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This study evaluates the event-related potential (ERP) components in a single outcome gambling task that involved monetary losses and gains. The participants were 50 healthy young volunteers (25 males and 25 females). The gambling task involved valence (loss and gain) and amount (50 cent and 10 cent) as outcomes. The outcome-related negativity (ORN/N2) and outcome-related positivity (ORP/P3) were analyzed and compared across conditions and gender. Monetary gain (compared to loss) and higher amount (50 cent compared to 10 cent) produced higher amplitudes and shorter latencies in both ORN and ORP components. Difference wave plots showed that earlier processing (200-400 ms) is dominated by the valence (loss/gain) while later processing (after 400 ms) is marked by the amount (50 cent/10 cent). Functional mapping using Low Resolution Electromagnetic Tomography (LORETA) indicated that the ORN separated the loss against gain in both genders, while the ORP activity distinguished the 50 cent against 10 cent in males. This study further strengthens the view that separate brain processes/circuitry may mediate loss and gain. Although there were no gender differences in behavioral and impulsivity scores, ORN and ORP measures for different task conditions had significant correlations with behavioral scores. This gambling paradigm may potentially offer valuable indicators to study outcome processing and impulsivity in normals as well as in clinical populations.

In this report, we present results of a genome-wide linkage scan using as a phenotype the number of externalizing symptoms associated with alcohol use disorders. Subjects were collected by the Collaborative Study on the Genetics of Alcoholism project from families in which at least three first degree relatives were affected by alcohol dependence. We use a novel non-parametric regression method based on kernel smoothing for our analysis. We report a statistically significant linkage close to the ADH gene cluster on Chromosome 4. We also obtain evidence for epistatic interaction between a region on Chromosome 1 and one on Chromosome 15. Although alcoholism as a covariate does not have any effect on the linkage scan, it has an effect on the epistatic interaction.

The EEG bipolar power spectra provide more localization than spectral measures obtained from monopolar referencing strategies, and have been shown to be useful endophenotypes of psychiatric disorders such as alcoholism. We estimated the additive genetic heritability of resting bipolar EEG power spectra in a large sample of non-twin sibling pairs. The corresponding heritabilities ranged between 0.220 and 0.647 and were highly significant at all 38 electrode pairs for theta (3-7 Hz), low-alpha (7-9 Hz), high-alpha (9-12 Hz), low-beta (12-16 Hz), middle-beta (16-20 Hz) and high-beta (20-28 Hz) frequency bands. The heritabilities were the highest in the high-alpha and low-beta bands at most electrode pairs. The heritabilities were most variable across the head in the three beta bands. Other heritability patterns were also identified within each frequency band. Our results suggest that substantial proportions of the variability in the bipolar EEG measures are explained by genetic factors.

Objective: Impulsivity is an important characteristic of many psychiatric disorders, including substance-related disorders. These disinhibitory disorders have a similar underlying genetic diathesis, with each disorder representing a different expression of the same underlying genetic liability. This study assessed whether there is a relationship between impulsivity and alcohol dependence, and their correlations with P3 (P300) amplitude, a proposed endophenotype of alcoholism. Methods: Healthy control subjects (n 5 58) and subjects with DSM-IV diagnosis of alcohol dependence (n 5 57) were assessed with a visual oddball task. Event-Related Potentials (ERPs) were recorded from 61 scalp electrodes and P3 amplitudes measured. Barratt Impulsiveness Scale (BIS), version 11, was used to evaluate impulsivity. Source localization of P3 was computed using low-resolution brain electromagnetic tomography (LORETA). Results: Alcoholic subjects manifested reductions in target P3 amplitudes (po0.0001). Using LORETA, significantly reduced activation was mapped in the cingulate, medial, and superior frontal regions in alcoholic subjects and highly impulsive subjects. Alcoholic subjects had significantly higher scores on the BIS (po0.0001) than nonalcoholic individuals. There were significant negative correlations between total scores on BIS and P3 amplitude (r 5 0.274, p 5 0.003, on Pz; r 5 0.250, p 5 0.007, on Cz). Conclusions: Our results demonstrate a strong frontal focus of reduced activation during processing of visual targets in alcoholic subjects and individuals with higher impulsivity. The findings suggest that impulsivity may be an important factor that underlies the pathogenesis of alcohol dependence. Studies are underway to examine the relationship between impulsivity and ERPs in offspring of alcoholic subjects, and to identify genes associated with the underlying predisposition involved in disinhibitory disorders.

