Elsevier

NeuroImage

Volume 55, Issue 2, 15 March 2011, Pages 644-657
NeuroImage

Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: A standardized low resolution tomography (sLORETA) study

https://doi.org/10.1016/j.neuroimage.2010.12.004Get rights and content

Abstract

Prefrontal transcranial direct current stimulation (tDCS) with the anode placed on the left dorsolateral prefrontal cortex (DLPFC) has been reported to enhance working memory in healthy subjects and to improve mood in major depression. However, its putative antidepressant, cognitive and behavior action is not well understood. Here, we evaluated the distribution of neuronal electrical activity changes after anodal tDCS of the left DLPFC and cathodal tDCS of the right supraorbital region using spectral power analysis and standardized low resolution tomography (sLORETA). Ten healthy subjects underwent real and sham tDCS on separate days in a double-blind, placebo-controlled cross-over trial. Anodal tDCS was applied for 20 min at 2 mA intensity over the left DLPFC, while the cathode was positioned over the contralateral supraorbital region. After tDCS, EEG was recorded during an eyes-closed resting state followed by a working memory (n-back) task. Statistical non-parametric mapping showed reduced left frontal delta activity in the real tDCS condition. Specifically, a significant reduction of mean current densities (sLORETA) for the delta band was detected in the left subgenual PFC, the anterior cingulate and in the left medial frontal gyrus. Moreover, the effect was strongest for the first 5 min (p < 0.01). The following n-back task revealed a positive impact of prefrontal tDCS on error rate, accuracy and reaction time. This was accompanied by increased P2- and P3- event-related potentials (ERP) component-amplitudes for the 2-back condition at the electrode Fz. A source localization using sLORETA for the time window 250–450 ms showed enhanced activity in the left parahippocampal gyrus for the 2-back condition. These results suggest that anodal tDCS of the left DLPFC and/or cathodal tDCS of the contralateral supraorbital region may modulate regional electrical activity in the prefrontal and anterior cingulate cortex in addition to improving working memory performance.

Research Highlights

► Prefrontal tDCS (tDCS) reduces slow-wave activity. ► Prefrontal RtDCS tend to increase high-frequency activity. ► Prefrontal rtDCS improves performance (errors, accuracy) in a working memory task (n-back). ► This is accompanied by P2- and P3-amplitude increases. ► And by an increased left parahippocampal activity (sLORETA).

Introduction

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that shifts neuronal resting membrane potentials towards depolarization or hyperpolarization, depending on whether anodal or cathodal stimulation is applied, leading to changes of cortical excitability and other functional parameters (Nitsche et al., 2008, Nitsche et al., 2003a, Nitsche et al., 2003b). More recently, Nitsche and Paulus, 2000, Nitsche and Paulus, 2001 revisited this approach in humans and demonstrated that anodal tDCS increases and cathodal tDCS decreases motor cortex excitability (Nitsche and Paulus, 2000, Nitsche and Paulus, 2001). When applied for 9–13 min, tDCS produces post-stimulation effects in the human motor cortex that are stable for up to 1 h and longer (Nitsche et al., 2003c, Nitsche and Paulus, 2001). As demonstrated in animal experiments, the primary mechanism of tDCS appears to be a subthreshold modulation of neuronal resting membrane potential (Purpura and McMurtry, 1965). Accordingly, pharmacologically blocking voltage-dependent ion channels in humans abolishes any effect of depolarizing anodal tDCS on cortical excitability, but does not influence the impact of hyperpolarizing cathodal tDCS (Nitsche et al., 2003a). Pharmacological studies have proven that tDCS related effects depend on changes of NMDA receptor-efficacy (Liebetanz et al., 2002). Recently, Stagg et al. (2009) demonstrated changes in GABA levels after anodal tDCS using magnetic resonance spectroscopy (MRS), suggesting that anodal excitatory effects do affect GABAergic inhibition in addition to NMDA-receptor dependency (Stagg et al., 2009). Based on initial studies, combining tDCS and EEG, a direct impact of tDCS on oscillatory activity was observed (Ardolino et al., 2005, Marshall et al., 2004). During slow-wave sleep (SWS) bilateral frontal sinusoidal anodal tDCS reduced the average power in the theta and alpha-1-bands in frontal, central and parietal electrode locations (Marshall et al., 2004). Compared to placebo stimulation, frontal anodal tDCS during SWS-rich sleep distinctly increased the retention of word pairs (Marshall et al., 2004). Ardolino et al. (2005) also found a widespread impact of tDCS on the EEG (Ardolino et al., 2005). Increasing amounts of delta and theta activity were found after cathodal DC stimulation (15 min, 1.5 mA) to the right motor cortex, extending beyond the primary stimulation site (Ardolino et al., 2005). These EEG pilot studies are indicative of possible large-scale network changes following tDCS. Using positron emission tomography, Lang et al. (2005) showed that anodal tDCS increased the rCBF in widespread cortical and subcortical areas in comparison to cathodal tDCS, while cathodal stimulation entailed an excitability decrease of the metabolic activity in the corresponding areas (Lang et al., 2005).

