Transcranial Direct Current Stimulation to the Left Dorsolateral Prefrontal Cortex Improves Cognitive Control in Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Behavioral and Neurophysiological Study

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with significant morbidity and mortality that may affect over 5% of children and approximately 2.8% of adults worldwide. Pharmacological and behavioral therapies for ADHD exist, but critical symptoms such as dysexecutive deficits remain unaffected. In a randomized, sham-controlled, double-blind, crossover mechanistic study, we assessed the cognitive and physiological effects of transcranial direct current stimulation (tDCS) in 40 adult patients with ADHD in order to identify diagnostic (cross-sectional) and treatment biomarkers (targets).

Methods: Patients performed three experimental sessions in which they received 30 minutes of 2 mA anodal tDCS targeting the left dorsolateral prefrontal cortex, 30 minutes of 2 mA anodal tDCS targeting the right dorsolateral prefrontal cortex, and 30 minutes of sham. Before and after each session, half the patients completed the Eriksen flanker task and the other half completed the stop signal task while we assessed behavior (reaction time, accuracy) and neurophysiology (event-related potentials).

Results: Anodal tDCS to the left dorsolateral prefrontal cortex modulated cognitive (reaction time) and physiological (P300 amplitude) measures in the Eriksen flanker task in a state-dependent manner, but no effects were found in the stop signal reaction time of the stop signal task.

Conclusions: These findings show procognitive effects in ADHD associated with the modulation of event-related potential signatures of cognitive control, linking target engagement with cognitive benefit, proving the value of event-related potentials as cross-sectional biomarkers of executive performance, and mechanistically supporting the state-dependent nature of tDCS. We interpret these results as an improvement in cognitive control but not action cancellation, supporting the existence of different impulsivity constructs with overlapping but distinct anatomical substrates, and highlighting the implications for the development of individualized therapeutics.

Trial registration: ClinicalTrials.gov NCT04175028.

Keywords: ADHD; Cognitive control; EEG; ERP; Executive function; tDCS.

Figure 1.

Modeling of the normal component of the electrical field (V/m) created by the montage targeting the left dorsolateral prefrontal cortex (DLPFC) and right DLPFC. Specifically, the anodal electrode was placed on the scalp at the F4 (for right DLPFC stimulation) or F3 (for left DLPFC stimulation) positions, according to the International 10–20 system for electroencephalography. The cathode was placed in the contralateral supraorbital region (Fp1 or Fp2). The four electrodes were always placed at both sides for all stimulation conditions (left, right, and sham) to ensure the blinding of the patient and the operator. For the sham condition, the current was applied only for the 15-second ramp-up phase at the beginning and the end of a 30-minute sham stimulation period, to simulate the potential experience of local tingling sensation that real stimulation produces but without sustained effect on cortical activity. The stimulation is usually not noticeable between the ramp-up and the ramp-down for either active or sham transcranial direct current stimulation, thus ensuring the blinding of the patient. The modeling is based on a finite element model included in the Starstim’s software NIC.

Figure 2.

Flanker task and stop signal task scheme. (A) The flanker task consisted of 140 trials in two blocks of 70. Each subject had a different, fully random sequence of congruent and incongruent trials, with two congruent trials for each incongruent trial, in order to build a tendency toward congruent responses and thus increase the difficulty of conflict detection in incongruent trials. The task had a total duration of 10 minute, with 1 minute of training before the task started. The flanker arrows were first presented alone for duration of 136 ms, 114 ms, 92 ms, 70 ms, or 48 ms, and were then joined by the target arrow for 62 ms, 52 ms, 42 ms, 32 ms, or 22 ms, respectively (values were adjusted to the psychometric “sweet spot” in which each patient achieved a performance in the range of 80%–85%). These values were calibrated just once at the first session for each participant to avoid confounding the outcomes, so the same values were used for all sessions within participants. Stimulus presentation was followed by a black screen for 500 ms. The time window for participants’ response was 600 ms after target onset. If the participant did not respond within the response window, a screen reading “TOO SLOW!” was presented for 300 ms. Participants were told that if they saw this screen, they should speed up. If a response was made before the deadline, the “TOO SLOW!” screen was omitted, and the black screen remained on screen for the 300-ms interval. Finally, each trial ended with presentation of the fixation cross for an additional randomly chosen duration (200, 300, or 400 ms) in order to avoid any habituation or expectation by the subject. Thus, trial durations varied between 1070 and 1400 ms. (B) The stop signal task consisted of 160 Go trials (80%) and 40 Stop trials (20%). There were only two types of Go trials: “A” and “Z.” The “A” or “Z” stimuli were first presented for 100 ms and they were followed by a black screen for 500 ms. Patients had to press the left mouse button whenever the “A” stimulus was presented and press the right mouse button whenever the “Z” stimulus was presented. For the Stop trials, the stop signal initially appeared 400 ms after the “A” or “Z” stimuli, and was adjusted dynamically according to the subject’s performance, increasing or decreasing by 50 ms after a successful or unsuccessful answer, respectively, within a range of 50–500 ms in order to yield approximately 50% successful inhibition of the Stop trials (Figure S1). RT, reaction time.

Figure 3.

Flanker task results. (A) Mean reaction time (RT) and (B) accuracy for incongruent trials and p values with multivariate correction. Error bars indicate confidence intervals. Significance indicated as *p < .05, ***p < .001. (C) Grand average event-related potentials time-locked to incongruent stimuli. Waveforms correspond to the average of the F3, Fz, and F4 positions. The red circle indicates the significant amplitude changes compared with sham. See Figure S3 for event-related potentials at individual electrodes. (D) Scalp topographies of POST-PRE difference of P200, N200, and P300 amplitude (μV). Averaging time window for P300 = [260, 360] ms. Averaging time window for N200 = [180, 230] ms.

Figure 4.

Stop signal task results. (A) Mean reaction time (RT) for Go trials. (B) Stop signal reaction time (SSRT) for Stop trials. Error bars indicate confidence intervals. Significance indicated as *p < .05, **p < .01. (C) Grand average event-related potentials time-locked to Go trials. The red circle indicates the significant amplitude changes compared with sham. (D) Grand average event-related potentials time-locked to Stop trials. Waveforms correspond to the average of the F3, Fz, and F4 positions.

Figure 5.

State dependencies. Scatterplots, regression lines, and confidence intervals for significant state dependencies in the Eriksen flanker task (EFT). (Top row) Change in P300 as a function of P300 (left) and N200 (right) at baseline in the EFT. (Middle row) Change in N200 amplitude as a function of P300 (left) and N200 (right) amplitude at baseline in the EFT. (Bottom row) Change in P200 amplitude as a function of P300 (left) and P200 (right) amplitude at baseline in the EFT. tDCS, transcranial direct current stimulation.