Alpha/beta-gamma decoupling in methylphenidate medicated ADHD patients

Abstract

There is much interest to understand how different neural rhythms function, interact and are regulated. Here, we focus on WM delay gamma to investigate its coupling with alpha/beta rhythms and its neuromodulation by methylphenidate. We address this through the use of human EEG conducted in healthy and ADHD subjects which revealed ADHD-specific electrophysiological deficits and MPH-induced normalization of gamma amplitude and its coupling with alpha/beta rhythms. Decreased alpha/beta-gamma coupling is known to facilitate memory representations via disinhibition of gamma ensembles coding the maintained stimuli. Here, we present EEG evidence which suggests that these dynamics are sensitive to catecholaminergic neuromodulation. MPH decreased alpha/beta-gamma coupling and this was related to the increase in delay-relevant gamma activity evoked by the same drug. These results add further to the neuromodulatory findings that reflect an electrophysiological dimension to the well-known link between WM delay and catecholaminergic transmission.

Keywords: ADHD; EEG; coupling; methylphenidate; neural oscillations; working memory.

Figure 1

Tasks and electrode configuration. (A) DMTS task. The WM-CTR was exactly identical to the DMTS task, except that it lasted up until the delay offset. (B) Electrode configuration used in the study.

Figure 2

Gamma oscillations and WM delay. In TD subjects, the delay period (0–3,000 ms) of the DMTS task evoked stronger gamma power relative to the delay period (0–3,000 ms) in the WM-CTR task. This effect was pronounced in the (A) parietal and (B) frontal scalp regions. Scalp maps reflect the averaged gamma power (30–100 Hz) during the 0–3,000 ms window following delay period onset. The outline in the spectrograms demarcates gamma frequencies where statistically significant (two-sided test, p < 0.025) enhancements were recorded.

Figure 3

WM delay gamma deficits in ADHD. The delay period (0–3,000 ms) of the DMTS task recorded in TD subjects evoked stronger gamma power relative to the delay period (0–3,000 ms) recorded in ADHD subjects when not under MPH medication. This effect is evident in (A) parietal and (B) frontal scalp regions. (C,D) There were no frequency activity differences during the delay period (0–3,000 ms) of the DMTS task between TD and ADHD subjects when under MPH medication. MPH normalized delay gamma activities in the ADHD subjects. Scalp maps reflect the averaged gamma power (30–100 Hz) during the 0–3,000 ms window following delay period onset. The outline in the spectrograms demarcates gamma frequencies where statistically significant (two-sided test, p < 0.025) enhancements were recorded.

Figure 4

WM delay gamma and MPH. When the delay period (0–3,000 ms) activity of the DMTS task was compared across medication conditions, MPH triggered significant gamma enhancements within the (A) parietal and (B) frontal scalp regions of subjects with ADHD. (C) The MPH-induced delay gamma enhancements in the left central parietal scalp regions were significantly and positively correlated with the corresponding changes in DMTS score. Scalp maps reflect the averaged gamma power (30–100 Hz) during the 0–3,000 ms window following delay period onset. The outline in the spectrograms demarcates gamma frequencies where statistically significant (two-sided test, p < 0.025) enhancements were recorded.

Figure 5

WM delay PAC and MPH. (A) In ADHD subjects, MPH induced a direct and significant decrease in frontal-parietal PAC during the delay period (0–3,000 ms) of the DMTS task. This PAC decrement emerged between the phase of the alpha/beta rhythm and amplitude of the gamma rhythm. Scalp PAC profiles display the average modulation index (MI) across statistically significant phase (7–20 Hz) and amplitude frequencies (30–100 Hz). (B) MPH-induced decrements in delay alpha-gamma and beta-gamma PAC were significantly and negatively correlated with the MPH-induced gamma amplitude enhancements. This effect was recorded in electrodes: PO7, CP3, F8, and TP7. (C) The coupling between the beta phase and gamma amplitude in TD was decreased when compared with ADHD subjects in the “OFF” medication condition. Scalp PAC profiles display the average modulation index (MI) across statistically significant phase (7–20 Hz) and amplitude frequencies (30–100 Hz). (D) There were no significant differences in the frontal-parietal PAC coupling between TD and ADHD subjects when under MPH. Scalp topographies showing MPH-induced normalization of PAC profiles across TD and ADHD subjects. Scalp PAC profiles display the average modulation index (MI) across alpha/beta phase frequencies (7–20 Hz) and gamma amplitude frequencies (30–100 Hz). The outline in the comodulograms demarcates statistically significant (two-sided test, p < 0.025) PAC decrements.