This study investigates early evoked gamma band activity in male adolescent subjects at high risk for alcoholism (HR; n=68) and normal controls (LR; n=27) during a visual oddball task. A time-frequency representation method was applied to EEG data in order to obtain stimulus related early evoked (phase-locked) gamma band activity (29-45 Hz) and was analyzed within a 0-150 ms time window range. Significant reduction of the early evoked gamma band response in the frontal and parietal regions during target stimulus processing was observed in HR subjects compared to LR subjects. Additionally, the HR group showed less differentiation between target and non-target stimuli in both frontal and parietal regions compared to the LR group, indicating difficulty in early stimulus processing, probably due to a dysfunctional frontoparietal attentional network. The results indicate that the deficient early evoked gamma band response may precede the development of alcoholism and could be a potential endophenotypic marker of alcoholism risk.

Background: Electroencephalographic (EEG) measures of hemispheric asymmetry in anterior brain activity have been related to a variety of indices of psychopathology and emotionality. However, little is known about patterns of frontal asymmetry in alcohol-dependent (AD) samples. It is also unclear whether psychiatric comorbidity in AD subjects accounts for additional variance in frontal asymmetry, beyond a diagnosis of AD alone. Methods: We compared 193 AD subjects with 108 control subjects on resting brain activity in anterior and posterior regions, as indexed by asymmetries in a band power in the left and right hemispheres. Within the AD group alone, we examined whether comorbid major depressive disorder (MDD) or antisocial personality disorder (ASPD) had effects on regional asymmetry. Results: Compared with control subjects, AD subjects exhibited lower left, relative to right, cortical activation in anterior regions. Evidence that comorbidity in AD subjects accounted for further variance in EEG asymmetry was mixed; AD subjects with comorbid ASPD were not significantly different from those without ASPD, while AD subjects with a lifetime history of MDD showed less asymmetry in anterior regions than those without MDD. Conclusions: Our findings indicate that AD subjects exhibit a pattern of frontal asymmetry similar to that found in other psychiatric groups. Results examining the effects of comorbidity in AD on EEG asymmetry were inconclusive. The implications of our findings for future work are described.

Objective Decomposition of event-related potential (ERP) waveforms using time-frequency representations (TFR's) is becoming increasingly common in electrophysiology. The P300 potential is an important component of the ERP waveform and has been used to study cognition as well as psychiatric disorders such as alcoholism. In this work, we aim to further understand the nature of the event-related oscillation (ERO) components which form the P300 wave and how these components may be used to differentiate alcoholic individuals from controls. Methods The S-transform decomposition method is used to derive TFR's from single trial and trial-averaged ERP data acquired during a visual oddball task. These TFR's are averaged within time and frequency windows to provide ERO measures for further investigation. ERO measures are compared with conventional ERP amplitude measures using correlation analyses. Statistical analyses was performed with MANOVA and stepwise logistic regressions to contrast an age-matched sample of control ( N =100) and alcoholic male subjects ( N =100). Results The results indicate that the P300 waveform, elicited using infrequent salient stimuli, is composed of frontal θ and posterior δ activations. The frontal θ activation does not closely correspond to any of the conventional ERP components and is therefore best analyzed using spectral methods. Between group comparisons and group predictions indicate that the δ and θ band ERO's, which underlie the P300, show deficits in the alcoholic group. Additionally, each band contributes unique information to discriminate between the groups. Conclusions ERO measures which underlie and compose the P300 wave provide additional information to that offered by conventional ERP amplitude measures, and serve as useful genetic markers in the study of alcoholism. Significance Studying the ERP waveform using time-frequency analysis methods opens new avenues of research in electrophysiology which may lead to a better understanding of cognitive processes, lead to improved clinical diagnoses, and provide phenotypes/endophenotypes for genetic analyses.

We report genetic linkage and association findings which implicate the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) in the modulation of a scalp-recorded electrophysiological phenotype. The P3 (P300) response was evoked using a three-stimulus visual oddball paradigm and a phenotype that relates to the energy in the theta band (4-5 Hz) was analyzed. Studies have shown that similar electrophysiological measures represent cognitive correlates of attention, working memory, and response selection; a role has been suggested for the ascending cholinergic pathway in the same functions. The results of our genetic association tests, combined with knowledge regarding the presence of presynaptic cholinergic M2 autoreceptors in the basal forebrain, indicate that the cognitive processes required by the experiment may in part be mediated by inhibitory neural networks. These findings underscore the utility of electrophysiology and neurogenetics in the understanding of cognitive function and the study of brain-related disorders.

