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COGNITIVE NEUROSCIENCE AND NEUROPSYCHOLOGY Time-dependent e¡ect of transcranial direct current stimulation on the enhancement of Suk Hoon Ohna, Chang-Il Parkd, Woo-Kyoung Yooe, Myoung-Hwan Kof, Kyung Pil Choia, Gyeong-Moon Kimb, Yong Taek Leec and Yun-Hee Kima Departments of aPhysical Medicine and Rehabilitation, Division for Neurorehabilitation, bNeurology, Stroke and Cerebrovascular Center, Samsung Medical Center, cDepartment of Physical Medicine and Rehabilitation, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Suwon, dDepartment and Research Institute of Rehabilitation Medicine,Yonsei University College of Medicine, Seodaemun-gu, Seoul, eDepartment of Physical and Rehabilitation Medicine, Hallym University Sacred Heart Hospital, Pyoungchon-dong, Dongan-ku, Anyang and fDepartment of Physical Medicine and Rehabilitation, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea Correspondence toYun-Hee Kim, MD, PhD, Professor and Chairperson, Department of Physical Medicine and Rehabilitation, Division for Neurorehabilitation, Stroke and Cerebrovascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul,135 -710, Republic of Korea Tel: + 82 2 3410 2824, 2818; fax: + 82 2 3410 0388; e-mail: yun1225.kim@samsung.com, yunkim@skku.edu This work was carried out at Samsung Medical Center, Sungkyunkwan University School of Medicine.
Received 30 August 2007; accepted 26 September 2007 The time-dependent e¡ect of transcranial direct current stimula- was signi¢cantly increased after 20 min of tDCS application, and tion (tDCS) on working memory was investigated by applying was further enhanced after 30 min of stimulation. This e¡ect was anodal stimulation over the left prefrontal cortex.This single-blind, maintained for 30 min after the completion of stimulation. These sham-controlled crossover study recruited15 healthy participants.
results suggest that tDCS at 1mA enhances working memory A three-back verbal working-memory task was performed in a time-dependent manner for at least 30 min in healthy parti- before, during, and 30 min after 1mA anodal or sham tDCS.
Anodal tDCS, compared with sham stimulation, signi¢cantly improved working-memory performance. Accuracy of response Keywords: anodal stimulation, transcranial direct current stimulation, working memory memory in healthy participants is improved by 10 min of Working memory is used for temporary storage and continuous anodal stimulation at 1 mA, using 35-cm2-sized manipulation of information, and plays a basic role in electrodes over the prefrontal cortex, whereas Boggio et al.
long-term memory, language, and executive function [1].
[9] reported that continuous tDCS for 20 min at 2 mA Working memory has long been associated with the (but not at 1 mA) using the same-sized electrodes improved prefrontal cortex, in which verbal working memory is working memory in patients with Parkinson's disease.
handled mainly by the left hemisphere and spatial working Marshall et al. [8], however, applied intermittent tDCS for memory by the right hemisphere [2]. Understandably, 15 min using smaller electrodes (8-mm diameter) over the memory enhancement is a major field of interest for those bilateral frontal lobes and reported a negative effect on involved in cognitive neuroscience and rehabilitation. In working memory. Therefore, it is conceivable that stimula- addition to pharmacotherapeutic and psychotherapeutic tion methods, intensity and duration, site of stimulation, approaches, brain stimulation using magnetic or electrical and size of electrode are all important variables in the effects techniques has recently been investigated as a means of of tDCS on working memory in healthy participants and in enhancing memory. Transcranial direct current stimulation those with brain disease. To our knowledge, no clear (tDCS) changes the membrane potential and modulates consensus has been established on a safe and cognitively cerebral excitability [3,4]. In humans, anodal polarization enhancing intensity and duration of tDCS.
increases the excitabilities of the motor, visual, and In this study, we applied 1mA anodal tDCS to the left prefrontal cortices, to improve motor learning, working prefrontal cortex of healthy participants for up to 30 min, and evaluated its cognitive-enhancing effects and the Recently, the effect of tDCS on working memory was residual effects after tDCS administration. We also investi- investigated using different application methods with gated participant concentration and fatigue versus applica- variable results. Fregni et al. [5] reported that working tion time, to evaluate the potential side effects of tDCS.
c Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
This study enrolled 15 healthy participants (age 26.573.5 years; 5 men, 10 women); they received both anodal and sham tDCS over the left prefrontal cortex. All participantswere right-handed, and their mean time spent in full-time education was 15.771.0 years. No participant had a history of neuropsychiatric or cardiovascular disease. Writteninformed content was obtained from all participants beforethey entered the study, and the study protocol wasapproved by our local ethics committee.
