The Intensity-Dependent Effects of Cortical Electrical Stimulation on Motor Learning and the Role of Dopamine

Background Introduction

Nowadays, non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) are widely used in neuroplasticity research to modulate cognition and behavior. However, optimizing stimulation protocols to maximize their benefits remains a challenge. This necessitates a better understanding of how stimulation regulates cortical function and behavior. Although there is increasing evidence supporting a dose-response relationship between tDCS intensity and brain excitability, little is known about its relationship with behavior. Even fewer studies have explored the neurobiochemical mechanisms that might drive this dose-response relationship. In this study, the authors investigated the effects of three different intensities of tDCS (1 mA, 2 mA, 4 mA) on motor sequence learning and evaluated the role of dopamine in this dose-response relationship.

Study Source

This paper was written by Li-Ann Leow, Jiaqin Jiang, Samantha Bowers, Yuhan Zhang, Paul E. Dux, and Hannah L. Filmer from The University of Queensland and Edith Cowan University. It was published in April 2024 in the journal Brain Stimulation.

Study Overview

Study Design

This study adopted a pre-registered design (https://osf.io/jegsr) using a factorial design, incorporating dose (sham, 1 mA, 2 mA, 4 mA) and drug (levodopa, placebo) as between-subject variables and assessments of repeated versus random sequences and different experimental blocks as within-subject variables. All participants were randomly assigned to one of eight experimental conditions, and all performed a five-element sequence learning task in different blocks.

Participants

Participants were right-handed, aged between 18 and 35 years (mean age 20 years, standard deviation 4 years), without known neurological or psychiatric diseases, and without contraindications to brain stimulation or levodopa. Additionally, participants had less than 13 years of musical training and currently engaged in less than 20 hours of music or gaming training per week. Participants were pseudo-randomly assigned to levodopa sham tDCS (n = 17), levodopa 1 mA (n = 16), levodopa 2 mA (n = 19), levodopa 4 mA (n = 18), placebo sham tDCS (n = 17), placebo 1 mA (n = 17), placebo 2 mA (n = 17), and placebo 4 mA (n = 16) groups. The study was approved by The University of Queensland Human Research Ethics Committee and complied with the Helsinki Declaration. All participants signed written informed consent forms.

Drug and Stimulation Manipulation

In the first session of the experiment, participants first underwent blood pressure and mood assessments and then received either a vitamin (placebo) or levodopa (madopar 125: 100 mg levodopa and 25 mg benserazide hydrochloride), crushed and dispersed in orange juice. Participants then completed some morning-evening questionnaires and mood assessments. The stimulation electrodes were subsequently set up.

In the task portion of the experiment, participants first familiarized themselves with the task procedure and then performed a motor sequence learning task in both base and training sessions, during which stimulation occurred. For the 1 mA, 2 mA, and 4 mA conditions, stimulation lasted 11 minutes; for the sham condition, stimulation lasted only 1 minute and 15 seconds, with minimal pulse maintenance thereafter. Interestingly, emotional guessing results in the sham and active groups showed that the probability of correctly guessing sham stimulation in the sham group was lower than chance, consistent with previous research results.

Experimental Results Analysis

Using Bayesian analytical methods, reaction time was used to estimate motor sequence learning (also known as learning) and was standardized by subtracting the reaction time of the random sequence. We examined learning across different reinforcement stages and hormone expression time.

Baseline

Before training, there was no difference in sequence learning across different stimulation conditions (main effect: p > 0.05 for intensity and drug interaction).

Sequence Learning

Overall, training improved participants’ performance. Specifically, reaction time for sequence trials significantly decreased, whereas random trials did not show the same effect. These advantages persisted even after a delay of more than 48 hours, with subsequent reaction times significantly faster than baseline.

Effect of Hormones and Levodopa on Acquisition Process

In the absence of levodopa, 4 mA tDCS improved sequence acquisition, while 1 mA tDCS reduced acquisition efficiency. The effect of levodopa reversed this outcome. This suggests a significant interaction between stimulation intensity and drug at different training stages for the acquisition process.

End of Acquisition, Retention, and Transfer

At the end of acquisition, stimulation intensity and levodopa did not significantly alter performance. Additionally, while the retention stage showed similar performance, 2 mA tDCS led to the worst inter-hand transfer effect. Levodopa did not significantly modify this process.

Discussion

This study provides the first evidence of dopamine’s causal role in the intensity-dependent effects of tDCS. While existing research had shown that as stimulation intensity increases, tDCS has a positive effect on sequence learning, this effect is reversed when combined with levodopa. This might be because levodopa increases midbrain dopamine levels, while tDCS alone provides sufficient dopamine release to reach or exceed an optimal dose.

Notably, unlike previous studies, we did not observe the effect of levodopa on sequence learning in the absence of tDCS. Future research should continue to explore the mechanisms behind this difference, considering individual differences in responsiveness to tDCS and drugs.

The findings of this study have important implications for the application of tDCS in populations with altered dopamine function (such as the elderly and Parkinson’s patients), suggesting that rationally designed stimulation protocols and drug combinations may enhance efficacy in these groups.

Conclusion

This study reveals the nonlinear dose effects of tDCS on explicit motor sequence learning and demonstrates the critical role of dopamine in this process. This research significantly advances our understanding of how stimulation regulates the motor learning process and provides new insights and directions for future customized tDCS applications across various populations.