In the last three decades, much emphasis has been placed on neural oscillations in vitro, in vivo, as well as in the human brain. These brain oscillations have been studied extensively in the resting electroencephalogram (EEG), as well as in the underlying evoked oscillations that make up the event-related potentials (ERPs). There are several approaches to elucidate the possible mechanisms of these brain oscillations. One approach is to look at the neurophysiology and neurochemistry involved in generating and modulating these oscillations. Another more recent approach is to examine the genetic underpinnings of these neural oscillations. It is proposed that the genetic underpinnings of these oscillations are likely to stem from regulatory genes which control the neurochemical processes of the brain, and therefore influence neural function. Genetic analyses of human brain oscillations may identify genetic loci underlying the functional organization of human neuroelectric activity. Brain oscillations represent important correlates of human information processing and cognition. They represent highly heritable traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures. Therefore these oscillations may be utilized as phenotypes of cognition and as valuable tools for the understanding of some complex genetic disorders. Genetic loci that have been recently identified regarding both resting and evoked brain oscillations involving the GABAergic and cholinergic neurotransmitter systems of the brain are discussed. It is concluded that the advent of genomics and proteomics and a fuller understanding of gene regulation will open new horizons on the critical electrical events so essential for human brain function.

Results from twin studies suggest that overlapping genetic factors influence alcohol dependence and illicit drug dependence. Using data from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined the association between 69 SNPs in the GABAA receptor gene cluster on chromosome 4 and marijuana and illicit drug dependence, individually, and as co-occurring phenotypes with alcohol dependence. Results suggested association between marijuana dependence and illicit drug dependence with SNPs in the GABRA2 gene. Interestingly, the evidence for association previously observed with alcohol dependence came only from individuals with comorbid illicit drug dependence. There was no association with other genes in the GABAA cluster on chromosome 4 with illicit drug dependence.

We investigated the early evoked gamma frequency band activity in alcoholics (n=122) and normal controls (n=72) during a visual oddball task. A time-frequency representation method was applied to EEG data in order to obtain phase-locked gamma band activity (29-45 Hz) and was analyzed within a 0-150 ms time window range. Significant reduction of the gamma band response in the frontal region during target stimulus processing was observed in alcoholic compared to control subjects. In contrast, significantly higher gamma band response for the non-target stimulus was observed in alcoholics compared to controls. It is suggested that the reduction in early evoked frontal gamma band response to targets may be associated with frontal lobe dysfunction commonly observed in alcoholics. This perhaps can be characterized by a deficient top-down processing mechanism.

We use findings from the behavior genetics literature about how genetic factors (latently) influence alcohol dependence and related disorders to develop and test hypotheses about the risk associated with a specific gene, GABRA2, across different developmental stages. This gene has previously been associated with adult alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA) sample [Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. K., Nurnberger Jr., J. I., O'Connor, S. J., Reich, T., Rice, J., Schuckit, M., Porjesz, B., Foroud, T., and Begleiter, H. (2004). Am. J. Hum. Genet. 74:705-714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B:104-109; Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., and Gelernter, J. (2005). Alcohol. Clin. Exp. Res. 29:493-498]. In a sample of children and adolescents ascertained as part of the COGA project, we find that GABRA2 is significantly associated with childhood conduct disorder symptoms, but not with childhood alcohol dependence symptoms. A consistent elevation in risk for alcohol dependence associated with GABRA2 is not evident until the mid-20s and then remains throughout adulthood. GABRA2 is also associated with other drug dependence in our sample, both in adolescence and adulthood.

A coding single-nucleotide polymorphism (cSNP), K172N, in hTAS2R16, a gene encoding a taste receptor for bitter beta -glucopyranosides, shows significant association with alcohol dependence (P = .00018). This gene is located on chromosome 7q in a region reported elsewhere to exhibit linkage with alcohol dependence. The SNP is located in the putative ligand-binding domain and is associated with an increased sensitivity to many bitter beta -glucopyranosides in the presence of the N172 allele. Individuals with the ancestral allele K172 are at increased risk of alcohol dependence, regardless of ethnicity. However, this risk allele is uncommon in European Americans (minor-allele frequency [MAF] 0.6%), whereas 45% of African Americans carry the allele (MAF 26%), which makes it a much more significant risk factor in the African American population.

Response inhibition is considered a core dimension in alcoholism and its co-existing disorders. The major objective of this study is to compare the magnitude and spatial distribution of ERP components during response activation and inhibition in alcoholics (N = 30) and normal controls (N = 30) using a visual Go/No-Go task. The results indicate that alcoholics manifest a decreased P3(00) amplitude during Go as well as No-Go conditions. The difference between Go and No-Go processing was more evident in controls than in alcoholics. The topography of current source density in alcoholics during the P3 response was found to be very different from that of normals, suggesting that alcoholics perhaps activated inappropriate brain circuitry during cognitive processing. The significantly reduced No-Go P3 along with the relatively less anteriorized CSD topography during No-Go condition suggests poor inhibitory control in alcoholics. It is proposed that the No-Go P3, the electrophysiological signature of response inhibition, can be considered as an endophenotypic marker in alcoholism.

