Large-scale collaboration in ENIGMA-EEG: A perspective on the meta-analytic approach to link neurological and psychiatric liability genes to electrophysiological brain activity.

BACKGROUND AND PURPOSE: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain. METHODS: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations. RESULTS: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters. CONCLUSION: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.

Reprint of: Using a co-twin control design to evaluate alternative trait measures as indices of liability for substance use disorders.

To establish a trait-dispositional variable as an indicator of liability for the development of substance use disorders (SUDs), the trait must share heritable variance with SUDs and its association should not be primarily attributable to a direct impact of SUDs on characteristics that define the trait. The current work applied a co-twin control (CTC) modeling approach to data from two monozygotic twin samples to investigate the degree to which different measures of trait-impulsiveness represent indicants of vulnerability to SUDs (liability indicators), or outcomes or concomitants of SUDs (exposure indicators). The Five Factor Model (FFM) trait of conscientiousness was assessed via self-report, and a counterpart neurobehavioral trait of disinhibition was assessed both through self-report and using self-report and brain response measures combined. FFM trait data were available for one twin sample (N = 298); data for variants of P3 brain response were available along with a scale measure of disinhibition in the other (N = 258). CTC analyses revealed only an exposure effect of SUD symptomatology on FFM conscientiousness, indicating that this self-report assessed trait does not index liability for SUDs. By contrast, the disinhibition scale measure showed pronounced liability and weaker exposure-based associations with SUDs - and when quantified using scale scores together with P3 brain response, the exposure-based association was eliminated, such that this disinhibition measure related to SUD symptoms exclusively as a function of liability influences. These findings highlight a distinct advantage of quantifying traits in neurobehavioral terms - namely, the capacity to effectively index dispositional liability for psychopathological outcomes.

Using a co-twin control design to evaluate alternative trait measures as indices of liability for substance use disorders.

To establish a trait-dispositional variable as an indicator of liability for the development of substance use disorders (SUDs), the trait must share heritable variance with SUDs and its association should not be primarily attributable to a direct impact of SUDs on characteristics that define the trait. The current work applied a co-twin control (CTC) modeling approach to data from two monozygotic twin samples to investigate the degree to which different measures of trait-impulsiveness represent indicants of vulnerability to SUDs (liability indicators), or outcomes or concomitants of SUDs (exposure indicators). The Five Factor Model (FFM) trait of conscientiousness was assessed via self-report, and a counterpart neurobehavioral trait of disinhibition was assessed both through self-report and using self-report and brain response measures combined. FFM trait data were available for one twin sample (N = 298); data for variants of P3 brain response were available along with a scale measure of disinhibition in the other (N = 258). CTC analyses revealed only an exposure effect of SUD symptomatology on FFM conscientiousness, indicating that this self-report assessed trait does not index liability for SUDs. By contrast, the disinhibition scale measure showed pronounced liability and weaker exposure-based associations with SUDs - and when quantified using scale scores together with P3 brain response, the exposure-based association was eliminated, such that this disinhibition measure related to SUD symptoms exclusively as a function of liability influences. These findings highlight a distinct advantage of quantifying traits in neurobehavioral terms - namely, the capacity to effectively index dispositional liability for psychopathological outcomes.

Reduced premovement positivity during the stimulus-response interval precedes errors: Using single-trial and regression ERPs to understand performance deficits in ADHD.

Brain mechanisms linked to incorrect response selections made under time pressure during cognitive task performance are poorly understood, particularly in adolescents with attention-deficit hyperactivity disorder (ADHD). Using subject-specific multimodal imaging (electroencephalogram, magnetic resonance imaging, behavior) during flanker task performance by a sample of 94 human adolescents (mean age = 15.5 years, 50% female) with varying degrees of ADHD symptomatology, we examined the degree to which amplitude features of source-resolved event-related potentials (ERPs) from brain-independent component processes within a critical (but often ignored) period in the action selection process, the stimulus-response interval, were associated with motor response errors (across trials) and error rates (across individuals). Response errors were typically preceded by two smaller peaks in both trial-level and trial-averaged ERP projections from posterior medial frontal cortex (pMFC): a frontocentral P3 peaking about 390 ms after stimulus onset, and a premovement positivity (PMP) peaking about 110 ms before the motor response. Separating overlapping stimulus-locked and response-locked ERP contributions using a "regression ERP" approach showed that trial errors and participant error rates were primarily associated with smaller PMP, and not with frontocentral P3. Moreover, smaller PMP mediated the association between larger numbers of errors and ADHD symptoms, suggesting the possible value of using PMP as an intervention target to remediate performance deficits in ADHD.

Causal Network Modeling of the Determinants of Drinking Behavior in Comorbid Alcohol Use and Anxiety Disorder.

BACKGROUND: Anxiety and depression disorders (internalizing psychopathology) occur in approximately 50% of patients with alcohol use disorder (AUD) and mark a 2-fold increase in the rate of relapse in the months following treatment. In a previous study using network modeling, we found that perceived stress and drinking to cope (DTC) with negative affect were central to maintaining network associations between internalizing psychopathology INTP and drinking in comorbid individuals. Here, we extend this approach to a causal framework. METHODS: Measures of INTP, drinking urges/behavior, abstinence self-efficacy, and DTC were obtained from 362 adult AUD treatment patients who had a co-occurring anxiety disorder. Data were analyzed using a machine-learning algorithm ("Greedy Fast Causal Inference"[ GFCI]) that infers paths of causal influence while identifying potential influences associated with unmeasured ("latent") variables. RESULTS: DTC with negative affect served as a central hub for 2 distinct causal paths leading to drinking behavior, (i) a direct syndromic pathway originating with social anxiety and (ii) an indirect stress pathway originating with perceived stress. CONCLUSIONS: Findings expand the field's knowledge of the paths of influence that lead from internalizing disorder to drinking in AUD as shown by the first application in psychopathology of a powerful network analysis algorithm (GFCI) to model these causal relationships.

