Varieties of attention-deficit/hyperactivity disorder-related intra-individual variability

Abstract

Intra-individual variability in behavior and functioning is ubiquitous among children with attention-deficit/hyperactivity disorder (ADHD), but it has not been systematically examined or integrated within causal models. This article seeks to provide a conceptual, methodologic, and analytic framework as a foundation for future research. We first identify five key research questions and methodologic issues. For illustration, we examine the periodic structure of Eriksen Flanker task reaction time (RT) data obtained from 24 boys with ADHD and 18 age-matched comparison boys. Reaction time variability in ADHD differed quantitatively from control subjects, particularly at a modal frequency around .05 Hz (cycle length approximately 20 sec). These oscillations in RT were unaffected by double-blind placebo and were suppressed by double-blind methylphenidate. Together with converging lines of basic and clinical evidence, these secondary data analyses support the speculative hypothesis that the increased power of multisecond oscillations in ADHD RT data, and by inference, in attentional performance, represents a catecholaminergic deficit in the ability to appropriately modulate such oscillations in neuronal activity. These results highlight the importance of retaining time-series data and quantitatively examining intra-subject measures of variability as a putative endophenotype for ADHD.

Figure 1

Multisecond oscillations in heart rate variability correlate with multisecond oscillations in firing rate of rodent globus pallidus (GPe) and subthalamic (STN) neurons. Single-unit activity of the GPe and STN neurons was recorded extracellularly from awake, locally anesthetized and immobilized rats (Ruskin et al 2003), and heart rate was determined from simultaneously recorded electrocardiographic activity. Robust multisecond oscillations in heart rate variability and firing rate of these basal ganglia nuclei are induced following administration of the direct dopamine agonist apomorphine (.32 mg/kg, IV). Oscillations have a period of approximately 10 sec. The dopamine antagonist haloperidol (.2 mg/kg, IV) eliminated the periodic oscillatory activity. X-axis units are in seconds. Unpublished observations, P.L. Tierney, D.A. Bergstrom, and J.R. Walters.

Figure 2

Top panels: Time-series (reaction time [RT] plotted against elapsed time) for two representative individuals during the second of six blocks of the Eriksen Flanker task. The control subject (left panels) shows less power in RT oscillations compared with the unmedicated subject with attention-deficit/hyperactivity disorder (ADHD) during baseline (right panels). Middle panels: Power spectral plots (fast Fourier transforms) of the same data, showing that the most prominent RT oscillations (the highest power spectral density [PSD]) were centered at a frequency of .05 Hz. Bottom panels: Morlet wavelet analyses produced with the Matlab 6.5 Time-Frequency Toolbox (The MathWorks, Natick, Massachusetts) with wavelet half-length set at 37 with 150 frequencies (scales) sampled in the frequency band between .03 Hz and .079 Hz. The color bar expresses the distribution of energy of the signal in the time-scale plane, as power per frequency unit. The increased power of the oscillation at a modal frequency of .06 Hz in the boy with ADHD is clearly visible.

Figure 3

The area under the fast Fourier power spectra was integrated for the .02–.07-Hz band for each of the five conditions for the attention-deficit/hyperactivity disorder (ADHD) group and for the normal comparison boys during baseline. The mean spectral density for control boys is shown at the far left, next to the value for boys with ADHD during unmedicated baseline (p = .01). From left to right, the next four bars depict spectral density for the ADHD groups receiving placebo and low, medium, and high doses of methylphenidate, administered in a randomized, double-blind, crossover fashion (see Scheres et al 2003). The reaction time oscillations were markedly reduced to an equivalent degree by all doses of methylphenidate (p = .0005) and were equivalent to those of the control boys. PSD, power spectral density.