Event-related oscillations (ERO) offer an alternative theoretical and methodological approach to the analysis of event-related EEG responses. The P300 event-related potential (ERP) is elicited through the superposition of the delta (1-3 Hz) and theta (3-7 Hz) band oscillatory responses. The cholinergic neurotransmitter system has a key function in modulating excitatory post-synaptic potentials caused by glutamate, and therefore influences P300 generation and the underlying oscillatory responses. Here we report significant linkage and linkage disequilibrium between target case frontal theta band, visual evoked brain oscillations and a single nucleotide polymorphism (SNP) from the cholinergic muscarinic receptor gene (CHRM2) on chromosome 7. We also demonstrate significant linkage disequilibrium between CHRM2 SNPs and target case parietal delta band visual evoked oscillations (LD P

This study examines the differences in beta (12-28 Hz) band power in offspring of male alcoholics from densely affected alcoholic families. We have attempted to investigate if the increase in beta power is a 'state' or 'trait' marker for alcoholism. This study also explores the gender differences in the expression of this potential risk marker. Absolute beta power in three bands-beta 1(12-16 Hz), beta 2 (16-20 Hz), and beta 3 (20-28 Hz)-in the eyes closed EEG of 171 high risk (HR) subjects who were offspring of male alcoholics and 204 low risk (LR) subjects with no family history of alcoholism, were compared for each gender separately using a repeated measures analysis of variance design. Alcoholic and non-alcoholic subjects within the high risk group were compared using a repeated measures design as a follow-up analysis. The present study demonstrated increased beta power in the resting EEG of offspring of male alcoholics. Male HR subjects had higher beta 1 (12-16 Hz) power and female HR subjects had increased power in beta 2 (16-20 Hz) and beta 3 (20-28 Hz) as compared with low risk participants. Female HR subjects also showed significantly increased beta 2 and beta 3 power if they had two or more alcoholic first-degree relatives when compared with HR females having only an affected father. Risk characteristics are expressed differentially in males and females and may be an index of differential vulnerability to alcoholism. The results indicate that increased EEG beta power can be considered as a likely marker of risk for developing alcoholism and may be used as a predictive endophenotype.

Background: Evidence from human, animal, and in vitro cell models suggests that γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive. Methods: We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes:GABRA5, GABRB3, and GABRG3. Results: Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes. Conclusions: These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.

Background: In this study, the magnitude and spatial distribution of theta power in the resting EEG were examined to explore the changes in the neurophysiological status of the alcoholic brain. Some state- and trait-related issues of theta power increases in the EEG of alcoholics were also examined. Methods: Absolute theta (3–7 Hz) power in eyes-closed EEGs of 307 alcohol-dependent subjects and 307 age- and gender-matched unaffected controls were compared by using a repeated-measures ANOVA for the entire region and three subregions (frontal, central, and parietal) separately. Supplementary to the main analysis, the effect of three clinical variables on absolute theta power was examined separately for each gender by using correlation and regression analyses. Gender differences in the theta log power difference between alcoholics and controls were explored by using regional repeated-measures ANOVA. Results: Increased absolute theta power was seen in alcohol-dependent subjects at all scalp locations. The theta log power increase in male alcoholics was prominent at the central and parietal regions and in female alcoholics at the parietal region when compared with the respective matched controls. Correlation of drinking variables with log theta power exhibited no group-specific differences. Conclusions: Increased tonic theta power in the EEG may reflect a deficiency in the information-processing capacity of the central nervous system in alcoholics. The theta power increase may also be an electrophysiological index of the imbalance in the excitation-inhibition homeostasis in the cortex. It is likely that the theta power increase is a trait-related phenomenon and is expressed to differing degrees in the two genders.

GABA receptor genes have been postulated as candidates affecting the risk for alcoholism. The potential association between genes encoding five subunits of the GABAA receptors and alcoholism (alcohol dependence) was analyzed in the multiplex alcoholic pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA) using family-based association tests. We found consistent, although weak, linkage disequilibrium between GABRB1 (located on chromosome 4) and alcoholism (P

Abnormalities in the P300 ERP, elicited by the oddball task and measured using EEG, have been found in a number of central nervous system disorders including schizophrenia, Alzheimer's disease, and alcohol dependence. While electrophysiological studies provide high temporal resolution, localizing the P300 deficit has been particularly difficult because the measurements are collected from the scalp. Knowing which brain regions are involved in this process would elucidate the behavioral correlates of P300. The aim of this study was to determine the brain regions involved in a visual oddball task using fMRI. In this study, functional and high-resolution anatomical MR images were collected from seven normal volunteers. The data were analyzed using a randomization-based statistical method that accounts for multiple comparisons, requires no assumptions about the noise structure of the data, and does not require spatial or temporal smoothing. Activations were detected (P

