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A new study by CUMC researchers has found that nicotine does indeed have an effect on concentration, as smokers have long claimed. Nicotine seems to jam some of the "background noise" sent through the brain's neurons while letting more important messages pass through. The results of the study appear in the June issue of Nature Neuroscience.

"Nicotine ends up being a filter and that may explain why it helps increase concentration and memory of people with attention deficit disorder and Alzheimer's disease, and why so many people with schizophrenia smoke," says Dr. David Sulzer, associate professor of neurology and psychiatry and the study's senior author. "Smoking has always been suspected to be a form of self-medication in schizophrenia and now we have evidence for that idea."

The researchers found that at levels typically experienced by smokers, nicotine acts as a filter by stopping slow-firing neurons – which are carrying less important signals – from releasing dopamine into the brain. The drug only allows more rapidly firing neurons – which are related to acts of concentration and to short-term memory – to release dopamine, which then transmits the information to other parts of the brain.

"The filtering mechanism helps you concentrate by dampening less important inputs and letting more important ones go through," Dr. Sulzer says. "In people with schizophrenia, the nicotine may help by filtering out hallucinations."

Dr. Sulzer and co-author Dr. Hui Zhang, associate research scientist in neurology, do not advocate smoking to improve concentration, because the harm from smoking far outweighs any benefit from nicotine. Dr. Sulzer suggests, instead, that nicotine or similar drugs delivered in a safer manner could be used to improve concentration and memory and reduce hallucinations.

The finding also solves a paradox about nicotine addiction. Nicotine is believed to be addictive because it increases the amount of dopamine in pleasure centers in the brain. But researchers have struggled to explain how dopamine levels rise because they believed nicotine shuts down dopamine release from all neurons only a few seconds after it reaches the brain.

The discovery that nicotine allows dopamine release from rapid-firing neurons explains how dopamine levels can increase in the brain at the same time that slow-firing neurons stop releasing this neurotransmitter.

The research was supported by the National Institute on Drug Abuse, the Lowenstein Foundation and the Parkinson's Disease Foundation.

–Susan Conova

Despite a higher risk of stroke, patients in the last stages of heart failure who receive a heart pump fare significantly better than patients who are managed with medications, according to a post-hoc analysis of clinical trial data.

The pumps, called left ventricular assist devices (LVADs), were initially used to extend the lives of heart failure patients until a donor heart could be implanted. In 2001, results from a clinical trial led by Dr. Eric Rose, chairman of surgery and the Morris and Rose Milstein/Johnson & Johnson Professor of Surgery, showed the pumps could also benefit severely ill patients ineligible for a transplant.

Though that trial showed the pumps doubled the recipient's one-year survival rate, the success was tempered by a high rate of neurological events, including stroke. To further investigate whether stroke lessens the survival benefits of LVAD for these patients, Dr. Ronald Lazar, professor of clinical neuropsychology in neurology and neurological surgery at P&S and the study's principal investigator, and his colleagues, calculated a new combined endpoint of death or stroke from the trial's original data plus additional, longer-term follow-up information collected after the trial ended.

"In this analysis, we took the view that outcome should be considered in terms of both survival and significant disability," says Dr. Lazar.

Sixteen percent of the LVAD patients had a stroke, compared with 3 percent in the medically-managed group. Using the combined mortality-disability endpoint, however, the researchers found that LVAD support was associated with a 44 percent lower rate of death or stroke over a mean follow-up of 341 days for the LVAD recipients and 226 days for the medically managed patients.

Strokes in the LVAD recipients also tended to occur in one of either two time periods: in the month immediately following the surgery or after a year on the device.

"This means the early flurry of strokes may be related to the risk of clotting following surgery, and the later strokes related to the disease process itself," Dr. Lazar says.

"Design modifications and better medical management should result in fewer complications, but people considering this device should realize that there are risks that go along with the considerable benefits."

The study was supported by the National Heart, Lung, and Blood Institute of the NIH.

–Susan Conova

title - Antidepressants Helpful for Drug Abusers

Psychiatrists at CUMC and the New York State Psychiatric Institute suggest doctors do not need to withhold antidepressants from patients who are also struggling with drug or alcohol addiction. Clinicians often hesitate to prescribe antidepressants for such patients because it's easy to confuse symptoms caused by drug use with symptoms of underlying depression.

