Whole genome sequence association and ancestry-informed polygenic profile of EEG alpha in a Native American population.

EEG alpha activity is the dominant oscillation in most adult humans, is highly heritable, and has been associated with a number of cognitive functions. Two EEG phenotypes, low- and high-voltage alpha (LVA & HVA), have been demonstrated to have high heritabilities. They have different prevalence depending on a population's ancestral origins. In the present study we assessed the influence of ancestry admixture on EEG alpha power, and conducted a whole genome sequencing association analysis and an ancestry-informed polygenic study on those phenotypes in a Native American (NA) population that has a high prevalence of LVA. Seven common variants, in LD with each other upstream from gene ASIC2, reached genome-wide significance (p = 2 × 10-8 ) having a positive association with alpha voltage. They had lower minor allele frequencies in the NAs than in a global population sample. Overall correlations between lower degrees of NA (higher degree European) ancestry and HVA, and higher degrees of NA and LVA were also found. Additionally a rare-variant gene-based study identified gene TIA1 being negatively associated with LVA. Approximately 3% of SNPs exhibited a 15-fold enrichment that explained nearly half of the total SNP-heritability for EEG alpha. These regions showed the most significant anti-correlations between NA ancestry and alpha voltage, and were enriched for genes and pathways mediating cognitive functions. Our findings suggested that these regions likely harbor causal variants for HVA, and lacking of such variants could explain the high prevalence of LVA in this NA population, possibly illuminating the ancestral origin and genetic basis for EEG alpha.

Photosensitive epilepsy is associated with reduced inhibition of alpha rhythm generating networks.

See Hamandi (doi:10.1093/awx049) for a scientific commentary on this article.Photosensitivity is a condition in which lights induce epileptiform activities. This abnormal electroencephalographic response has been associated with hyperexcitability of the visuo-motor system. Here, we evaluate if intrinsic dysfunction of this network is present in brain activity at rest, independently of any stimulus and of any paroxysmal electroencephalographic activity. To address this issue, we investigated the haemodynamic correlates of the spontaneous alpha rhythm, which is considered the hallmark of the brain resting state, in photosensitive patients and in people without photosensitivity. Second, we evaluated the whole-brain functional connectivity of the visual thalamic nuclei in the various populations of subjects under investigation. Forty-four patients with epilepsy and 16 healthy control subjects underwent an electroencephalography-correlated functional magnetic resonance imaging study, during an eyes-closed condition. The following patient groups were included: (i) genetic generalized epilepsy with photosensitivity, 16 subjects (mean age 25 ± 10 years); (ii) genetic generalized epilepsy without photosensitivity, 13 patients (mean age 25 ± 11 years); (iii) focal epilepsy, 15 patients (mean age 25 ± 9 years). For each subject, the posterior alpha power variations were convolved with the standard haemodynamic response function and used as a regressor. Within- and between-groups second level analyses were performed. Whole brain functional connectivity was evaluated for two thalamic regions of interest, based on the haemodynamic findings, which included the posterior thalamus (pulvinar) and the medio-dorsal thalamic nuclei. Genetic generalized epilepsy with photosensitivity demonstrated significantly greater mean alpha-power with respect to controls and other epilepsy groups. In photosensitive epilepsy, alpha-related blood oxygen level-dependent signal changes demonstrated lower decreases relative to all other groups in the occipital, sensory-motor, anterior cingulate and supplementary motor cortices. Coherently, the same brain regions demonstrated abnormal connectivity with the visual thalamus only in epilepsy patients with photosensitivity. As predicted, our findings indicate that the cortical-subcortical network generating the alpha oscillation at rest is different in people with epilepsy and visual sensitivity. This difference consists of a decreased alpha-related inhibition of the visual cortex and sensory-motor networks at rest. These findings represent the substrate of the clinical manifestations (i.e. myoclonus) of the photoparoxysmal response. Moreover, our results provide the first evidence of the existence of a functional link between the circuits that trigger the visual sensitivity phenomenon and those that generate the posterior alpha rhythm.

Evidence for genetic regulation of the human parieto-occipital 10-Hz rhythmic activity.

Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable (h(2)  > 0.75). Variance component-based analysis of 28 000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 (LOD = 2.814, nominal P < 0.03). This genomic region contains several functionally plausible genes, including GRID1 and ATAD1 that regulate glutamate receptor channels mediating synaptic transmission, NRG3 with functions in brain development and HRT7 involved in the serotonergic system and circadian rhythm. Our data suggest that the alpha oscillation is in part genetically regulated, and that it may be possible to identify its regulators by genetic analyses on a realistically modest number of samples.

Gender differences in association between serotonin transporter gene polymorphism and resting-state EEG activity.

Human brain oscillations represent important features of information processing and are highly heritable. Gender has been observed to affect association between the 5-HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism and various endophenotypes. This study aimed to investigate the effects of 5-HTTLPR on the spontaneous electroencephalography (EEG) activity in healthy male and female subjects. DNA samples extracted from buccal swabs and resting EEG recorded at 60 standard leads were collected from 210 (101 men and 109 women) volunteers. Spectral EEG power estimates and cortical sources of EEG activity were investigated. It was shown that effects of 5-HTTLPR polymorphism on electrical activity of the brain vary as a function of gender. Women with the S/L genotype had greater global EEG power compared to men with the same genotype. In men, current source density was markedly different among genotype groups in only alpha 2 and alpha 3 frequency ranges: S/S allele carriers had higher current source density estimates in the left inferior parietal lobule in comparison with the L/L group. In women, genotype difference in global power asymmetry was found in the central-temporal region. Contrasting L/L and S/L genotype carriers also yielded significant effects in the right hemisphere inferior parietal lobule and the right postcentral gyrus with L/L genotype carriers showing lower current source density estimates than S/L genotype carriers in all but gamma bands. So, in women, the effects of 5-HTTLPR polymorphism were associated with modulation of the EEG activity in a wide range of EEG frequencies. The significance of the results lies in the demonstration of gene by sex interaction with resting EEG that has implications for understanding sex-related differences in affective states, emotion and cognition.

