For the past twenty years 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 young offspring of alcoholics at high risk (HR) for developing alcoholism. These observations suggested that reduced amplitudes of the P3 component in HR individuals might antecede the development of alcohol dependence. There is some evidence that reduced P3 voltage in childhood and adolescence in HR individuals is associated with externalizing disorders (conduct disorder, attention deficit hyperactivity, oppositional defiant disorder and adult antisocial behavior) and increased substance use, and may predict later substance and alcohol abuse. A meta-analysis of all HR studies concluded that the low amplitude P3 in HR individuals provides a reliable phenotypic marker of alcoholism, and it has been postulated to be indicative of increased Central Nervous System (CNS) disinhibition. Thus P3 as a potential vulnerability marker may provide insight into some causative pathophysiology process involved in the development of alcohol dependence. Here it is hypothesized that the P3 amplitude may index some CNS vulnerability (e.g. disinhibition) which may result in any one of a number of adverse conditions, such as alcohol dependence, 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. In the present renewal a complementary strategy is proposed based on a """"""""neurophysiological high-risk"""""""" model. In this model, individuals are hypothesized to be at high-risk based solely on their extreme scores on neurophysiological features (e.g. visual P3 amplitude), well established to be associated with a number of clinical conditions such as alcohol dependence, substance abuse, etc. Several scientific issues will be examined with the use of this novel approach, using innovative neurophysiological assays and methods. Specifically, electrophysiological measures (P3 and other measures) will be recorded in a large randomly ascertained sample of adolescents (15-17). The P3b amplitude provides a quantitative variable that typically yields a normal distribution in the general population. This distribution will be divided into the lower, upper and middle third. These three groups based on P3b amplitude will provide the basis for subsequent dependent variables, such as other EEG/ERP experiments, the clinical data to be collected (externalizing symptoms, other psychiatric symptoms, alcohol use, drug use, family history of psychiatric disorders, etc.). It is hypothesized that those individuals at the low end of the P3 amplitude distribution will manifest more evidence of electrophysiological disinhibition, externalizing traits, and substance use. Moreover, it is proposed that individuals with low P3b amplitude will manifest significantly greater prevalence of externalizing traits, alcohol and drug abuse compared to subjects with high P3b amplitude when retested four years later (ages 19-21). Retesting will begin in the last year of this application, and will continue in the future. The identification of individuals with neuroelectric deficits will have great utility in prevention initiatives.
