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.

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.

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.

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.

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.

Resting EEG in offspring of male alcoholics: beta frequencies.

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.

Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: implications for human brain dynamics and cognition.

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<0.001). These findings were not observed for the equivalent non-target case data, suggesting a role for the CHRM2 gene in higher cognitive processing in humans.

Reduced frontal lobe activity in subjects with high impulsivity and alcoholism.

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=58) and subjects with DSM-IV diagnosis of alcohol dependence (n=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 (p<0.0001). 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 (p<0.0001) than nonalcoholic individuals. There were significant negative correlations between total scores on BIS and P3 amplitude (r=-0.274, p=0.003, on Pz; r=-0.250, p=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.

A cholinergic receptor gene (CHRM2) affects event-related oscillations.

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.

Auditory P3 in female alcoholics.

BACKGROUND: The P3 (P300) has been considered to be a phenotypical marker of the risk for alcoholism. Although reductions in visual P3 in male and female alcoholics have been replicated, studies of auditory target P3 have been inconsistent. Our objective was to study the magnitude of auditory P3 reduction in female alcoholics and to establish the association between P3 reduction and alcoholism while taking into account comorbid depression and psychoactive drug dependence. The characteristics of P3 reduction were further examined by studying the reduction in family history-positive and -negative individuals. METHODS: Auditory target P3s recorded from 61 scalp electrodes in female alcoholics (n = 71) were compared with P3s from female controls (n = 159) ranging in age from 18 to 50 years. The amplitudes and latencies were statistically analyzed, by using repeated-measures ANOVA, in six regional electrode arrays and at representative electrode sites, with age and comorbid depression as covariates. The effects of family density and clinical variables such as depression and drug dependence were also examined with correlation analysis. RESULTS: Alcoholic women had significantly lower P3 amplitudes in all six regions and at midline electrode sites. The reductions were not associated with comorbid depression, as shown by low correlations and similar P3 amplitudes at Pz in female alcoholics with and without depression. The P3 amplitudes in women with a high family density were smaller than those in women with a low family density of alcohol dependence. Drug dependency did not influence P3 amplitude, as shown by similar responses in drug-dependent and non-drug-dependent alcoholic women. CONCLUSIONS: These findings highlight the significance of P3 reductions associated with alcoholism in women, independently of comorbid depression. Family density effects further support the evidence that these findings are heritable. These results suggest that P3 can be considered as a phenotypical marker of vulnerability to alcoholism in women.

Theta power in the EEG of alcoholics.

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.