Experimental protocolThis study was designed as a single-blind, crossover, sham-controlled experiment. All participants participated in bothanodal and sham tDCS. The order of stimulation was counterbalanced and randomized across all participants. To minimize carryover effects, the interval between tDCS Initially, the participants were familiarized with the cognitive tasks. Participants practiced the three-back verbalworking-memory task until response accuracy reached a plateau. Working-memory assessments were performed before (Baseline), during tDCS at 10 min (T1), at 20 min (T2), at 30 min (T3), and 30 min after tDCS completion (T4) (Fig. 1a). The five task sets and the stimuli presented in eachtask were randomized to avoid difficulty bias. Participant (a) Experimental design. For familiarization purposes, partici- concentration and fatigue were each recorded using a visual pants practiced tasks 10 times, until working memories reached a plateau.
analog scale (i.e. 1 represented 'no concentration or no Each participant was tested every 10 min during anodal or sham stimula- fatigue' and 10 represented 'highest levels of concentration or tion, and at 30 min after stimulation. Anodal and sham stimulations wererandomized for each participant, and the order was counterbalanced fatigue') at the same times as the working-memory assessments.
across participants. The three-back verbal working-memory test con-sisted of Korean letters. (b) Participants were required to respond (press a keyboard space bar) if the presented letter was the same as the letterpresented three stimuli before.
To evaluate changes in working memory during and aftertDCS, we used a three-back verbal working-memory taskthat was similar to the one previously described [5,9,10].
over 5 s. After the stimulator had been turned off, the Participants were presented with a pseudorandom set of 28 electrodes were kept in place for 30 min. This method of Korean letters. Stimuli were generated using SuperlabPro v.
sham stimulation has also been used in other tDCS studies 2.0 software (Cedrus Corporation, San Pedro, California, USA). Each letter was displayed on a computer monitor for900 ms, followed by a blank screen for 100 ms betweenstimuli. Participants were required to memorize the letters and to press the space bar on a keyboard with a left finger, if The primary outcomes of this study were accuracy, error the presented letter was the same as the letter presented rate, and response time during/after anodal stimulation three stimuli before (Fig. 1b). The total number of targets versus sham stimulation. Analyses were performed using was 30, and the total number of foil stimuli was 60.
SPSS 13.0 statistical software (Chicago, Illinois, USA).
Accuracy (number of correct responses/total targets), error Evaluations performed at different times were analyzed rate (number of incorrect responses/total foils), and using repeated-measures analysis of variance. Posthoc response time (interval between target presentation and comparisons were made using Bonferroni-corrected t-tests, pressing the space bar) were determined.
to determine whether stimulation time had an effect on theprimary outcome. The differences between anodal andsham tDCS at each assessment were analyzed by indepen- Transcranial direct current stimulation application dent t-tests. Data were reported as means and standard Direct current was transferred using a pair of saline-soaked deviations, and significance was accepted at Po0.05.
surface sponge electrodes (5 Â 5 cm), and was deliveredusing a constant current stimulator, Phoresor PM850(IOMED, Salt Lake City, Utah, USA). For anodal stimulation of the left dorsolateral prefrontal cortex, the anode was placed over F3 (according to the 10-20 international system Accuracies measured at baseline did not differ between the for electroencephalogram electrode placement), and the anodal and sham tDCS groups. Accuracies recorded after 20 cathode was placed over the contralateral right supraorbital (T2) and 30 (T3) minutes of stimulation, and at 30 min after area. A constant current of 1 mA was applied for 30 min. For completing stimulation (T4), however, differed significantly sham stimulation, the same electrode placement was used, from those after sham tDCS stimulation. Anodal tDCS but the current was applied for 5 s, and was then tapered off induced significantly larger increases in accuracy than sham Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1 Changes in accuracy, error rate, and reaction time induced by tDCS aSigni¢cant at Po0.05 vs. baseline.
bSigni¢cant at Po0.05 vs. previous test.
cSigni¢cant at Po0.05 vs. sham.
T1, after 10 min of tDCS; T2, after 20 min of tDCS; T3, after 30 min of tDCS; T4, 30 min after completing tDCS.
tDCS, transcranial direct current stimulation.
stimulation did at these time points (Po0.05), and accuracy tDCS is known to induce a polarity-dependent excitability at T3 was significantly higher than for sham (Po0.05).
shift of stimulated brain areas, which has a modulatory Repeated-measures analysis of variance revealed that effect on behavioral outcomes [4,13,14]. According to extended treatment had a significant effect on accuracy previous studies, the effect of tDCS on brain activity seems (F¼5.37; Po0.01, Table 1, Fig. 2a).
to depend on stimulation polarity [4,15]. In particular,anodal tDCS is known to induce neuronal depolarization in the neuronal membrane and to increase local excitability.
Error rates measured at T1, T2, T3, and T4 were not Therefore, improvements in working memory observed significantly different compared with baseline for real or during this study are considered to be due to enhanced local sham tDCS treatments (Table 1, Fig. 2b).
cortical excitability in the left dorsolateral prefrontal cortex.