Background: Alcohol dependence is a clinically and etiologically heterogeneous disorder. Accordingly, a variety of subtypes of alcohol-dependent individuals have been proposed, and multiple operational definitions of alcohol use, abuse, and dependence have been used in linkage analyses directed toward detecting genes involved in alcohol use and problems. Here, we develop quantitative phenotypes that characterize drinking patterns among both alcoholic and nonalcoholic subjects, and use these phenotypes in subsequent linkage analyses. Methods: More than 9000 individuals from alcoholic and control families were administered a semistructured interview and personality questionnaire as part of the initial stage of the Collaborative Study on the Genetics of Alcoholism (COGA). A principal component analysis was conducted on items that captured many of the dimensions of drinking and related behaviors, including aspects of alcohol use, antisocial behavior and affective disturbance when drinking, and personality. Factor scores were computed for all individuals. Nonparametric linkage analyses were conducted on these factor scores, in the initial COGA sample consisting of 987 individuals from 105 extended families, and in a replication sample consisting of 1295 individuals from 157 extended families. Results: Three factors were identified, accounting for 68% of the total variance. The most promising regions of linkage appeared for factor 2, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance. Chromosome 1 yielded consistent evidence of linkage in both samples, with a maximum lod score of 3.3 when the samples were combined for analysis. Consistent suggestion of linkage also was found to chromosome 15. Conclusions: Developing novel phenotypes that more accurately model the effect of influential genes may help efforts to detect genes involved in complex disorders. Applying principal component analysis in the COGA sample provided support for some regions of linkage previously reported in COGA, and identified other new, promising regions of linkage.

Human brain oscillations represent important features of information processing and are highly heritable. A common feature of beta oscillations (13–28 Hz) is the critical involvement of networks of inhibitory interneurons as pacemakers, gated by γ-aminobutyric acid type A (GABA A ) action. Advances in molecular and statistical genetics permit examination of quantitative traits such as the beta frequency of the human electroencephalogram in conjunction with DNA markers. We report a significant linkage and linkage disequilibrium between beta frequency and a set of GABA A receptor genes. Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing.

Background: There is controversy in the literature regarding the relationship between event-related-potential (ERP) abnormalities in abstinent alcoholics and stimulus-processing modality (i.e., visual versus auditory). The first purpose of this study was to address questions about whether ERP abnormalities observed in alcoholics are modality specific. The second purpose was to employ current source density (CSD) analyses to investigate topographic differences between alcoholics and controls within each modality. Methods: Data were collected from 30 sober male alcoholics and 39 normal males in a typical auditory oddball task and in a visual oddball paradigm with novel stimuli, with an extensive set of 61 scalp electrodes. Visual and quantitative assessment of CSD maps as well as analyses of variances on both raw and normalized ERP data were performed. Results: Positive findings were limited to the N1 and P3 components. The visual N1 amplitude was significantly smaller in alcoholics than in controls at the parietal region; no significant group differences in N1 were found in the auditory modality. Alcoholics had widespread reductions in P3 amplitudes in both modalities compared with controls, although in the frontal region this effect was partially due to the influence of age. These P3 reductions in alcoholics were statistically more pronounced in the posterior compared with the anterior regions regardless of modality. Topographically, sources in CSD maps were weaker in alcoholics than in controls; in the frontal and central regions, the weakness was more pronounced in the auditory modality but, in parietal and occipital regions, it was more pronounced in the visual modality. Conclusions: The results suggest that, in abstinent alcoholics, abnormalities in auditory ERPs may be localized to more anterior sources, while abnormalities in visual ERPs may be localized to more posterior sources. ERP topographic features are more sensitive than amplitude measurements in assessing alcoholic-related modality effects.

We describe a method to obtain estimates of EEG signal complexity using the well-established wavelet packet transform with best basis selection. In particular, we use the two-dimensional wavelet packet transform to obtain estimates of the complexity of two-dimensional images. This allows us to calculate complexity estimates of high-resolution brain potential maps generated from 61 scalp electrode Visual Oddball paradigm, grand-mean data. A significant reduction in the complexity of the surface Laplacian time-slices is observed during and after the Visual Potential 300 (P3) event for the target case, possibly as a result of increased spatial synchrony associated with visual-related tasks. We also present the results of a statistical analysis of the largest principal component of the time-varying complexity curves, for control, high-risk, and alcoholic groups of male subjects. Parametric and non-parametric analyses show differences in the complexity data which are significant between the control group and the alcoholic and high-risk groups.

