A novel non-parametric regression reveals linkage on chromosome 4 for the number of externalizing symptoms in sib-pairs.

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.

High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors.

CONTEXT: Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alcoholic subjects have low levels of dopamine D(2) receptors in striatum, and increasing D(2) receptor levels in laboratory animals reduces alcohol consumption. OBJECTIVES: To test whether high levels of D(2) receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control). DESIGN: Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a negative family history) sample. SETTING: Outpatient setting. PARTICIPANTS: Fifteen nonalcoholic subjects who had an alcoholic father and at least 2 other first- or second-degree relatives who were alcoholics (family-positive group) and 16 nonalcoholic controls with no family history of alcoholism (family-negative group). MAIN OUTCOME MEASURES: Results of positron emission tomography with raclopride C 11 to assess D(2) receptors and with fludeoxyglucose F 18 to assess brain glucose metabolism (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire. RESULTS: Availability of D(2) receptors was significantly higher in caudate and ventral striatum in family-positive than family-negative subjects. In family-positive but not family-negative subjects, striatal D(2) receptors were associated with metabolism in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of positive emotionality. CONCLUSIONS: The higher-than-normal D(2) receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D(2) receptors may protect against alcoholism. The significant associations between D(2) receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high levels of D(2) receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.

Genetic influences on bipolar EEG power spectra.

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.

Delta and theta oscillations as risk markers in adolescent offspring of alcoholics.

BACKGROUND: Visual P300 is consistently lower in alcohol-dependent individuals, their offspring and subjects at risk. Delta and theta event-related oscillations (ERO) are the major contributors to the P300 signal. The total and evoked power in delta and theta bands in the 300 to 700 ms post-stimulus window (corresponding to the zone of P300 maxima) was compared between adolescent offspring of alcoholics (high-risk) and age-matched normal controls (low-risk), to assess the utility of the risk markers. METHODS: EEG was recorded during the performance of a visual oddball task. The S-transform algorithm decomposed the EEG signals into different frequency bands and the group differences in total and evoked power in the oscillatory responses during the P300 time window (300 to 700 ms) were analyzed using a multivariate design. Similar analysis was performed on P300 peak amplitude for the target. RESULTS: The high-risk group showed significantly lower parietal post-stimulus evoked and total power in the delta band for targets. A decrease in total power was seen centrally and parietally in the theta band. The P300 peak amplitude in the parietal electrodes was also significantly lower in the high-risk group. CONCLUSIONS: The decreased total theta power and total and evoked delta power for visual targets in high risk individuals may serve as an endophenotypic marker in the development of alcoholism and other disinhibitory disorders. The differences seen between the offspring of alcoholics and controls may have a cholinergic basis. The ERO measures appear to be more robust than the P300 amplitude in differentiating the groups.

Event-related oscillations in offspring of alcoholics: neurocognitive disinhibition as a risk for alcoholism.

BACKGROUND: Event-related oscillations (EROs) are increasingly being used to assess neurocognitive functioning in normal and clinical populations. The current study compares different frequency activities in offspring of alcoholics (OA) and in normal control subjects (NC) to examine whether the OA group exhibits any abnormality in oscillatory activity while performing a Go/NoGo task. METHODS: The S-transform algorithm was employed to decompose the electroencephalographic (EEG) signals into different time-frequency bands, and the oscillatory responses in the P300 time window (300-700 milliseconds) were statistically analyzed in both groups. RESULTS: The OA group manifested significantly decreased activity in delta (1-3 Hz), theta (4-7 Hz), and alpha1 (8-9 Hz) bands during the NoGo condition, as well as reduced delta and theta activity during the Go condition. This reduction was more prominent in the NoGo than in the Go condition. CONCLUSIONS: The decreased response in delta, theta, and alpha1 oscillations, especially during the NoGo condition in high-risk individuals, is perhaps suggestive of cognitive and neural disinhibition and may serve as an endophenotypic marker in the development of alcoholism and/or other disinhibitory disorders.

S-transform time-frequency analysis of P300 reveals deficits in individuals diagnosed with alcoholism.

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 theta and posterior delta activations. The frontal theta 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 delta and theta 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.

Genetics of human brain oscillations.

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.

Amplitude modulation of gamma band oscillations at alpha frequency produced by photic driving.

