess the morning -- early, early morning -- of June 6 why everything starts moving. Then we went up to our boat foreman, and we assembled with hundreds and hundreds of ships -- I had never seen anything like it in my life. And then I guess we were on our way.

00:02:23 Baumgarten - Chaplain Kelly held the mass service on the deck of the Anvil in which he requested God to see us through the landing safely. We left the Anvil on British LCA, and huge bluish black waves rose high over the sides of our little craft, and battered the boat as well as us with unimaginable fury. It was as if the waves were trying to crush our soft boat and we in it. We were all soaking wet. I tried to keep my rifle dry but, I put my plastic cover over the rifle.

00:03:11 Adolph "Bud" Warnecke - We were so loaded down with equipment -- every man had at least one anti-tank mine, and we had bundles in the doors, bundles under the aircraft, and the C-47 was loaded to the point where he could take off but he couldn't land with it so he had to drop it. We had rendezvoused for quite a while to get the air Amanda into a formation. When we crossed the English Channel, I was standin' in the door. We looked down, we looked out, looked down, and there was the most beautiful moonlight evening. Looked down and had never seen so many ships in all my life and probably will never see 'em again. You coulda walked across the English Channel -- not that you had to walk on water -- you could just step from ship to ship -- that is how it looked from the air.

00:04:20 Juleen - Its so hard to describe... it was massive, it was massive -- I can imagine being a German lookin' out through a binoculars and seeing all of this (laughing) no wonder Hitler didn't believe us.

00:04:35 Baumgarten - The fury of the water broke our front ramp and the boat began to fill with icy channel water, but Lt. Donelson rammed his body against the unit door of the ship and said "Well what are you waiting for? Take off your helmets and start bailing the water out."

00:04:54 Dragotto - As the landing craft inched closer to the beach shells began to explode around us. The craft next to us hit a mine and exploded.

00:05:06 Juleen - But as we were about to land they had huge obstacles in the water. Big railroad tracks cris-crossed and stickin' up out of the water so nobody could get close.

00:05:22 Warnecke - Well there was a ground fog, we were supposed to be flying at about 600 feet -- that was gonna be our jump altitude. We couldn't see any landmarks, we couldn't see where we were, where we were going or anything, but the order was before we left, that no one would come back in the aircraft whether we found our objective or DZs or not -- we would go out somewhere over Normandy. Just as soon as I bailed out, I knew that was the end of it. I was not coming back anymore because I had never seen so many tracers in all my life. Tracers were all over the place and shooting at us. I'd hardly got the thoughts out of my mind when I went through an apple tree. My feet just barely touched the ground, the top of my canopy had caught my fall and I just hung there real nice -- no problem. Took my knife, cut myself out of my harness, and immediately started to gather the people together that jumped from our aircraft.

00:06:40 Baumgarten - I saw the beach, with a huge seawall, at the foot of a massive 150 foot bluff. An 88 millimeter shell landed right in the middle of the LCA on the side of us, and splinters of the boat, equipment and bodies were thrown into the air. The ramp was lowered and the unit door was opened and a German machine gun trained on the opening and took a heavy toll of lives. I waded through the waist-deep water watching many of my buddies fall alongside of me. I expected a bullet to rip through me at any moment, from the right. I reached the stone wall. I looked down and being washed around by the incoming water. I saw the bodies of my buddies who had tried in vain to clear the beach.

00:07:33 Dragotto - When we hit the beach, I knelt down and kissed the dirt, whispered "Thank you God." I then looked around and saw many dead in the water and on the beach. My company was being held up by machine gun fire from the hill then Col. Peynold regimental commander said "If we have to die, let's die on the hill." We moved on and took the hill, and given the Allies a foothold in France.

After 65 years, hero talks about D-Day assault

After 65 years, hero talks about D-Day assault

By Susan Lisovicz
CNN Correspondent



CNN's Susan Lisovicz sat down with her uncle Lenny Lisovicz, a decorated D-Day veteran, to talk about his experiences at war.

HOUSTON, Texas (CNN) -- Decorated D-Day veteran Lenny Lisovicz says the whispers are true.

For 65 years my family had heard whispers that he and 220 men stormed Omaha Beach and that he and his captain later went AWOL in Paris, France.

They heard he returned to combat and fought all the way to Germany and his courage was rewarded with the prestigious Silver Star.

Then -- after that sacrifice and loss -- he was committed to a hospital.

On the 65th anniversary of D-Day, Uncle Lenny finally talked at length about everything he had seen and done. And he said it was all true.

Nowadays, Uncle Lenny lives a tranquil life. At 91, he is proud of his garden, where he grows corn, tomatoes and grapefruit. He takes in stray cats, attends Mass and sends money regularly to Catholic missionaries.

