John Polich - US grants

Because the P3 (P300) event-related brain potential (ERP) indexes the information processing events associated with memory function, attempts have been made to use the P3 as a measure of the cognitive changes found in Alzheimer's disease and other dementing illnesses. However, the clinical utility of the P3 as a diagnostic tool for neurological disorders has been hampered by the variability observed for its amplitude and latency in normal subjects. Recent findings suggest that this variability stems in part from a number of biological and psychological variables (body temperature, recency of food consumption, and cognitive ability) which have not been controlled since little was known about the effects of such factors on the ERP. Because previous studies may have been confounded by these extraneous variables, the present proposal seeks to re-evaluate the utility of the P3 as a non-invasive measure of cognitive function in Alzheimer's disease. The proposed studies have been designed so that they will: (1) facilitate the development of the P3 as a clinical measure of mental function by assessing Alzheimer patients in the early stages of the disease and normal elderly controls with ERP procedures designed to tap specific cognitive functions, and (2) permit a systematic determination of how effective the P3 component can be as an index for the mental decline found Alzheimer's disease. These procedures should enhance the sensitivity of ERPs as measures of the cognitive deterioration observed in Alzheimer's disease through the use of focused paradigms and experimental control of factors now known to affect P3 measures. Thus, the results will provide a much needed data base that will guide accurately the development of ERPs as a diagnostic and prognostic tool for the assessment of Alzheimer's disease.

A wide variety of studies have indicated that electrophysiological measures are sensitive to the effects of nicotine and nicotine deprivation. In addition, the predisposition to use tobacco appears to be genetically influenced and is related to differences in various personality dimensions. These findings are reviewed and it is concluded that electrophysiological measures in conjunction with a personality inventory may provide a sensitive metric with which to discriminate individuals prone to use tobacco. The present proposal will employ electroencephalographic (EEG) and event-related potential (ERP) techniques to assess individuals who smoke and who do not smoke. These groups will be selected so that representative individuals who vary from low to medium to high on the sensation-seeking personality scale will be studied, with equal numbers of male and female subjects assessed. The nature of the approach will provide a comprehensive data set on the possible central nervous system differences, as revealed by electrophysiological measures, between smokers and non-smokers with respect to personality variables that are related to the predisposition to use tobacco. The results of the proposed study will determine: (1) whether EEG and ERPs can be used as markers or predictors for increased likelihood for tobacco use in predisposed individuals, (2) whether smokers differ from nonsmokers with respect to specific EEG and ERP measures and personality, and (3) whether males differ from females with respect to these factors.

DESCRIPTION: (Applicant's Abstract) The goal of this research application is to develop electrophysiological measures for evaluating the central nervous system (CNS) as it is affected by marihuana. This goal will be pursued by assaying young adults who only occasionally ( 1/month) or chronically ( 3/week) smoke marihuana (low- vs. high-risk subjects), with equal and sufficiently large numbers of both male and female subjects employed for all comparisons. Electroencephalographic (EEG) and event-related brain potential (ERP) paradigms that are sensitive to attention and memory processes will be performed by each subject before and after smoking a placebo or marihuana cigarette on two independent occasions. This approach will optimize CNS electrophysiological differences between occasional (low-risk) and chronic (high-risk) adult marihuana users and produce for the first time a comprehensive assessment of marihuana's effect on CNS function. Because both male and female subjects will be employed in each assessment condition, reliable information on gender differences for marihuana's short- and long-term influence also will be acquired. The most sensitive and effective paradigms will provide reliable neuroelectric signatures that reflect marihuana's cognitive effects.

DESCRIPTION: (Applicant's Abstract) The goal of this research application is to develop electrophysiological measures for evaluating the central nervous system (CNS) as it is affected by marihuana. This goal will be pursued by assaying young adults who only occasionally ( 1/month) or chronically ( 3/week) smoke marihuana (low- vs. high-risk subjects), with equal and sufficiently large numbers of both male and female subjects employed for all comparisons. Electroencephalographic (EEG) and event-related brain potential (ERP) paradigms that are sensitive to attention and memory processes will be performed by each subject before and after smoking a placebo or marihuana cigarette on two independent occasions. This approach will optimize CNS electrophysiological differences between occasional (low-risk) and chronic (high-risk) adult marihuana users and produce for the first time a comprehensive assessment of marihuana's effect on CNS function. Because both male and female subjects will be employed in each assessment condition, reliable information on gender differences for marihuana's short- and long-term influence also will be acquired. The most sensitive and effective paradigms will provide reliable neuroelectric signatures that reflect marihuana's cognitive effects.

DESCRIPTION: (provided by applicant) The goal of this research application is to evaluate residual central nervous system effects of previous MDMA (3, 4-methylenedioxymethamphetamine or 'Ecstasy') use. Considerable evidence from animal and human studies suggests that MDMA can substantially affect serotonergic reuptake, such that its repletion mechanisms may be permanently altered. The present application proposes to employ sophisticated electroencephalographic (EEG), sensory auditory brainstem responses (ABRs), and cognitive event-related brain potential (ERP) paradigms to assess the central nervous system (CNS) functional effects of MDMA use. This goal will be implemented in two phases: STUDY 1addresses the issue of whether specific CNS deficits result from MDMA use by assaying young adult recreational MDMA users, polydrug users with no MDMA exposure, and control subjects with no drug exposure. Based on previous data reviewed herein, it is likely that appreciable group differences will be found and the CNS effects of MDMA can be characterized. STUDY 2will extend this approach by assessing individuals who differ in their lifetime level of MDMA exposure by comparing occasional (1-5 occasions of MDMA use) and heavy (20+ occasions of MDMA use) users. Survey data of local university populations indicate that such individuals are readily available. In addition, both studies will use sufficiently large samples of female and male subjects so that possible gender differences for MDMA effects can be ascertained. The proposed neuroelectric measures will delineate the general cortical areas (EEG), brainstem (ABRs), and cognitive attention and memory processes (ERPs) affected by MDMA use. This approach will optimize CNS neuroelectric differences between MDMA and other drugs in young adult MDMA users. In particular, the proposed ERP paradigms are designed to provide a comprehensive assessment of MDMA effects on cognitive capability by assaying a variety of factors. These results will provide fundamental data on how MDMA use may alter CNS function.