The new meta-analysis by Dr. Edward Nunes, associate professor of clinical psychiatry, and Dr. Frances Levin, the Q.J. Kennedy Associate Professor of Clinical Psychiatry, shows that antidepressants are about as effective in reducing depression in substance abusers as they are in patients who only suffer from depression. In some cases the antidepressants also reduced drug and alcohol use, though the researchers say this effect is not strong enough for the medications to be used alone as a treatment for addiction. The research was published in the April 21 issue of the Journal of the American Medical Association.

The authors say their results provide the clearest evidence yet to support recommendations during the past decade to prescribe the medications.

But they also caution that, before prescribing antidepressants, clinicians need to determine that underlying depression, and not the drug use itself, is the cause of the patient's depressive symptoms. The best way to make that distinction is to observe the patient after a week or more of abstinence, though Dr. Nunes admits it is often difficult for such patients to become abstinent.

The study was supported by the National Institute on Drug Abuse and the New York State Psychiatric Institute.

–Susan Conova

New imaging techniques have revealed differences in the brain that distinguish memory loss caused by Alzheimer's disease from memory loss caused by normal aging.

Using two different techniques, Dr. Scott Small, Irving Assistant Professor of Neurology, and his colleagues found that memory loss caused by normal aging seems to stem from poor performance of only one of several regions of the hippocampus – the dentate gyrus. Alzheimer's disease, in contrast, is known to damage a separate region of the hippocampus – the entorhinal cortex – first, before spreading to other parts of the brain.

The differences in the hippocampus of the Alzheimer's brain and the normal aging brain suggest that one of the techniques, MRI, could be used to detect Alzheimer's disease at its earliest stages when it causes only mild forgetfulness and is often mistaken for other types of memory loss.

The difference also establishes that all memory loss during aging is not Alzheimer's disease, as some investigators have suggested. The research was published in the May 4 issue of Proceedings of the National Academy of Sciences.

In the study, Dr. Small used two different techniques to view the hippocampus. Using MRI, he detected low blood volume – an indicator of poor brain function – mainly in the dentate gyrus of aging Rhesus monkeys who performed poorly on memory tests.

A second technique used more direct cellular evidence to implicate the dentate gyrus. This time, using rats, the researchers detected a drop in the activity of a gene associated with cellular correlates of memory only in the dentate gyrus among older animals.

Because neither rats nor rhesus monkeys develop Alzheimer's disease, the researchers can be certain that other aging processes, not Alzheimer's disease, cause the changes in the dentate gyrus.

Dr. Small is now looking in people to see if the early changes in the hippocampus detected by MRI can distinguish between memory loss caused by aging and loss caused by Alzheimer's disease. Furthermore, he and his colleagues are using cellular techniques to determine the molecules that make each hippocampal subregion vulnerable to either Alzheimer's disease or to aging.

The research was supported by the NIH, the American Federation of Aging, the Institute for the Study on Aging, and the McKnight Endowment Fund for Neuroscience.

–Susan Conova

America's seniors suffer a disproportionate burden of oral disease while having fewer resources for appropriate care – and these issues will be exacerbated as the elderly population grows. Now, the dean of Columbia's School of Dental and Oral Surgery has issued a "call to action" on geriatric oral health and has outlined initiatives that he hopes other institutions will emulate in order to prevent a health crisis among the nation's aged.

Writing in the May issue of the American Journal of Public Health Dr. Ira B. Lamster, SDOS dean, outlines ways to address this hidden health problem. His proposal covers dental education, provision of new dental services, changes in public policy, and prevention initiatives.

"The needs of the nation's seniors do not mesh with the availability of services," Dr. Lamster says. "While America's elderly population continues to grow, its dental needs have received little attention and almost no public health or public policy interventions."

The senior population is expected to increase rapidly – by 2030 about 20 percent of Americans will be 65 or older. "This is why we must take action now," Dr. Lamster says.

A head-cooling device called "CoolCap" prevents brain damage in some oxygen-deprived newborn babies, providing the first evidence in humans that many birth-related neurological problems can be reversed, according to an international multi-center clinical trial that included CUMC.

Using brain-wave analysis at birth, researchers identified babies who might benefit from treatment. In the group of infants with moderate to severe injury, the percentage of babies who experienced an unfavorable outcome – death or neurodevelopmental disability – was significantly reduced from 66 percent to 48 percent by the cooling.