But his thoughts are never far away from a sliver of sand thousands of miles away. He turned down my offer to visit Normandy.

"I don't want to see it. I try to rub that out of my mind. It won't go away," he said.

But now, he finally agreed to share his memories. VideoWatch Uncle Lenny describe storming the beach »

It began with The Longest Day: June 6, 1944. My uncle was a 26-year-old lieutenant with the Army 1st Infantry Division, the famed "Big Red One." They had been training in England for something big for months.

Then, over the loudspeakers in the barracks came the famous declaration from Gen. Dwight Eisenhower: "You are about to embark on the Great Crusade."

The Germans were taken by surprise in one of the greatest amphibious invasions of all time, which would mark a turning point of the war in Europe.

"I just imagined what that enemy observer felt when he looked through that concrete bunker and looked out at that ocean and all he could see was boats, warships," Lisovicz said.

But the Nazis had a superior position.

"They had you pinpointed. It was just like shootin' ducks on a pond. Your comrades would get artillery busted. A hand flying here, a leg there, guts laying out on the ground, asking for help and you couldn't help them. You had to move. You just had to push them aside," he recalled.

But the Allies couldn't push their way onto the cliffs until a massive air assault began.

"At times there were so many planes in the sky you couldn't see the sky... ," Lisovicz said. "You could see them forming from all directions coming into one pattern. And that's how we got off the beach, darlin'."

Their orders were to meet up with the paratroopers, who landed behind enemy lines. My uncle said they found them by smell, because they were all dead.

"They backed them in a corner and machine gunned them down and didn't have enough decency to cover them," he said.

That was when an unwritten order came down: "No prisoners. And we didn't take any."

It was shortly after this that he decided he had enough. He and the captain went AWOL in Paris. To add insult to injury, they stole the major's jeep. Their freedom lasted only about a week.

"The MP told us he was going to shoot us for going AWOL. But who cares? You didn't care anymore," Lisovicz said. "You were just fed up with war, fed up with killing, just absolutely fed up."

But they weren't shot -- not by Americans, anyway.

My uncle and the captain went back into combat. The captain was killed by a camouflaged tank. My uncle was now the commanding officer. And the fighting was ferocious as he battled his way into Germany.

He set trip wires for flares in one pivotal battle. At about 3 a.m., the flares went off. The Germans had overrun the outer defenses of the platoon. It was chaos.

The Silver Star says that he "skillfully deployed men and weapons into strategic positions and with accurately directed fire, held the foe at bay until supporting troops arrived and repulsed the attack."

But there was more.

"When I looked up I seen a man walking up with two of my comrades. It was a German. So I went after him. And got him and brought my men back," he said.

The Silver Star described it as "extraordinary gallantry and aggressive leadership."

Only 22 of the 220 men that stormed the beach with him came home alive.

That was the last time my uncle saw combat. He had been hit. He learned about his Silver Star in the hospital.

He wanted to return, but he was shell-shocked.

"It took them a year and a half of my life for them to straighten me out and get back to civilian life," he said.

WWII slave soldiers reunite after 64 years, prepare for honors

By Wayne Drash
CNN.com Senior Producer

ORLANDO, Florida (CNN) -- Samuel Fahrer and Sidney Lipson shake hands and smile. It's the first time the men have seen each other in 64 years. They were U.S. soldiers back on a forced death march in Nazi Germany in April 1945.

"How you doing?" Fahrer says.

It's a subdued moment for the two men. There are no tears, no pats on the back. The men have endured years of contained emotions from what happened six decades ago when they were prisoners of war and held as slaves inside Germany.

They have come to a hotel in Orlando to be honored by the Army this weekend for the first time. VideoWatch slave camp survivors reunite »

Fahrer and Lipson were among 350 soldiers held at the slave labor camp called Berga an der Elster, a largely forgotten legacy of the war and a subcamp of Buchenwald where soldiers were beaten, starved and forced to work in tunnels to hide German equipment.

More than 100 soldiers died at the camp and on the death march. Buchenwald was one of the largest and first concentration camps on German soil. PhotoSee photos inside Berga »

The Berga soldiers are being honored thanks in part to CNN.com users, who demanded the Army recognize the men, all in their 80s, after a series of reports late last year. The Army then conducted a months-long review of Berga at the urgings of Rep. Joe Baca, D-California, and Rep. Spencer Bachus, R-Alabama.

"These soldiers endured extreme hardships of forced labor, beatings, poor living conditions, and ultimately a forced march of over 250 kilometers [about 155 miles] prior to liberation by advancing U.S. Armed Forces," Army Secretary Peter Geren said at the conclusion of the review.

"The survivors of Berga certainly deserve both our thanks and recognition for their service and sacrifice."