DESCRIPTION (provided by applicant): The purpose of this application is to apply event-related brain potential (ERP) measures as possible neuroelectric markers that reflect individual differences for susceptibility to alcohol abuse. This goal will be pursued by assaying well-defined groups of Mexican American individuals at Iow (LR) and high-risk (HR) for alcoholism, with equal and large numbers of female and male subjects employed for all comparisons. The effects of placebo beverage will be compared with an ethanol challenge condition before and after consumption using ERP paradigms evaluated during the Pl?s previous Alcohol Research Center grant period (1998-2002). Subjects in each group will be matched on relevant between-group factors to maximize neuroelectric differences. Preliminary data from Mexican American subjects suggest that the ERP profiles will differ between Mexican American LR and HR subjects in their response to ethanol intake. With sufficiently large and well-defined samples of female and male Mexican American LR and HR subjects, the complete results will provide insight on the utility of using ERP signatures as a possible endophenotype marker for alcoholism risk.

DESCRIPTION (provided by applicant): The present application represents a systematic extension of funded studies by the PI on MDMA use in young adult (18-29 y/o) university students. The major goal is to evaluate residual central nervous system (CNS) effects of previous Ecstasy (MDMA or 3, 4-methylenedioxymethamphetamine) use in young adults. Considerable evidence suggests that MDMA can substantially affect serotonergic reuptake because its repletion mechanisms may be permanently altered. This outcome appears to produce deficits in cognitive processes, although the source of the effects is debated. The present application will employ sensory evoked potential (EP) auditory brainstem responses (ABRs), cognitive event-related brain potentials (ERPs), and electroencephalographic (EEG) paradigms to assess the CNS functional effects of MDMA use by comparing well-defined subject groups: (1) non-using Controls, (2) primarily Ecstasy users, and (3) Ecstasy-Plus (+) mpoly-drug users. Preliminary Studies indicate that these neuroelectric measures reveal considerable CNS drug-related damage. The application is organized around two approaches: STUDY 1 will assess the 3 subject groups using previously successful sensory EP and new cognitive ERP paradigms. The goal is to refine the measures and findings in order to identify the possible sources of neurocognitive insult from Ecstasy. STUDY 2 will assess non-use Control and Ecstasy users who vary systematically in the amount and recency of MDMA use in attempt to quantify the possible long-term effects of Ecstasy intake. Equal numbers of female and male subjects will be assessed in all phases. The proposed methods will characterize CNS differences from MDMA use to provide assessment of drug effects on cognition.

DESCRIPTION (provided by applicant): The purpose of this application is to further develop risk-markers for individual susceptibility to alcoholism using neuroelectric measures. The motivation for this approach stems from the PI's previous projects on familial alcoholism risk-group status and central nervous system (CNS) function as assessed by event-related brain potentials (ERPs). Recent neuroelectric findings indicate that alcohol consumption levels as well as tobacco smoking status modulate CNS activity. The proposed studies are designed to provide a much needed empirical assessment of well-defined groups of young adults who vary in their typical alcohol "binge" drinking level. All subjects will be screened to eliminate individuals at high-risk for alcoholism by virtue familial incidence in order to reduce neuroelectric variability. As ERP measures are sensitive to smoking status, subjects who have never smoked will be compared to individuals who smoke daily across the drinking levels. Equal numbers of each gender will be employed in each group. STUDY1 will employ affective, working memory, P3a/P3b, error-related negativity (ERN), and EEG paradigms in low, medium, and high binging young adults. STUDY 2 will use the most sensitive of these tasks to assay low- and high-binging young adults before and after a placebo/alcohol challenge protocol, with never-smoked and currently smoking individuals compared. Characterization of the likely differential responsivity to regular ethanol consumption level when tobacco smoking history is controlled will provide highly useful and hitherto unavailable information on how the neuroelectric signatures are affected by these factors. Subsequent control over these variables should substantially enhance the application of straightforward neuroelectric assessment of alcoholism risk and other drug use. PUBLIC HEALTH RELEVANCE: Alcohol and Tobacco CNS Effects in Binge Drinkers The goal of the proposed project is to further develop risk-markers for individual susceptibility to alcoholism by using neuroelectric measures to study binge drinking. The studies are designed to provide an empirical assessment of young adults who vary in their alcohol intake from low, medium, to high "binge" drinking. Subjects who have never smoked tobacco will be compared to individuals who smoke daily across drinking levels, with equal numbers of each gender assessed. Characterization of CNS activity with respect of alcohol binging and smoking history will facilitate subsequent control over these variables and will enhance the application of neuroelectric assessment of alcoholism risk and other drug use.