Background: The etiological factors associated with the predisposition to develop alcohol dependence remain largely unknown. In recent years, neurophysiological anomalies have been identified in ...young and adult offspring of alcoholic probands. These neuroelectric features have been replicated in several laboratories across many different countries and are observed in male and female alcoholics and some of their relatives and offspring. Moreover, these electrophysiological abnormalities are heritable and predictive of future alcohol abuse or dependence.
Methods: A model is presented which hypothesizes that the genetic predisposition to develop alcoholism involves an initial state of central nervous system (CNS) disinhibition/hyperexcitability. We propose that the event‐related brain potential (ERP) anomalies reflect CNS disinhibition. This homeostatic imbalance results in excess levels of CNS excitability which are temporarily alleviated by the ingestion of alcohol. It is hypothesized that this hyperexcitability is heritable, and is critically involved in the predisposition toward alcoholism and the development of dependence. A brief review of the relevant literature is presented.
Results: Neurophysiological, neurochemical, and genetic evidence support the proposed model. In addition, strikingly similar observations between animal research and the human condition are identified. Finally, it is asserted that the proposed model is primarily biological in nature, and therefore does not account for the entire clinical variance.
Conclusion: A putative CNS homeostatic imbalance is noted as a critical state of hyperexcitability. This hyperexcitability represents a parsimonious model of what is inherited in the predisposition to develop alcoholism. It is our hope that this model will have heuristic value, resulting in the elucidation of etiological factors involved in alcohol dependence.
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.
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.
The use of endophenotypes has been proposed as a strategy to aid gene identification efforts for complex phenotypes Gottesman, I. I., and Shields J. (1972). Schizophrenia and Genetics: A Twin Study ...Vantage Point. London: Academic. As part of the Collaborative Study of the Genetics of Alcoholism (COGA) project, we have analyzed electrophysiological endophenotypes, in addition to clinical diagnoses, as part of our effort to identify genes involved in the predisposition to alcohol dependence. In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence GABRA2 (Edenberg et al., (2004). Am. J. Hum. Genet. 74:705-714) and CHRM2 (Wang et al., (2004). Hum. Mol. Genet. 13:1903-1911). Our experience in the COGA project has been that the analysis of endophenotypes provides several advantages over diagnostic phenotypes, including the strength and localization of the linkage signal. Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972.
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.
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° to 180°. 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.
Genetics of human brain oscillations Begleiter, Henri; Porjesz, Bernice
International journal of psychophysiology,
05/2006, Volume:
60, Issue:
2
Journal Article
Peer reviewed
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.
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.
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.
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.
Quantitative neuroelectric measures (EEG, ERPs, EROs) provide valuable endophenotypes in the study of genetic risk to develop alcoholism and related disorders.
Genetic studies of neuroelectric endophenotypes offer a powerful strategy for identifying susceptibility genes for developing psychiatric disorders, and provide novel insights into etiological factors.
Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed ...individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.
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