Gamma band response to visual stimulation in humans has been observed to have both burst and resonance properties. Amplitude modulation of gamma activity at low frequencies has been seen in rat hippocampus and modeled in a number of forms. Significant amplitude modulation (p=0.05) of 33 Hz gamma frequency activity at the frequency of an 8 1/3 Hz photic driving stimulus, which also produced strong alpha entrainment, was observed in 67% of the channels in 42 human subjects. Similar amplitude modulation was found at a range of frequencies from greater than 50 Hz to about 28 Hz. The peak of the gamma amplitude modulation curve trailed the peak of the alpha signal by 25 to 30 ms, corresponding to a phase difference of 150 degrees to 180 degrees. The phase consistency of the gamma signal, measured across comparable times of the alpha signal, was least at the minimum amplitude modulation, and largest at the maximum. Although there was no consistent overall relation between the gamma amplitude and alpha amplitude, peak gamma amplitude values were consistently higher during post-target-stimulus alpha suppression, which occurs about 300-750 ms subsequent to stimulus presentation, than they were at the time of maximum alpha activity during the immediate post-stimulus period. It is hypothesized that there is an interaction between the alpha and gamma generating systems, in which gamma triggers alpha activity and is subsequently inhibited by it, thus producing the observed amplitude modulation. The transition from dark to light of the photic driving stimulus begins a phase resetting process in the gamma system and a concomitant burst of gamma activity; this produces an activation in the alpha system, similar to that found in the P1-N1 response in evoked potential experiments, and a subsequent inhibition of gamma production.

Suppression of early evoked gamma band response in male alcoholics during a visual oddball task.

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.

Evoked gamma band response in male adolescent subjects at high risk for alcoholism during a visual oddball task.

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.

Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction.

OBJECTIVE: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence. METHOD: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of approximately 900 individuals from control families to test the generalizability of results. RESULTS: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status. CONCLUSIONS: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of "environmental" risk factors.

Description of the data from the Collaborative Study on the Genetics of Alcoholism (COGA) and single-nucleotide polymorphism genotyping for Genetic Analysis Workshop 14.

The data provided to the Genetic Analysis Workshop 14 (GAW 14) was the result of a collaboration among several different groups, catalyzed by Elizabeth Pugh from The Center for Inherited Disease Research (CIDR) and the organizers of GAW 14, Jean MacCluer and Laura Almasy. The DNA, phenotypic characterization, and microsatellite genomic survey were provided by the Collaborative Study on the Genetics of Alcoholism (COGA), a nine-site national collaboration funded by the National Institute of Alcohol and Alcoholism (NIAAA) and the National Institute of Drug Abuse (NIDA) with the overarching goal of identifying and characterizing genes that affect the susceptibility to develop alcohol dependence and related phenotypes. CIDR, Affymetrix, and Illumina provided single-nucleotide polymorphism genotyping of a large subset of the COGA subjects. This article briefly describes the dataset that was provided.

The utility of neurophysiological markers in the study of alcoholism.

OBJECTIVE: This review attempts to differentiate neuroelectric measures (electroencephalogram (EEG), event-related potentials (ERPs) and event-related oscillations (EROs)) related to acute and chronic effects of alcohol on the brain from those that reflect underlying deficits related to the predisposition to develop alcoholism and related disorders. The utility of these neuroelectric measures as endophenotypes for psychiatric genetics is evaluated. METHODS: This article reviews the main findings of EEG and ERP abnormalities in alcoholics, offspring of alcoholics at high risk to develop alcoholism and the electrophysiological effects of alcohol on high risk compared to low-risk offspring. It highlights findings using EROs, a fast developing tool in examining brain function and cognition. It also reviews evidence of genetic findings related to these electrophysiological measures and their relationship to clinical diagnosis. RESULTS: Many of these abnormal neuroelectric measures are under genetic control, may precede the development of alcoholism, and may be markers of a predisposition toward the development of a spectrum of disinhibitory conditions including alcoholism. Genetic loci underlying some neuroelectic measures that involve neurotransmitter systems of the brain have been identified. CONCLUSIONS: Quantitative neuroelectric measures (EEG, ERPs, EROs) provide valuable endophenotypes in the study of genetic risk to develop alcoholism and related disorders. SIGNIFICANCE: Genetic studies of neuroelectric endophenotypes offer a powerful strategy for identifying susceptibility genes for developing psychiatric disorders, and provide novel insights into etiological factors.

Spatial-anatomical mapping of NoGo-P3 in the offspring of alcoholics: evidence of cognitive and neural disinhibition as a risk for alcoholism.

OBJECTIVE: The concept of disinhibition as a behavioral and biological trait has been considered to be involved in the etiology of alcoholism and its co-existing disorders. The magnitude and functional mapping of event-related potential P3(00) components were analyzed, in order to examine the possible response inhibition deficits in the offspring of alcoholics. METHODS: The P3 components were compared between 50 offspring of alcoholics (OA) and a matched normal control group (NC) using a visual Go/NoGo task. The low-resolution electromagnetic tomography (LORETA) was used to analyze the functional brain mapping between groups. RESULTS: The results indicated that the OA group manifested decreased P3 amplitude during the NoGo but not the Go condition compared to the NC group. The voxel-by-voxel analysis in LORETA showed group differences at several brain regions including prefrontal areas during the processing of NoGo but not Go signals. CONCLUSIONS: The decreased NoGo-P3 suggests that cognitive and neural disinhibition in offspring of alcoholics may serve as a neurocognitive index for a phenotypic marker in the development of alcoholism and related disorders. SIGNIFICANCE: Dysfunctional neural and response inhibition in the offspring of alcoholics perhaps provides an endophenotypic marker of risk for the development of alcoholism and related disorders.

