Genetic overlap between evoked frontocentral theta-band phase variability, reaction time variability, and attention-deficit/hyperactivity disorder symptoms in a twin study

Abstract

Background: Electrophysiological and hemodynamic activity is altered in attention-deficit/hyperactivity disorder (ADHD) during tasks requiring cognitive control. Frontal midline theta oscillations are a cortical correlate of cognitive control influencing behavioral outcomes including reaction times. Reaction time variability (RTV) is consistently increased in ADHD and is known to share genetic effects with the disorder. The etiological relationship between the cognitive control system, RTV, and ADHD is unknown. In a sample of twins selected for ADHD and matched control subjects, we aimed to quantify the strength of the phenotypic, genetic, and environmental relationships between event-related midline theta oscillations, RTV, and ADHD.

Methods: Our sample included 134 participants aged 12 to 15 years: 67 twin pairs (34 monozygotic; 33 dizygotic) with concordance or discordance for ADHD symptomatology assessed at 8, 10, and 12 years of age. Our main outcome measures were frontal midline theta activity, derived from both channel and source decomposed electroencephalographic data, and behavioral performance on a response-choice arrow flanker task known to elicit theta activity.

Results: Variability in stimulus event-related theta phase from frontal midline cortex is strongly related to both RTV and ADHD, both phenotypically and genetically.

Conclusions: This is the first finding to confirm the genetic link between the frontal midline cognitive control system and ADHD and the first to identify a genetically related neurophysiological marker of RTV in ADHD. Variability in the timing of the theta signal in ADHD may be part of a dysfunctional brain network that impairs regulation of task-relevant responses in the disorder.

Keywords: ADHD; EEG; biomarker; cognitive control; genetic; twin study.

Figure 1

Stimulus-locked and response-locked single-trial and mean event-related potentials (ERPs) in the incongruent-correct condition for the extracted frontocentral independent component cluster. Event-related potential image plots (42) of single trials across control participants and attention-deficit/hyperactivity disorder (ADHD) participants ordered by reaction time (RT) and smoothed vertically with a 100-trial moving average. Color corresponds to relative potential in μV normalized to unit power in the baseline (red > 0, green = 0, blue < 0). Average ERP waveforms of the single trial ERP traces. Scalp maps show the mean interpolated scalp potential projection of the cluster, averaged over all participants. STs, stimulus onset times.

Figure 2

Correlated factors solution of the trivariate model for attention-deficit/hyperactivity disorder (ADHD), variability in reaction time (RTV), and electroencephalographic theta measures. Circles represent latent additive genetic (A1, A2, A3), shared environmental (C1, C2, C3), and nonshared environmental (E1, E2, E3) factors. rG and rE represent genetic and environmental correlations between ADHD, RTV, and theta activity. Parameters for ADHD (heritability and unique environmental estimates) are fixed values selected according to meta-analysis (57).

Figure 3

Interference effects on the mean event-related potential amplitude and mean theta power in attention-deficit/hyperactivity disorder (ADHD) and control (Ctrl) subjects. (A) Event-related potentials for the central midline independent component (left) and Cz channel average (right). The difference in mean potentials between the congruent and the incongruent conditions is plotted. (B) The difference in theta power between the congruent and the incongruent conditions in a 350-millisecond sliding window event-related spectral perturbation (ERSP).