EXCEED THE SPACE PROVIDED. It has been repeatedly observed that the P3(00) component of the event-related potential (ERP) is not only significantly lower in alcoholics, but also in offspring of alcoholics at high risk for developing alcoholism, suggesting that reduced P3 amplitude antecedes the development of alcoholism. Reduced P3 voltage in childhood and adolescence is also associated with externalizing disorders (attention deficit hyperactivity, oppositional defiant disorder, conduct disorder, and adult antisocial behavior) and increased substance use, and may predict later substance and alcohol abuse. It is hypothesized that P3 amplitude may index some CMS vulnerability (e.g. disinhibition) which is involved in a predisposition toward the development of a spectrum of disinhibitory disorders including alcoholism (e.g. drug abuse, antisocial personality, attention deficit hyperactivity disorder, conduct disorder, oppositional disorder, etc.). The research strategy used to date has been based on a familial high-risk model, because it is well known that children of alcoholics are at high risk to develop alcohol dependence. Here a complementary strategy has been proposed based on a """"""""neurophysiological high-risk"""""""" model where individuals are hypothesized to be at high-risk based solely on their extreme scores on neurophysiological features (e.g. P3 amplitude, beta power), well established to be associated with a number of clinical conditions such as alcohol dependence, substance abuse, etc. Progress in the last few years of this project indicates that this neurophysiological high risk model is very promising. A combined electrophysiological """"""""high risk"""""""" phenotype was derived based on both low P3 amplitude and high resting EEC fast beta power; individuals manifesting this combined high risk phenotype endorse more symptoms of alcohol use, substance use and externalizing disorders. We propose to build on these findings in the next 5 years. Several scientific issues will be examined with the use of this novel approach, using innovative neurophysiological assays and methods. Specific focus will be on inhibitory and frontal lobe function and the underlying neural oscillations (EROs) of various ERP components. Electrophysiological measures (P3, beta, EROs) will continue to be recorded to construct a large randomly ascertained sample of both male and female adolescents (18-21). Individuals who are both in the lowest third of the P3 distribution and highest third of the fast beta distribution (High Risk phenotype) will be compared to individuals in the highest third of the P3 distribution and lowest third of the beta distribution (Low Risk phenotype) regarding clinical data: externalizing symptoms, other psychiatric symptoms, alcohol use, drug use, family history of psychiatric disorders, etc. It is hypothesized that those individuals with the High Risk phenotype will manifest more evidence of electrophysiological disinhibition (on other EEG/ERP measures), externalizing traits, and substance use. Moreover, it is proposed that individuals with this High Risk phenotype will manifest significantly greater prevalence of externalizing traits, alcohol and drug abuse compared to subjects with the Low Risk phenotype when retested four years later (ages 22-25). The identification of individuals with high risk neuroelectric phenotypeswill have great utility in prevention initiatives.