Alcoholism is a disinhibitory disorder: neurophysiological evidence from a Go/No-Go task.

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.

Beta power in the EEG of alcoholics.

BACKGROUND: In this study, the magnitude and spatial distribution of beta power in the resting electroencephalogram (EEG) were examined to address the possibility of an excitation-inhibition imbalance in the central nervous system of alcoholics. METHODS: Log transformed absolute power in the Beta 1 (12.5-16 Hz), Beta 2 (16.5-20 Hz), and Beta 3 (20.5-28 Hz) bands in the eyes-closed EEG of 307 alcohol-dependent subjects and 307 unaffected age- and gender-matched control subjects were compared using a multivariate repeated measures design. Effect of gender, age, and drinking variables was examined separately. RESULTS: Increased Beta 1 (12.5-16 Hz) and Beta 2 (16.5-20 Hz) absolute power was observed in alcohol-dependent subjects at all loci over the scalp. The increase was most prominent in the central region. Increased Beta 3 (20.5-28 Hz) power was frontal in the alcoholics. Age and clinical variables did not influence the increase. Male alcoholics had significantly higher beta power in all three bands. In female alcoholics the increase did not reach statistical significance. CONCLUSIONS: Beta power in all three bands of resting EEG is elevated in alcoholics. This feature is more prominent in male alcoholics. The increased beta power in the resting EEG may be an electrophysiological index of the imbalance in the excitation-inhibition homeostasis in the cortex.

Functional magnetic resonance imaging of brain activity in the visual oddball task.

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<0.01) bilaterally in the supramarginal gyrus (SMG; BA 40), superior parietal lobule (BA 7), the posterior cingulate gyrus, thalamus, inferior occipitotemporal cortex (BA 19/37), insula, dorsolateral prefrontal cortex (BA 9), anterior cingulate cortex (ACC), medial frontal gyrus (BA 6), premotor area, and cuneus (BA 17). Our results are consistent with previous studies that have observed activation in ACC and SMG. Activation of thalamus, insula, and the occipitotemporal cortex has been reported less consistently. The present study lends further support to the involvement of these structures in visual target detection.

Event-Related Potentials and Cognitive Function in Alcoholism.

Subtle cognitive deficits can be studied using event-related potentials (ERP), brain waves elicited in response to sensory stimuli. ERP studies suggest that certain memory processes are impaired in alcoholics; therefore, each incoming stimulus must be evaluated anew. Some ERP anomalies occur in nonalcoholic subjects from alcoholic families, indicating that these anomalies may antecede the development of alcoholism.

Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes.

Linkage analyses of highly heritable electrophysiological phenotypes (EEG, ERP) that can potentially identify individuals at risk for alcoholism were performed on a large sample of families with a high density of alcohol dependence as part of the Collaborative Study on the Genetics of Alcoholism (COGA); these genetic findings are summarized. Quantitative trait loci (QTLs) were identified for several ERP characteristics (P300, N100, N400) and for the beta frequencies of the EEG where we report linkage and linkage disequilibrium at a GABA(A) receptor gene on chromosome 4. Genetic analyses of ERPs suggest that several regions of the human genome contain genetic loci related to the generation of N100, N400 and P300, which are possible candidate loci underlying the functional organization of human neuroelectric activity. 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.

The role of brain oscillations as functional correlates of cognitive systems: a study of frontal inhibitory control in alcoholism.

Event-related oscillations play a key role in understanding the brain dynamics and human information processing. In the present study, the Go/No-Go paradigm has been used to examine whether alcoholics have poor inhibitory control as compared to control subjects in terms of different oscillatory brain responses. The matching pursuit algorithm was used to decompose the event-related electroencephalogram into oscillations of different frequencies. It was found that alcoholics (n=58) showed significant reduction in delta (1.0-3.0 Hz) and theta (3.5-7.0 Hz) power during No-Go trials as compared to controls (n=29). This reduction was prominent at the frontal region. The decreased delta and theta power associated with No-Go processing perhaps suggests a deficient inhibitory control and information-processing mechanism. A neuro-cognitive model has been provided to explain the findings. It is suggested that the oscillatory correlates during cognitive processing can be an endophenotypic marker in alcoholism.