Alpha-theta border EEG abnormalities in preclinical Huntington's disease.

BACKGROUND: Brain dysfunction precedes clinical manifestation of Huntington's disease (HD) by decades. This study was aimed to determine whether resting EEG is altered in preclinical HD mutations carriers (pre-HD). METHODS: We examined relative power of broad traditional EEG bands as well as 1-Hz sub-bands of theta and alpha from the resting-state EEG of 29 pre-HD individuals and of 29 age-matched normal controls. RESULTS: The relative power of the narrow sub-band in the border of theta-alpha (7-8 Hz) was significantly reduced in pre-HD subjects as compared to normal controls, while the alterations in relative power of the broad frequency bands were not significant. In pre-HD subjects, the number of CAG repeats in the huntingtin (HTT) gene as well as the disease burden score (DBS) showed a positive correlation with relative power of the delta and theta frequency bands and their sub-bands and a negative correlation with alpha band relative power and the differences of relative power of the 7-8 Hz and 4-5 Hz frequency sub-bands. CONCLUSION: The obtained results suggest that EEG alterations in pre-HD individuals may be related to the course of the pathological process and to HD endophenotype. Analysis of the narrow EEG bands was found to be more useful for assessing EEG alterations in pre-HD individuals than a more traditional approach using broad bandwidths.

Dopamine-d2-receptor blockade reverses the association between trait approach motivation and frontal asymmetry in an approach-motivation context.

Individual differences in the behavioral approach system (BAS)-referred to as trait approach motivation or trait BAS)-have been linked to both frontal electroencephalogram (EEG) alpha asymmetry between left and right hemispheres (frontal alpha asymmetry) and brain dopamine. However, evidence directly linking frontal alpha asymmetry and dopamine is scarce. In the present study, female experimenters recorded EEG data in 181 male participants after double-blind administration of either a placebo or a dopamine D2 blocker. As expected, trait BAS was associated with greater left- than right-frontal cortical activity (i.e., greater right- than left-frontal EEG alpha) in the placebo group, but a reversed association emerged in the dopamine-blocker group. Furthermore, frontal alpha asymmetry was associated with a genetic variant known to modulate prefrontal dopamine levels (the catechol-O-methyltransferase Val158Met polymorphism). Finally, each of these effects was significant only in the subgroup of male participants interacting with female experimenters rated as most attractive; this finding suggests that associations between frontal alpha asymmetry and both dopamine and trait BAS are detectable only in approach-motivation contexts.

A shared low-frequency oscillatory rhythm abnormality in resting and sensory gating in schizophrenia.

OBJECTIVES: We hypothesized that an oscillatory abnormality that is consistently observed across various testing paradigms may index an elementary neuronal abnormality marking schizophrenia risk. METHODS: Compared neural oscillations in resting EEG and sensory gating conditions in schizophrenia patients (n=128), their first-degree relatives (n=80), and controls (n=110) and calculated phenotypic and/or genetic correlation of the abnormal measure across these conditions. RESULTS: Using a uniform, single trial analytical approach, we identified two prominent oscillatory characteristics in schizophrenia: (1) augmented neural oscillatory power was pervasive in medicated schizophrenia patients in most frequencies, most prominent in the theta-alpha range (4-11 Hz) across the two paradigms (all p<0.007); and (2) their first-degree relatives shared significantly augmented oscillatory energy in theta-alpha frequency in resting (p=0.002) and insufficient suppression of theta-alpha in sensory gating (p=0.01) compared with normal controls. Heritability estimates for theta-alpha related measures for resting and gating conditions ranged from 0.44 to 0.49 (p<0.03). The theta-alpha measures were correlated genetically with each other (RhoG=0.82±0.43; p<0.05). CONCLUSIONS: Augmented theta-alpha rhythm may be an elementary neurophysiological problem associated with genetic liability of schizophrenia. SIGNIFICANCE: This finding helps to refine key electrophysiologic biomarkers for genetic and clinical studies of schizophrenia.

Transition to absence seizures and the role of GABA(A) receptors.

Absence seizures appear to be initiated in a putative cortical 'initiation site' by the expression of medium-amplitude 5-9Hz oscillations, which may in part be due to a decreased phasic GABA(A) receptor function. These oscillations rapidly spread to other cortical areas and to the thalamus, leading to fully developed generalized spike and wave discharges. In thalamocortical neurons of genetic models, phasic GABA(A) inhibition is either unchanged or increased, whereas tonic GABA(A) inhibition is increased both in genetic and pharmacological models. This enhanced tonic inhibition is required for absence seizure generation, and in genetic models it results from a malfunction in the astrocytic GABA transporter GAT-1. Contradictory results from inbred and transgenic animals still do not allow us to draw firm conclusions on changes in phasic GABA(A) inhibition in the GABAergic neurons of the nucleus reticularis thalami. Mathematical modelling may enhance our understanding of these competing hypotheses, by permitting investigations of their mechanistic aspects, hence enabling a greater understanding of the processes underlying seizure generation and evolution.