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity.

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1-3.75 Hz, theta 4-7.75 Hz, alpha 8-12.75 Hz, and beta 13-30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2-a known genetic marker for alcohol use disorder and epilepsy-significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q < .05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex-genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

One-year developmental stability and covariance among oddball, novelty, go/no-go, and flanker event-related potentials in adolescence: A monozygotic twin study.

ERP measures may index genetic risk for psychopathology before disorder onset in adolescence, but little is known about their developmental rank-order stability during this period of significant brain maturation. We studied ERP stability in 48 pairs of identical twins (age 14-16 years) tested 1 year apart. Trial-averaged voltage waveforms were extracted from electroencephalographic recordings from oddball/novelty, go/no-go, and flanker tasks, and 16 amplitude measures were examined. Members of twin pairs were highly similar, whether based on ERP amplitude measures (intraclass correlation [ICC] median = .64, range = .44-.86) or three factor scores (all ICCs ≥ .69) derived from them. Stability was high overall, with 69% of the 16 individual measures generating stability coefficients exceeding .70 and all factor scores showing stability above .75. Measures from 10 difference waveforms calculated from paired conditions within tasks were also examined, and were associated with lower twin similarity (ICC median = .52, .38-.64) and developmental stability (only 30% exceeding .70). In a supplemental analysis, we found significant developmental stability for error-related negativity (range = .45-.55) and positivity (.56-.70) measures when average waveforms were based on one or more trials, and that these values were equivalent to those derived from averages using the current field recommendation, which requires six or more trials. Overall, we conclude that the studied brain measures are largely stable over 1 year of mid- to late adolescence, likely reflecting familial etiologic influences on brain functions pertaining to cognitive control and salience recognition.

Heritability and molecular-genetic basis of resting EEG activity: a genome-wide association study.

Several EEG parameters are potential endophenotypes for different psychiatric disorders. The present study consists of a comprehensive behavioral- and molecular-genetic analysis of such parameters in a large community sample (N = 4,026) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric heritability estimates ranged from .49 to .85, with a median of .78. The additive effect of all SNPs (SNP heritability) varied across electrodes. Although individual SNPs were not significantly associated with EEG parameters, several genes were associated with delta power. We also obtained an association between the GABRA2 gene and beta power (p < .014), consistent with findings reported by others, although this did not survive Bonferroni correction. If EEG parameters conform to a largely polygenic model of inheritance, larger sample sizes will be required to detect individual variants reliably.

Does electroencephalogram phase variability account for reduced P3 brain potential in externalizing disorders?

OBJECTIVE: Amplitude deficits of the P3 event-related potential (ERP) are associated with externalizing psychopathology but little is known about the nature of underlying brain electrical activity that accounts for this amplitude reduction. We sought to understand if group differences in task-induced phase-locking in electroencephalographic (EEG) delta and theta frequencies may account for P3-externalizing associations. METHODS: Adult males (N=410) completed a visual oddball task and frontal and parietal P3-related delta- and theta-band phase-invariant evoked energy and inter-trial phase-locking measures were investigated with respect to the externalizing spectrum, including substance dependence, adult antisociality, and childhood disruptive disorders. We hypothesized that P3-related phase-locking is weaker in externalizing-diagnosed individuals and this might mediate prior findings of reduced evoked P3 energy. RESULTS: Reductions in both evoked energy and phase-locking, in both frequency bands, at both scalp sites, were associated with greater odds of externalizing diagnoses. Generally, adding phase-locking to evoked energy came with better prediction model fit. Moreover, reduced theta-band phase-locking partially mediated the effects of within-frequency evoked energy on externalizing prediction. CONCLUSIONS: Inter-trial phase-locking underlying P3 appears to be an important distinction between externalizing and control subjects. SIGNIFICANCE: This cross-trial phase-variability for externalizing-diagnosed individuals might reflect deficient top-down "tuning" by neuromodulatory systems.

The effects of recurrent episodes of depression on startle responses.

Prior work suggests that major depression is associated with abnormal startle blink responses; however, only chronic or recurrent depression appears to be associated with this effect. The current study tested this hypothesis directly by examining whether recurrent major depression accounted for the anomalous startle seen in major depression using a sample of 515 female twins from the Minnesota Twin Family Study. Blink responses recorded at the age of 20 were examined in relation to number of episodes of depression prospectively assessed from ages 11 to 20. Results showed that only subjects who had experienced multiple episodes of depression showed abnormal startle responses. Subjects who had experienced just one episode of depression in their lifetime did not differ from controls. This lends additional support to the idea that recurrent depression may have a different etiological basis than nonrecurrent depression.

Association between P3 event-related potential amplitude and externalizing disorders: a time-domain and time-frequency investigation of 29-year-old adults.

This study determined whether time-domain P3 amplitude and time-frequency principal component (TF-PC) reductions are present in adulthood (age 29) when participants have largely passed through the age of heaviest substance misuse. Participants were assessed from age 17 through 29 for lifetime externalizing (EXT) disorders. EEG comparisons from three topographic regions were examined for P3 amplitude and TF-PCs at delta and theta frequency ranges. Significant P3 amplitude reductions were found in those with EXT for both regional and site-Pz analyses, with stronger effects observed the greater the EXT comorbidity. Reductions were also observed in all eight TF-PCs extracted, with a delta component yielding frontal effects not apparent in the time domain. Overall, results suggest that these brain measures continue, at age 29, to provide effective indices of EXT that potentially tap a neural substrate related to behavioral disinhibition.