Clinical depression and addiction can spin destructive realities – crushing careers, dreams, families, even life itself. Depression is considered a leading cause of disability in the Western world, affecting 120 million people, while some 90 million worldwide were diagnosed in 2003 with addictive disorders associated with alcohol and drug abuse. Recent studies show that these conditions share a common biological link in areas of the brain referred to collectively as the “reward system.”
Dr. Abraham Zangen of the Institute’s Neurobiology Department investigates the reward system's role in mitigating stress – one cause of depression. This part of the brain, he found in several experiments, produces chemical compounds in a number of stressful situations. For instance, rats pressing a lever received a mild electrical stimulus straight to their reward centers; when this pleasurable sensation was withheld, the brain released beta-endorphin – which has an effect much like a mild dose of morphine. This neurochemical response may be the reward system's way of coping – a sort of “consolation prize” to allow animals to adapt to a new situation and perhaps mitigate feelings of frustration and stress. Rats, humans and other mammals share a similar neurochemistry, suggesting that imbalances in these chemicals in the human brain’s reward system could be tied to depressive or addictive tendencies, in which stress is a key factor.
“In the black box of psycho-physics, the reward system is a small window to understanding how the mind and the brain relate,” says Zangen. He predicts that the several parallel paths of study he currently pursues will ultimately converge to improve understanding of the brain's reward system and its effects on behavior.
Another of his research paths targets chronic cocaine use, which can cause permanent changes to the network of neurons in the reward system, compromising its ability to mediate motivation and pleasure. Zangen wanted to see if stimulation to specific deep brain areas could reverse these neuro-logical changes. His team, which included Ph.D. student Dino Levy, found that rats treated with electrode stimulation of a specific reward-related brain region during cocaine detox exhibited 50% less cocaine-seeking behavior than the control group. There was also a measurable improvement in the treatment group’s brain chemistry: The electrode stimulation partly reversed cocaine-induced changes affecting glutamate, one of the reward system's key neuro-transmitters. Further study is in progress to elucidate the neurochemical effects of such electrode stimulation as well as the potential therapeutic benefits.
Could deep brain stimulation be applied to humans with problems related to reward system dysfunction? Zangen was interested in a non-invasive technique known as transcranial magnetic stimulation (TMS) – a method of triggering electrical responses in the brain through the use of external, rapidly alternating magnetic fields. TMS however, can penetrate only the outer layers of the brain – up to about 2 cm – whereas the reward system is buried much deeper. Efforts to increase its range by increasing the magnetic field intensity were unsuccessful, sometimes having an intolerably painful effect on subjects. Zangen conceived of a device that would produce low-level magnetic fields arranged radially so as to come together only at the desired deep brain region.
In collaboration with Yiftach Roth, a graduate student at Tel Aviv University, he designed and perfected the device, using computer modeling techniques and a “phantom” brain – a spherical container of a solution with the same conductivity as the brain. Their final design, the “H-coil,” was patented in 2002 by the National Institutes of Health, USA. Zangen and his colleagues recently tested the device on healthy volunteers in the U.S. and found it attained depths of up to 6 cm – deep enough to reach reward system centers.
The H-coil may, in the future, enhance many areas of brain research and treatment. For depression, Zangen believes the H-coil may offer an effective alternative to electroconvulsive therapy. Variations in the design of the H-coil may potentially be useful for the treatment of addiction, neurological disorders such as epilepsy, and diseases such as Alzheimer's and Parkinson's.
There is a large genetic component to depression. To link specific genetic factors to behavior, Zangen has employed a number of rat testing methods, including the swimming test – widely used for analyzing levels of motivation. Zangen and Ph.D. student Roman Gersner recently developed a novel approach that improves diagnostic accuracy and objectivity in this swimming test. Instead of timing periods of activity with a stopwatch, they use a joystick to measure the swimming rat’s limb motion, which is recorded and plotted by computer. Zangen predicts this methodology will contribute to a better mathematical analysis of behavior and potential drug effectiveness.
Dr. Abraham "Boomy" Zangen received a B.Sc. in pharmacology from the Hebrew University of Jerusalem in 1991, and from Bar Ilan University, an M.Sc. in biochemical pharmacology and a Ph.D. in psychopharmacology. In 1999, he travled to the US on fulbright and Fogarty scholarships to comlete postdoctoral research at the National Institutes of Health. In 2003 he returned to Israel to a position as senior scientist in the Weizmann Institute's Neurobiology Department. He has reiicved the annual proze of the Israel Society for Biological Psychiatry (twice), a Fellows Award for Research Excellence for the NIH and published over 25 papers in scientific journals.
Zangen lives in Jeruslaem with his wife, Rachel, and their four children.
Dr. Abraham Zangen’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Charles and M.R. Shapiro Foundation Endowed Biomedical Research Fund; and the Lord Sieff of Brimpton Memorial Fund. Dr. Zangen is the incumbent of the Joseph and Celia Reskin Career Development Chair.
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