Background: The P300 (P3) component of the event related potential has been established as a sensitive risk marker of vulnerability to alcoholism. Most alcoholism studies have focused on men; recent studies indicate that women are equally vulnerable to developing alcoholism. Methods: Visual P3 recorded from 31 electrode positions was evaluated in 44 alcoholic and 60 control women, 24-50 years of age. P3 amplitudes and latencies of the two groups were statistically compared using Analysis of Variance; source localization of surface amplitude values from each group were plotted using a low-resolution brain electromagnetic tomography. Results: The results indicated that alcoholic women had significantly smaller P3 amplitudes in the frontal and central regions compared with controls. Source localization showed lowered activation in alcoholic women in right dorso-lateral prefrontal cortex and the ventro-medial fronto-central regions. Conclusions: The results suggest that P3 is an equally sensitive endophenotypic marker of vulnerability to alcoholism in women. The findings are discussed in terms of functional and physiologic significance of the P3 amplitude in alcoholic women and its relationship to drinking behaviors.

Background: Substantial evidence indicates that alcoholism is biologically mediated by a genetic predisposition. As the decreased P300 (P3b) event-related brain potential component does not recover with prolonged abstinence, it is unlikely to be related to drinking history but is more likely to be genetically influenced. This is supported by findings that P3b amplitudes are reduced in subjects at high-risk compared to low-risk for alcoholism. Although there are few studies of P3a in HR subjects, lower P3a amplitudes have been reported with a novel nontarget stimulus paradigm, as well as with a difficult three-stimulus visual paradigm. Using a similar three-tone auditory paradigm in which the discriminability between the target and standard tone is difficult, the P3a component can also be reliably elicited with a rare nontarget perceptually distinct stimulus. This technique was employed in young adult subjects at low-risk and high-risk for alcoholism. Methods: A total of 17 low-risk and 24 high-risk male subjects were employed as subjects in an auditory paradigm that yielded a large amplitude P3a with a centro-frontal maximum to the nontarget and a robust low amplitude prolonged P3b with a parietal maximum amplitude to the target stimulus. Current source density maps were derived to assess topographic differences between low-risk and high-risk subjects. Results: The high-risk group manifested significantly lower P3a amplitudes than the low-risk group at the frontal electrodes to rare nontarget stimuli. High-risk subjects also demonstrated a more disorganized current source density map for P3a compared to low-risk subjects. Conclusions: The reduction of P3a in the high-risk group may be due to cortical dysfunction including the frontal and prefrontal cortex. The lower P3a amplitude coupled with more disorganized current source density maps suggest inefficient brain functioning in high-risk subjects.

Background: Evidence from P300 studies in both alcohol-dependent and high-risk (HR) individuals suggests that the reduced P300 amplitudes that often characterize these individuals may reflect a deficit in inhibition (hyperexcitability) in the central nervous system. In this context, the mismatch negativity (MMN) was investigated in the male and female HR offspring of alcohol-dependent fathers and a mixed-sex, low-risk (LR) control group. Methods: As subjects read popular materials, they received a random sequence of 500 binaurally presented tones of 600 Hz and 1600 Hz. The designation of the rare stimulus (n= 60 trials) and frequent stimulus (n= 440 trials) was alternated across subjects. Recordings of MMN were made from 61 electrodes; risk group comparisons were restricted to the five frontal midline electrodes: Fpz, Afz, Fz, Fcz, and Cz. The MMN was obtained by calculating the integral of the area under the curve for both the frequent and rare waveforms over an interval from 100 to 190 msec and then subtracting the former from the latter. Results: The primary observation was that MMN responses in the HR group were significantly larger than those in the LR group. In addition, both LR and HR individuals manifested differential responses to the rare and frequent stimuli, and MMN responses in both groups were largest at Fcz and smallest at Fpz. Discussion: The results indicate that individuals at high risk for alcoholism differ electrophysiologically from LR controls. These differences were manifested as larger magnitudes of the MMN. The findings suggest the possibility that as measured by the MMN, individuals at high risk for alcoholism may be characterized by a deficit in inhibition (excessive neural excitation). The presence of these preexisting central nervous system states may lead to ethanol use for self-medication, which then may facilitate the development of both tolerance to and dependence on ethanol.

Event-related brain potentials (ERPs) are altered in patients with a variety of psychiatric disorders and may represent quantitative correlates of disease liability that are more amenable to genetic analysis than disease status itself. Results of a genomewide linkage screen are presented for amplitude of the N4 and P3 components of the ERP, measured at 19 scalp locations in response to a semantic priming task for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. N4 and P3 amplitudes in response to three stimuli (nonwords, primed words [i.e., antonyms], and unprimed words) all showed significant heritabilities, the highest being .54. Both N4 and P3 showed significant genetic correlations across stimulus type at a given lead and across leads within a stimulus, indicating shared genetic influences among the traits. There were also substantial genetic correlations between the N4 and P3 amplitudes for a given lead, even across stimulus type. N4 amplitudes showed suggestive evidence of linkage in several chromosomal regions, and P3 amplitudes showed significant evidence of linkage to chromosome 5 and suggestive evidence of linkage to chromosome 4.

