David B. Chorlian

Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus.

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 (GABAA) 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 GABAA receptor genes. Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing.

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.

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.

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.

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.

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.

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.

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 (TFRs) 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 TFRs from single trial and trial-averaged ERP data acquired during a visual oddball task. These TFRs 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 EROs, 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.

Heritability of event-related brain potentials in families with a history of alcoholism

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. Estimates of heritability are presented for amplitude and latency of the N1 and P3 components of the ERP measured at 19 scalp locations in response to visual and auditory stimuli for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. Significant heritabilities were found for visual P3 amplitude in response to all stimuli and for visual P3 latency in response to target and novel, but not non-target, stimuli. Heritability of visual N1 latencies was uniformly low, whereas heritability of visual N1 amplitude was significant for all electrodes in response to the non-target stimuli but only for posterior electrodes in the other two stimulus conditions. Heritabilities for auditory target P3 were similar to those of the visual stimuli, with auditory target P3 amplitudes and latencies both demonstrating significant heritability. For auditory P2 in response to non-target stimuli, peak amplitude was heritable, but latency was not. Auditory N1 amplitude and latency were significantly heritable for both target and non-target conditions and did not demonstrate the anterior/posterior patterning obtained for visual N1 amplitude. This study represents the first systematic assessment of heritability of these potential neurophysiological markers in families with a history of alcoholism and suggests that many of these ERP phenotypes have heritabilities strong enough to justify genomic screening for loci jointly influencing ERP abnormalities and liability to alcoholism.

Neurocognitive deficits in male alcoholics: An ERP/sLORETA analysis of the N2 component in an equal probability Go/NoGo task

In alcoholism research, studies concerning time-locked electrophysiological aspects of response inhibition have concentrated mainly on the P3 component of the event-related potential (ERP). The objective of the present study was to investigate the N2 component of the ERP to elucidate possible brain dysfunction related to the motor response and its inhibition using a Go/NoGo task in alcoholics. The sample consisted of 78 abstinent alcoholic males and 58 healthy male controls. The N2 peak was compared across group and task conditions. Alcoholics showed significantly reduced N2 peak amplitudes compared to normal controls for Go as well as NoGo task conditions. Control subjects showed significantly larger NoGo than Go N2 amplitudes at frontal regions, whereas alcoholics did not show any differences between task conditions at frontal regions. Standardized low resolution electromagnetic tomography analysis (sLORETA) indicated that alcoholics had significantly lower current density at the source than control subjects for the NoGo condition at bilateral anterior prefrontal regions, whereas the differences between groups during the Go trials were not statistically significant. Furthermore, NoGo current density across both groups revealed significantly more activation in bilateral anterior cingulate cortical (ACC) areas, with the maximum activation in the right cingulate regions. However, the magnitude of this difference was much less in alcoholics compared to control subjects. These findings suggest that alcoholics may have deficits in effortful processing during the motor response and its inhibition, suggestive of possible frontal lobe dysfunction.