One mode of tDCS application, namely anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation of the right supraorbital region, has been associated with working memory enhancement and improvement in other cognitive domains (Boggio et al., 2006, Dockery et al., 2009, Elmer et al., 2009, Ferrucci et al., 2008, Fertonani et al., 2010, Fiori et al., 2010, Fregni et al., 2005, Kincses et al., 2004, Marshall et al., 2004, Ohn et al., 2008).

Memory processes of healthy subjects were enhanced after left anodal DLPFC tDCS with the cathode placed on the right frontocortical regions (Fregni et al., 2005, Kincses et al., 2004, Marshall et al., 2004, Marshall et al., 2005, Ohn et al., 2008). Moreover, prefrontal tDCS is supposed to modulate pain perception (Boggio et al., 2009, Boggio et al., 2008b), seems to influence social behavior (Knoch et al., 2008) and shows an impact on risk taking behavior (Beeli et al., 2008a, Beeli et al., 2008b, Fecteau et al., 2007a, Fecteau et al., 2007b). Prefrontal tDCS may even influence the desire for specific foods (Fregni et al., 2008) and the reaction time to lies (Priori et al., 2008).

In depressed subjects promising pilot data of prefrontal tDCS were reported, suggesting a therapeutic action of real tDCS compared to sham tDCS (Boggio et al., 2007, Boggio et al., 2008a, Ferrucci et al., 2009, Fregni et al., 2006, Rigonatti et al., 2008), whereas the effect of one single tDCS-session on healthy subjects had no mood-altering effects (Koenigs et al., 2009).

The mechanism of action of prefrontal tDCS is not completely understood and to date there has been no study about the effects of prefrontal tDCS on resting EEG. Moreover, as prefrontal tDCS seems to influence a wide range of disorders and behaviors, resting state EEG and source analysis techniques may help to better understand prefrontal tDCS induced post-stimulation effects. Furthermore, TMS, MRS and imaging studies are only an indirect proof of the neuronal activity and were predominantly applied to the motor cortex in the past to test the effects of tDCS on brain physiology. We therefore investigated the effects of anodal tDCS of the left DLPFC and cathodal tDCS of the supraorbital region in a placebo-controlled cross-over study in healthy subjects, applying resting state EEG with spectral power analysis and standardized low resolution tomography (sLORETA). Following resting-state EEG all healthy subjects underwent a working memory task (n-back) with event-related potential (ERP) recording. As prefrontal tDCS has been found to influence working memory performance, we intended to replicate this behavioral finding and hypothesized that neurophysiological correlates should be detectable in ERPs related to cognitive processes.

Section snippets

Subjects

Ten healthy subjects (five women, five men, mean age = 28.89 years, SD = 2.67) participated in this study. All subjects underwent a semi-structured interview (including the M-CIDI-S interview and a semantic word fluency task (Wittchen and Müller, 1998) showing that they were without history of neurological and/or psychiatric diseases and free of medication affecting the central nervous system. All subjects were right-handed (Edinburgh handedness test (Oldfield, 1971)) and homogenous with regard to

Distinguishability of DC stimulators

All subjects were asked if they perceived a difference between the stimulation conditions and if they could specifically discern real from placebo tDCS. Nobody was able to distinguish real and sham tDCS, nor did the reported sensations differ between stimulation conditions.

Mood changes

No side effects of stimulation were reported. There were no significant differences in the PANAS before and after tDCS (see Table 1). The Positive Affect Scale showed no main effects for time (F(1,9) = 0.02, p = 0.96, n.s.) and

EEG study

Our results suggest that anodal tDCS above the left DLPFC with the cathode placed supraorbitally on the contralateral side may influence regional electrical activity in the surface EEG and deeper in the prefrontal lobe as revealed by sLORETA. However, the underlying mechanisms are not well understood and several hypotheses might be discussed, e.g. neuroplastic effects by prolonged weak depolarization/hyperpolarization, effects on connected networks or even brain conductivity heterogeneities.

As

Acknowledgments

This study is part of the Ph.D. thesis of Daniel Keeser at the Faculty of Medicine of the Ludwig-Maximilians University of Munich (in preparation). We gratefully acknowledge T. Sprenger for his invaluable advise, and thank M. Hartmann, D. Bars und H.J. Engelbregt for critically reading our manuscript.

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