Geren is sending Maj. Gen. Vincent Boles to honor the survivors on Saturday. Six of the 22 Berga survivors will be at the event; most of those still living could not make it because of declining health.

Those here look forward to what the general has to say. They want desperately to know why the U.S. government commuted the death sentences of the two Berga commanders, Erwin Metz and his superior, Hauptmann Ludwig Merz.

Both were tried for war crimes and initially sentenced to die by hanging until their commutations in 1948.

"I'm very happy the Army is sending a general to see us," Fahrer says. "But they should've sent the general to see us a long time ago when some of the fellas were still alive. We're only 20 fellas left."

Fahrer was one of the primary survivors after the war who fought to get the government to carry out the death sentences for Metz and Merz.

In a letter to survivors in January 1949, he wrote, "Things are beginning to break our way. A little enthusiasm, a little more cooperation, a little more action, will accomplish a great, great deal now." Now, 60 years later, he may finally get some answers.

"Let's see what the general has to say when he gets here," Fahrer says.

His comrade, Morton Brooks, says, "I never wanted revenge, but I did think retribution would be proper. And I think they should've suffered a little bit longer for what they did. ... They wouldn't kick a dog, but they did that to us."

The two men finally hugged. "I'm glad to see you," Fahrer says.

Some of the Berga soldiers were killed in cold blood, such as Morton Goldstein, shot through the head and then machine-gunned. His bullet-riddled body was placed in front of the barracks for all to see.

Bernard Vogel and Izzy Cohen were forced to stand without food and water for days, pushed to their deaths.

Cohen was a 32-year-old father of two young children. When he left for war, he kissed his family goodbye at a train station in California. He looked at his wife, Florence, and said, "Whatever happens happens." It was the last words he ever spoke to her.

Vogel's last words at Berga were: "I want to die! I want to die!" Hear Martin Vogel finally learn about his brother's final minutes »

"They killed us slowly," Fahrer says. "They didn't feed us, they didn't give us anything, they didn't do anything."

The memories are so terrible, so horrific that Sid Lipson doesn't remember much of anything about his captivity. "I don't remember a damn thing from the march," he says.

Brooks says, "I think it's best." Brooks weighed 75 pounds when he was finally freed; Fahrer weighed 90.

"The United States government did not acknowledge the fact that we were put in this slave labor camp," Fahrer says, shaking his head. "We went through all these things and nobody wants to give us any help. And finally, now ..."

Brooks went on to become a psychologist. He says his time in captivity was a "$1 million experience that I wouldn't want to repeat for $2 million."

His message to the world about the whole ordeal:

"We have to learn to talk to one another and live together. It's not necessary to go kill people for no reason."

Deep brain stimulation: Expanding its reach to new patients

Electrical therapy, used for years to treat Parkinson's and other movement disorders, may soon tackle depression and more.
By Andreas von Bubnoff

June 1, 2009

Under the skin, a battery is surgically implanted -- generally within the upper chest. From the battery, wires snake up to the head, to tickle different targets deep inside the brain.

Such is the hardware for deep brain stimulation -- the equivalent of a cardiac pacemaker for the mind.

Until recently, deep brain stimulation was approved in the U.S. only to treat certain movement disorders, primarily those of Parkinson's disease, for which it diminishes tremors and rigidity and improves mobility. To date, more than 60,000 patients worldwide have had the devices implanted.

But now use of the technique seems set to mushroom.

This year, the Food and Drug Administration granted a so-called humanitarian device exemption for the treatment to be used in severe cases of obsessive-compulsive disorder -- the first approval of deep brain stimulation therapy for any psychiatric condition.

Large clinical trials are also in the works for use of deep brain stimulation for epilepsy and depression, and experimental studies in the U.S. and elsewhere -- still in their early stages -- are exploring the treatment for obesity, traumatic brain injury, severe chronic pain, Alzheimer's disease, anorexia, tinnitus and addiction.

There are discussions too on the possible use of deep brain stimulation to treat hypertension.

"The field is taking off," says Dr. Ali Rezai, director of functional neurosurgery at the Cleveland Clinic, who has been involved in research on movement disorders, traumatic brain injury, obsessive-compulsive disorder and severe depression, among others.

Some researchers warn, however, that with all this activity -- pushed in part by the industry that makes the brain-stimulation devices -- the field may be moving too fast.

"There is so much progress that's been made and so much potential -- you would hate to lose that potential," says Dr. Joseph Fins, chief of the division of medical ethics and a professor at Weill Cornell Medical College in New York.

Here's a look at deep brain stimulation as it moves beyond Parkinson's disease. (See the related story about reservations scientists have about the growth of the field, and go online at latimes.com/health for a look at less-explored applications such as traumatic brain injury and obesity.)