"While more research is needed, the findings offer hope that this condition – which affects thousands of babies worldwide – might be treatable," says Dr. Richard Polin, professor of pediatrics at P&S and director of the neonatal intensive care unit at Morgan Stanley Children's Hospital of NewYork-Presbyterian Hospital. Dr. Polin was a member of the study's scientific advisory committee.

The CoolCap circulates cold water to bring the infant's body temperature down to 94 degrees Fahrenheit. While it is not yet understood how the treatment works, factors may include slowing brain metabolism, reducing brain inflammation, preventing brain-cell death, and reducing potentially harmful toxins released after brain injury, Dr. Polin says.

In the study, infants wore the CoolCap for 72 hours. A daily neurological examination was performed for the first 72 hours, then after one week, and again at the time of discharge. At 18 months, infants had a neurological assessment by a pediatrician and developmental assessment by a psychologist as well as visual and auditory testing. The study's results were presented at the Society for Pediatric Research's annual meeting in May.

Olympic Medical Corp. of Seattle sponsored the research.

Pregnant women who are obese or morbidly obese are more likely to deliver babies by Caesarean section and have serious pregnancy-related complications than women with more healthy weights, according to a new study by CUMC researchers. The study was published in the May 2004 issue of the American Journal of Obstetrics and Gynecology.

"Caesarean sections for obese women can be complicated," says Dr. Mary D'Alton, leader of the study. "OB/GYN's should consider counseling obese and morbidly obese women about weight-reduction procedures including surgical services before pregnancy." Dr. D'Alton is the Willard C. Rappleye Professor of Obstetrics and Gynecology and chairwoman of obstetrics and gynecology in P&S.

Dr. D'Alton and her colleagues evaluated more than 16,000 pregnancies to determine if Caesarean births and pregnancy complications were related to obesity. The patients were divided into three groups based on their body mass index early in their pregnancy: normal and overweight (BMI less than 30); obese (between 30 and 34.9); and morbidly obese (BMI 35 or greater). By BMI standards, a woman 5 feet 4 inches tall is considered obese when she weighs 175 pounds or more; morbidly obese when she weighs 204 pounds or more.

The researchers found that obese women are 1.5 times more likely, and morbidly obese women are 2.3 times more likely, to deliver by Caesarean than women of lower weight. Nearly half (47.4 percent) of morbidly obese women in the study had C-sections, compared with 33.8 percent of the obese women and 20.7 percent of normal and overweight women. Previous studies have shown that C-sections in obese women are riskier because of a greater chance of excessive blood loss, longer operation times, and a greater chance of wound infection.

The researchers also found that obese and morbidly obese women were more likely to have complications during pregnancy, such as gestational hypertension and gestational diabetes. In addition, obese and morbidly obese women were more likely to deliver large-for-gestational age babies.

Other complications did not vary with BMI. These complications were: rupture of the amniotic sac before 37 weeks of pregnancy, placenta that grows improperly over the cervix, premature separation of the placenta from the uterus, and babies who are too small for their age.

The study was funded by the National Institute of Child Health and Human Development of the NIH.

–Susan Conova

Once melanoma spreads from its initial site, it is extremely resistant to current treatments. But a new study by CUMC researchers indicates that short-term treatment with low doses of arsenic, coupled with an inhibitor of a specific cell signaling pathway, might be able to stop melanoma by causing tumor cells to self-destruct.

Two researchers in the Center for Radiological Research, Dr. Vladimir Ivanov, associate research scientist, and Dr. Tom K. Hei, professor of radiation oncology and environmental health sciences, have found that arsenic alone was able to induce cell death in 40 percent of some melanomas in cell cultures and less than 10 percent in others while causing no harm to normal cells. When they applied preclinical drugs known to inhibit certain cell signaling pathways, they achieved a 90 percent kill-rate even among the most resilient tumor cells.

"Further research is necessary, first in animals and then in clinical trials, but this approach could have a profound impact on melanoma treatment," Dr. Hei says. The research, originally published online on March 17 in the Journal of Biological Chemistry, was published in the May 21 print issue.

Drs. Hei and Ivanov initiated the study because of the need to identify better treatment methods for a deadly cancer and because arsenic has been successful in treating some forms of leukemia. However, researchers have been reluctant to attempt using arsenic as a treatment because it is an environmental carcinogen that causes skin cancer and other cancers with prolonged treatment at high doses.

The research was supported by grants from the National Institute of Environmental Health Sciences.

–Matthew Dougherty


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