Henri Begleiter’s relentless search for the genetic and chemical roots of alcoholism has endured for almost 30 years, and there has been a great deal of progress made to this end.
“My real interest lies in pathogenesis- in identifying what parts of the brain and what neurotransmitters may be involved, as well as determining associated brain events and understanding what those brain events mean. Among other things, we want-to understand why some people are genetically at risk to develop alcohol dependence,” says APS Fellow Begleiter whose research has been supported largely by the National Institute on Alcoholism and Alcohol Abuse (NIAAA) throughout these 30 years.
But Begleiter’ s interests span the entire field of alcohol and alcoholism- best demonstrated, perhaps, by the broadly conceptualized nine-volume series of reviews of recent research on alcohol that Begleiter and his colleague Benjamin Kissin have undertaken for Oxford University Press. The first two volumes have already been published.1
Now a professor of psychiatry and neuroscience at the State University of New York Health Science Center at Brooklyn, Begleiter started his research with rats and monkeys in the 1960s. He looked at the effects of alcohol on the animals’ brains, trying to identify specific brain sites, and posed questions like: What does alcohol do to the brain? Where does it act first? What specific sites does it act on? What’s different about chronic alcohol intake?
Alcohol Dependence and Brain Recovery
Begleiter also began to move these same research questions into the human realm. Throughout his career Begleiter has been concerned primarily with hard-core alcoholics, especially with “the probably 45 to 50 percent of the hard-core alcohol-dependent individuals who manifest a genetic influence,” he says. By “alcoholics” he does not mean “alcohol abusers,” “problem drinkers,” or “heavy drinkers.” Those terms are too difficult to qualify and quantify, too amorphous, he says. He also does not mean college students who engage in “binge drinking” at parties.
“My alcoholics don’t go to college, I assure you,” he says. They are dysfunctional alcohol-dependent people. They have powerful cravings for alcohol, and when they try to abstain, they manifest withdrawal symptoms, he says. Alcohol has major deleterious, neurotoxic effects on their brain functions. If these people stop drinking for months or years, though, many of their brain functions become normal again, Begleiter and his fellow researchers have found.
“But some brain functions didn’t seem to recover at all,” Begleiter said, looking back at the groundbreaking work that he and his fellow researchers conducted in the early 1980s.
Chicken vs. Egg
“It was at that point that we began to entertain the possibility-a wild, crazy notion- that maybe the functions still deficient were the result of antecedent factors , not the result of alcohol. Perhaps their brain functions were deficient before those people ever had any alcohol at all.”
Many genetic and epidemiological studies were going on at that time, primarily in Scandinavia, and they were suggesting that sons of alcoholics were four to five times as likely as others to become alcoholics themselves, Begleiter said.
“So in the early 1980s we decided to look at sons of alcoholics ourselves,” he said. Begleiter and his colleagues gave their subjects event-related potential (ERP) tests. The tests use electrodes mounted on the surface of the subject’s scalp to record electrical activity emanating from the brain as the subjects detect “odd-ball” stimuli from monotonous, repetilious ongoing visual or auditory patterns. The electroencephalographic measures serve as an index of cognitive responsivity during the task.
Emerging from this research was the revelation that “that children of alcoholics had cognitive deficits identical to those of their fathers, even though the sons had had no exposure to alcohol whatsoever,” Begleiter said. “This finding has been replicated many, many times, looking at different brain systems. And we find indeed that there are a few systems that appear to be deficient in alcoholics and in people at high risk for developing alcoholism.” Using this cognitive deficiency as a “marker,” Begleiter and colleagues proceeded to test all the criteria that were essential to establish it as a phenotypic genetic marker.
Having achieved this, Begleiter and colleagues undertook a major genetic family study. In 1989 he formed a large consortium, which he now heads, with six sites in the United States and 11 sites in other countries. It assesses families, looks at the ERPs of all family members, and analyzes DNA to identify genotypes. The search is on for the multiple genes involved in what Begleiter refers to as “this genetically influenced” disease.
Genetic Diseases vs. Genetically Influenced Diseases
“Let me clarify that alcoholism is not a genetic disease. Huntington’s disease is a genetic disease, and so is neurofibromatosis and cystic fibrosis,” Begleiter hastens to add. “But alcoholism is a genetically influenced disease. In current scientific lingo, it is a complex disorder, one in which there is a gene-environment interaction,” Alcoholism is not a monogenic disorder in which only one gene is responsible for turning the disorder “on” or “off.” Rather, says Begleiter, multiple genes are involved, perhaps as many as six. “We know that already. The same thing is true for cancer, diabetes, hypertension, and other complex disorders. So it is possible for somebody to carry the genes and never manifest the disease, unless the environmental influence comes into play. The influence of environmental and psychological factors is very important,” he says. And to further examine this issue in relation to alcoholism, Begleiter presently is organizing a two-day conference titled “Genes and the Environment in Complex Diseases: A Focus on Alcoholism.” Funded by the NIAAA, the conference will be held on April 2-3 at the National Institutes of Health outside Washington, DC. (See announcement below.)
There is also an age-at-risk span where alcoholism of the genetically influenced type usually manifests itself, Begleiter pointed out. The span is between the teenage years and 25. “If you develop alcoholism at age 35, I can assure you it is not a genetically influenced disorder that you are looking at,” he said.
Teasing Out Brain Signals
Counting off the current challenges and goals of his laboratory group, Begleiter speaks first of their efforts to develop techniques for mathematically and statistically decomposing an evoked brain potential signal. He and his colleagues are trying to tease apart the several components of the signal that are produced by a variety of generators in the brain, overlapping in time. The purpose is to better understand the brain sources of the potentials.
“That’s something I’ve been working at for years- not very successfully, I might add,” he said. “In fact, it’s the only thing I’ve done that could be considered a series of dismal failures, except for some recent findings that we are now ready to publish and that are extremely encouraging and finally show some success.”
The second issue currently facing Begleiter is how to compare ERP topographical maps of two or more people. “It’s obviously not sufficient to tell the scientific world that it seems to me that this map is different from that one,” Begleiter says. “So we want to analyze these data statistically and mathematically.” Third, “we are trying to understand from the EEG scalp recordings where the ERPs are coming from in the brain. So there’s a lot of mathematical modeling that goes into this, and there’s lots of speculative work to do.”
Vive le Vin
Begleiter came to the United States in 1958 but never lost touch with France. He and his classmates at the University of Paris, where he did his undergraduate work, still get together for good times when he is over there. He has been invited to speak before France’s National Academy of Medicine. And he has seen no reason to deviate from the French rule of having a glass or two of wine with meals.
As to French drinking habits, Begleiter says, ”They drink a great deal more than we do- mostly wine, while we in America are more committed to hard liquor. The only problem that really manifests itself in France is cirrhosis of the liver; that’s probably more of a problem there than it is here.”
“But you know there is something called the “French paradox”:
Physicians in France encounter very few cardiovascular cases, even though the French intake of fat is really quite high,” he said. “My physician friends in France are absolutely convinced that alcohol has protective, salutary effects. Of course I love to hear that, and I hope it’s true. In fact , NIAAA has made several grants of late for research looking at the protective effects of alcohol.”