Citation: Voegtle, A.; Reichert, C.; Hinrichs, H.; Sweeney-Reed, C.M. Repetitive Anodal TDCS to the Frontal Cortex Increases the P300 during Working Memory Processing. Brain Sci. 2022, 12, 1545. https:// doi.org/10.3390/brainsci12111545 Academic Editor: Mohammed Ali Salehinejad Received: 13 October 2022 Accepted: 7 November 2022 Published: 14 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). brain sciences Article Repetitive Anodal TDCS to the Frontal Cortex Increases the P300 during Working Memory Processing Angela Voegtle 1, * , Christoph Reichert 2,3 , Hermann Hinrichs 2,3,4 and Catherine M. Sweeney-Reed 1,3, * 1 Neurocybernetics and Rehabilitation, Department of Neurology, Otto von Guericke University, 39120 Magdeburg, Germany 2 Department of Behavioral Neurology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany 3 Center for Behavioral Brain Sciences—CBBS, Otto von Guericke University, 39106 Magdeburg, Germany 4 Department of Neurology, Otto von Guericke University, 39120 Magdeburg, Germany * Correspondence: angela.voegtle@med.ovgu.de (A.V.); catherine.sweeney-reed@med.ovgu.de (C.M.S.-R.) Abstract: Transcranial direct current stimulation (TDCS) is a technique with which neuronal activity, and therefore potentially behavior, is modulated by applying weak electrical currents to the scalp. Application of TDCS to enhance working memory (WM) has shown promising but also contradictory results, and little emphasis has been placed on repeated stimulation protocols, in which effects are expected to be increased. We aimed to characterize potential behavioral and electrophysiological changes induced by TDCS during WM training and evaluate whether repetitive anodal TDCS has a greater modulatory impact on the processes underpinning WM than single-session stimulation. We examined the effects of single-session and repetitive anodal TDCS to the dorsolateral prefrontal cortex (DLPFC), targeting the frontal-parietal network, during a WM task in 20 healthy participants. TDCS had no significant impact on behavioral measures, including reaction time and accuracy. Analyzing the electrophysiological response, the P300 amplitude significantly increased following repetitive anodal TDCS, however, positively correlating with task performance. P300 changes were identified over the parietal cortex, which is known to engage with the frontal cortex during WM processing. These findings support the hypothesis that repetitive anodal TDCS modulates electrophysiological processes underlying WM. Keywords: TDCS; repetitive; working memory; n-back; ERP; P300 1. Introduction Transcranial direct current stimulation (TDCS) is a noninvasive technique, with which a weak direct current is applied noninvasively over the scalp to alter underlying cortical excitability. Anodal TDCS results in a change in the resting membrane potential towards depolarization, which increases the spontaneous firing of neurons [1–3]. It has gained increasing attention in recent years as a potential tool with which to modulate cognitive processing [4–6] and has been shown to modify behavioral performance in a range of cognitive tasks, including working memory (WM) processing. The term WM refers to a set of basic, rapidly accessible cognitive functions with limited capacity, which temporarily store and update information as well as manipulate it for use in higher cognitive processes, such as language comprehension, learning, and reasoning [7–9], which are crucial to daily life [9]. Although results have been mixed [10–14], a number of studies have been reported in which accuracy and/or reaction times (RTs) have indicated enhanced WM performance during or immediately after TDCS [11–13]. The effects are generally of short duration [2], but because the effect of TDCS can outlast the stimulation period itself [2,3,14–16], repetitive TDCS could have a cumulative effect, increasing its influence on cortical networks. Therefore, a growing body of research is investigating the influence of repetitive TDCS, with the findings so far suggesting a benefit in WM performance [17–22]. Contradictory and null results have also been reported, however [18,23–25]. Moreover, Brain Sci. 2022, 12, 1545. https://doi.org/10.3390/brainsci12111545 https://www.mdpi.com/journal/brainsci