Obsessive- compulsive disorder

In studies with a total of 26 patients with severe obsessive-compulsive disorder, 60% of those whose device was turned on demonstrated "very much improved" symptoms after months of deep brain stimulation as measured by interviews and questionnaires, says Dr. Benjamin Greenberg, an associate professor at Brown University Medical School and Butler Hospital in Providence, R.I., who was one of the study researchers.

The patients had previously failed on medicines as well as behavioral cognitive therapy.

Yet the data, published last year in Molecular Psychiatry, can't really nail the effect of the treatment, Greenberg says, because the patients for the most part knew whether their devices were turned on or off. Thus, researchers can't rule out that some of the observed improvements were due to a placebo effect.

Patients were stimulated in an area called ventral capsule/ventral striatum, chosen, in part, because removal of nerve fibers in that area is known to cause improvement in obsessive-compulsive symptoms.

Based largely on these findings, the FDA recently granted a limited humanitarian device exemption that permits the device to be used in as many as 4,000 of the country's most severe cases of obsessive compulsive disorder per year.

To get this kind of exemption, Medtronic -- makers of the only deep brain stimulation device that is FDA-approved -- needed only to show its safety and probable benefit.

Greenberg is now doing a randomized, double-blinded trial with 30 patients, some of whom have devices turned on right away and some who have them turned on after a delay. No one will know whose device is turned on for the first several months of the trial.

Epilepsy

Medtronic has conducted a large-scale randomized trial for deep brain stimulation on epilepsy. Data will be submitted to the FDA this year, says Paul Stypulkowski, senior director of therapy research of Medtronic.

The device was turned on, for three months, in half of the 110 volunteers, stimulating -- and thereby, paradoxically, inhibiting-- an area called the anterior nucleus of the thalamus. That area is believed to influence a circuit involved in seizures.

The data, presented in December at a meeting in Seattle, show that deep brain stimulation reduced the number of seizures by 38% compared with what was seen before implanting the device.

That is slightly better than improvement seen with vagus nerve stimulation, another FDA-approved electrical stimulation treatment, which reduces seizures by about 25%.

The control group whose device was kept turned off, also improved, by 14.5%. That could be due to a placebo effect. Or it might be because people who join trials are usually at their worst -- and often tend to improve somewhat on their own, says trial researcher Dr. Douglas Labar, of the Weill Cornell Medical College in New York.

If deep brain stimulation is approved, Labar says, patients will have the choice between a more efficient but also more risky treatment and the slightly less efficient but also less risky vagus nerve stimulation.

Depression

Medtronic and a second company, St. Paul, Minn.-based St. Jude Medical, have two large-scale randomized trials underway for severe, treatment-resistant depression. (St. Jude Medical recently received approval to sell its device for the treatment of Parkinson's disease in Europe and is now completing studies aimed at securing FDA approval for treating Parkinson's and another movement disorder in the U.S.)

Medtronic's depression trial will follow about 200 patients stimulated in an area called the anterior limb of the internal capsule for at least one year.

This brain target for depression was identified by accident: When obsessive-compulsive disorder patients who also had depression were stimulated in this area, their depression also improved.

In one case, a patient produced a one-sided smile when stimulated on one side of the brain and also expressed feelings of happiness, says study researcher Dr. Wayne Goodman of the National Institute of Mental Health.

In a recently published unblinded study, about half of 15 patients showed at least a 50% improvement in severe depression symptoms a year or more after surgery when the anterior limb of the internal capsule was stimulated, says Rezai, who was involved in the study.

St. Jude Medical chose a different brain target, area 25, for its depression trial, which will enroll more than 100 patients. Brain imaging studies have shown that area 25 is more active in depressed people.

In a study of 20 patients, 55% still responded to treatment as late as one year after surgery, says study author Dr. Helen Mayberg, professor of psychiatry and neurology at Emory University. That is an "unheard-of response rate" given that these patients had tried and failed every other treatment, including several medications and electroconvulsive therapy, Mayberg says.

By comparison, Mayberg says, stimulation of the vagus nerve in the neck, approved by the FDA for depression, has only a 15% response rate at 10 weeks in similarly severely depressed patients.

Dr. Thomas Schlaepfer, vice chairman of the department of psychiatry of the University of Bonn in Germany, has been treating severely depressed patients by stimulating yet a third brain target, the nucleus accumbens.

The nucleus accumbens doesn't show normal activity in depressed patients, which could explain why they are less able to experience pleasure.

Last year, Schlaepfer showed that deep brain stimulation in this area led to acute improvements in three severely depressed patients. He says he has extended the work to 10 patients, half of whom showed an improvement when examined a year later.

With deep brain stimulation now being tried in at least three brain areas for depression, the question is, which target is the best? All agree that it's too early to tell.