The Collaborative Study on the Genetics of Alcoholism (COGA) is a multicenter research program to detect and map susceptibility genes for alcohol dependence and related phenotypes. The measure M of "maximum number of drinks consumed in a 24-hour period" is closely related to alcoholism diagnosis in this dataset and provides a quantitative measure to grade nonalcoholic individuals. Twin studies have shown log(M) to have a heritability of approximately 50%. Genome screens for this trait were performed in two distinct genotyped samples (wave 1 and wave 2), and in the combined sample. MAPMAKER/SIBS was used to carry out Haseman-Elston based regression analyses. On chromosome 4, an unweighted all-pairs multipoint LOD of 2.2 was obtained between D4S2407 and D4S1628 in wave 1; in wave 2, the region flanked by D4S2404 and D4S2407 gave a LOD of 1.5. In the combined sample, the maximal LOD was 3.5 very close to D4S2407. This evidence for linkage is in the region of the alcohol dehydrogenase gene cluster on chromosome 4. These findings on chromosome 4 are consistent with a prior report from COGA in which strictly defined nonalcoholic subjects in wave 1 were analyzed. The present analysis on log(M) allows more individuals to be included and thus is potentially more powerful.

Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-111-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes “ever smoker” or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking. Am. J. Med. Genet. 90:299–302, 2000. © 2000 Wiley-Liss, Inc.

This paper describes a method for estimating a set of spatial components (brain maps) and temporal components (waveforms) of brain potentials. These components play the role of bases of a coordinate system, in the sense that the brain potentials of any subject can be represented as superpositions of these components. The representation is unique given the spatial and temporal components, and this decomposition is particularly appealing for comparing the brain potentials of different subjects (say alcoholics and controls). It can also be used for single trial modeling, clinical classification of patients, and data filtering. The method is based on the topographic component model (TCM, Mocks 1988) which models brain potentials in a trilinear form. We extend the TCM in two aspects. First, the diagonal amplitude matrix is replaced by a general loading matrix based on some neurophysiological considerations. Secondly, the number of spatial components and the number of temporal components can be different. The spatial components and temporal components are obtained respectively by performing singular value decomposition (SVD). This method is illustrated with visual P3 data.

SummaryThe availability of robust quantitative biological markers that are correlated with qualitative psychiatric phenotypes can potentially improve the power of linkage methods to detect quantitative-trait loci influencing psychiatric disorders. We apply a variance-component method for joint multipoint linkage analysis of multivariate discrete and continuous traits to the extended pedigree data from the Collaborative Study on the Genetics of Alcoholism, in a bivariate analysis of qualitative alcoholism phenotypes and quantitative event-related potentials. Joint consideration of the DSM-IV diagnosis of alcoholism and the amplitude of the P300 component of the Cz event-related potential significantly increases the evidence for linkage of these traits to a chromosome 4 region near the class I alcohol dehydrogenase locus ADH3. A likelihood-ratio test for complete pleiotropy is significant, suggesting that the same quantitative-trait locus influences both risk of alcoholism and the amplitude of the P300 component.

Background: The objective of the study was to expand the investigation of the match/mismatch mnemonic impairment in the semantic domain in sober alcoholics. Methods: Event-related potentials (ERPs) were recorded from 28 healthy adults and 36 sober alcoholics in a category (either animals or fruits/vegetables) match/nonmatch S1–S2 paradigm. Results: There was a significant interaction of ERP amplitude (c3) between groups (controls vs. alcoholics) and stimulus conditions (category match vs. nonmatch) at the posterior brain regions; the c3 component was smaller for the category match than for nonmatch trials in controls, with the absence of such c3 differences in alcoholics. There were no significant ERP differences between the two groups in processing the sample stimuli. The ERPs (c2) elicited by the animal category were larger than those for the vegetable category in both groups. The alcoholics showed prominent suppressed activation of left temporo-occipital brain regions under both matching and nonmatching conditions, as demonstrated by the current source density maps. The alcoholics were also slower and less accurate than the controls in judging both category matching and nonmatching stimuli, while neither of the two groups demonstrated shorter response times to the matching stimuli. Conclusions: These data suggest that alcoholics are less efficient in the semantic mnemonic match/nonmatch process, and are less likely to be deteriorated in the stage of forming the template for such match/nonmatch comparisons.

To examine the topographic relationship of P3(00) between the visual and auditory modalities, especially to examine whether there are any modality-specific hemispheric differences of P3 in normal adults. Methods: The P3s were recorded from the same 41 normal right-handed males between the ages of 20 and 33 in both a typical auditory oddball task and a visual oddball paradigm with novel stimuli, with an extensive set of 61 scalp electrodes. In addition to the visual comparison and quantitative assessment of current source density (CSD) maps between the two modalities, canonical correlation analyses on the P3 raw amplitudes and examination of interaction effects of modality × location on both raw and normalized P3 data were performed. Results: The canonical correlation between modalities was generally high, especially at the left parietal brain region. There were no significant hemispheric effects in anterior brain but significant left-greater- than-right hemispheric effects in posterior brain regions in both modalities; modality-specific hemispheric effect was observed only at the parietal region. Strong surface current density activities were observed in the midline parietal-occipital area, and left and right boundary areas of temporal and inferior frontal region. Conclusions: The topographic similarities between P3s recorded in the visual and auditory modality outnumber the differences. Combining data from CSD assessments and profile analysis of P3 topography support the hypothesis of multiple generators of P3 that are differentially active in processing stimuli from different sensory modalities and are not symmetrically distributed between the two hemispheres.

Using genotypes of 280 marker loci on the 22 autosomes of 105 alcohol-dependent probands, their affected and unaffected sibs, as well as their parents, we iteratively constructed a genetic similarity function that enabled us to quantify the interindividual genetic distances d(x(i), xj) between feature vectors x(i), xj made up by the allelic patterns of individuals i, j with respect to loci l1, l2,...,ln. Based on this similarity function, we investigated the sib-sib similarities that are expected to deviate from "0.5" in affected sib pairs if the region of interest contains markers close to disease-causing genes. The reference value "0.5" was derived from the parents-offspring similarities, because these are independent of the affection status. The question of population admixture was addressed by means of multivariate structural analyses. These analyses led to four "natural" groups whose validity was tested through the father-mother similarities. Additionally, we determined the eigenvectors that optimally represented the genetic variation and found several marker configurations on chromosomes 1, 3, 7, 15, and 17 that reproducibly discriminated (p < or = 0.01) affected probands/sibs from unaffected sibs, while no such differences were found between affected probands and affected sibs.

This paper describes a method for estimating the surface Laplacian of brain potentials. The method consists of two steps: local surface approximation by its tangent plane and local polynomial fitting. Compared to previous methods for estimating surface Laplacian, this method has some new features. First, it can estimate the surface Laplacian at any point of the scalp, including the locations of the peripheral electrodes. Secondly, it estimates the brain potential and the surface Laplacian at any point simultaneously. This reduces the risk of error propagation, which occurs when the brain potential is interpolated first and the surface Laplacian is then computed based on the interpolated brain potential. Finally, the method automatically adapts to noisy data by using more or less measurements at neighboring electrodes based on estimated noise level. Simulations suggest that this method is effective. Application to event-related potentials are also presented.

Problem 1 of Genetic Analysis Workshop 11 consists of data from a family study of the genetics of alcoholism and related traits contributed by the six centers making up the National Institute for Alcohol Abuse and Alcoholism sponsored by the Collaborative Study on the Genetics of Alcoholism (COGA). The family data included 1,214 members of 105 pedigrees ascertained for having three or more individuals affected with alcoholism. Data available to workshop participants included clinical phenotypes, personality measures, smoking behavior, event-related potentials, platelet monamine oxidase B activity, and a genome scan of 296 markers.

Objective : An event-related potential (ERP) correlate of visual short-term memory (VMP) has been identified in our laboratory. This study aims to determine how stimulus load modulates recognition processing of digits. Methods : ERPs were recorded from 117 healthy right-handed subjects during a delayed matching-to-sample paradigm, using number stimuli that were either low load (three digits long) or high load (five digits long). The bootstrap method [R. Srebro, A bootstrap method to compare the shapes of two scalp fields, Electroenceph. Clin. Neurophysiol. 100 (1996) 25–32.] was employed to evaluate the topographic features of the VMP revealed in the current source density (CSD) maps. Results : Response times were significantly shorter for matching stimuli than for non-matching stimuli only for low loads; longer response times were related to higher loads compared to low loads only for matching stimuli. The high loads were related to larger ERP responses. The ERP was significantly smaller for matching than for non-matching three-digit numbers, but not for five-digit numbers. The ERP was also reduced to the test stimuli compared to sample stimuli regardless of stimulus load. Both temporal and frontal regions were involved in the recognition of the digit stimuli, and the left hemisphere was more active in the non-matching processing of digits. Conclusions : The VMP spatial pattern in addition to its amplitude is sensitive to stimulus load in the encoding process.