Furthermore, tDCS might have an additional effect on theneuronal network associated with working memory beyond the sites of stimulation, as was demonstrated by a previous Reaction times measured at T1, T2, T3, and T4 were not significantly different compared with baseline for real or Recently, many studies on the effects of tDCS on working sham tDCS treatments (Table 1, Fig. 2c).
memory have been conducted in healthy participants and inpatients with brain disease [6,7,9,12]. These studies reported diverse behavioral effects that might have been due to Concentration and fatigue were recorded at T1, T2, T3, different methodologies relating to electrode position, and T4, and there was no significant difference between real current intensity, duration of application, and diversity of and sham tDCS (Table 1). All participants successfully cognitive paradigms employed [5,9,13]. In patients with completed the experimental procedure, and no participant Parkinson's disease, Boggio et al. [9] used 1 or 2 mA tDCS for 20 min with 35-cm2-sized electrodes, but found that workingmemory improved only after administration of 2 mA tDCS.
Fregni et al. [5,16] demonstrated that 1mA anodal tDCS over the left DLPFC in healthy participants increased working- The results of this study indicated that anodal tDCS over the memory performance after 10 min of stimulation, and found left dorsolateral prefrontal cortex (DLPFC) enhanced verbal that the behavioral results depended on the stimulation site working memory in healthy participants in a time-depen- and polarity. In contrast, Iyer et al. [6] reported that an dent manner. The accuracy of verbal working-memory tasks intensity of 2 mA (but not of 1 mA) for 20 min improved increased after 10 min of tDCS application, and this effect word generation in healthy participants. The mean age of the was further enhanced by 30 min of stimulation. The participants, however, differed in the above-mentioned accuracies at 30 min of stimulation were significantly studies; participants in Iyer's study [6] were older on different between anodal and sham tDCS. Furthermore, this average than those in Fregni's study. Importantly, age, memory-enhancing effect was maintained at 30 min after education level, and underlying disease might modulate discontinuation of tDCS. Error rates, reaction times, con- the effects of tDCS. Participants enrolled in this study were centration, and fatigue did not change significantly during healthy and young, and had spent more than 13 years in full- or after intervention. To our knowledge, this is the first time education, which might explain the positive effects of 1- study to explore the time-dependent effects of tDCS on mA tDCS on cognitive function in our study. Further studies at different intensities would provide more information Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
stimulation. Repetitive transcranial magnetic stimulationstudies have also demonstrated cognitive improvements and modulation of left DLPFC in healthy participants and in patients with clinical depression [18,19] or Parkinson's disease [20]. These two noninvasive brain stimulationmethods are, however, dissimilar in terms of their strengthsand weaknesses [21,22]. The tDCS device is simple, wearable, battery-powered, and allows participants to per-form their daily activities. Although the large electrode limits the focality of the stimulation, it operates at lowcurrent densities. Moreover, the large electrode and low current density allow protracted tDCS stimulation to beperformed safely over a large area. Therefore, tDCS canpresent benefits for stimulating the prefrontal cortex for an extended period of time [5]. These unique advantages of tDCS also make it more useful for promoting working In this study, only the accuracy of the working-memory task was improved, but not error rates or response times.
The accuracy of working memory can be mediated bycognitive processes such as encoding, maintenance, selec- tion, and decision-making, which are considered to becrucial functions of the DLPFC. In contrast, error detection might be mediated through coordinated function with other brain areas like the cingulate or temporoparietal cortices [23-25]. Therefore, it might not have been obviouslyimproved by tDCS administration to the DLPFC. Reaction times were also unchanged in this study after tDCSapplication. Before the experiment, participants attended familiarization sessions until their performances touched a plateau. We were thus able to eliminate the 'learning effect' of the working-memory task. In addition, to exclude thepossible influence of the excited motor cortex in thestimulated hemisphere, we instructed participants to per- form the tasks with their left hands while the left hemi-sphere was being stimulated. This might have preventedunwanted effects on reaction time owing to a spread ofcortical excitability. Moreover, concentration and fatigue could have confounded the observed cognitive perfor-mances. These parameters were, however, no different after anodal and sham stimulation, and were unchanged by tDCS. These findings suggest that concentration and fatiguewere not influenced by tDCS, and that they did not affectthe results of our study.
Changes in accuracy (a), error rate (b), and reaction time (c), induced by transcranial direct current stimulation (tDCS). (a) Accuracy In conclusion, we found that anodal tDCS administered to was improved by anodal tDCS. Repeated-measures analysis of variance the left DLPFC at 1 mA has a time-dependent, positive (ANOVA) showed a signi¢cant group  time factor interaction (F¼5.37, impact on working memory, without any noticeable side Po0.01). *Signi¢cant at Po0.05 versus baseline. wSigni¢cant at Po0.05versus the previous test. zSigni¢cant at Po0.05 versus sham. (b) Error effects, in healthy participants. Future studies should rates were not changed by anodal or sham tDCS. (c) Reaction times were address the durability of this effect after repeated tDCS about time-dependent changes in working memory inhealthy and diseased participants. In this study, we limited This study was supported by a KOSEF grant funded by the tDCS application to 30 min for safety reasons [6,9,17]. tDCS Korean government (MOST) (No. M10644000022-06N4400- stimulation, nevertheless, increased working memory in a time-dependent manner, and this effect was maintained at30 min after stimulation. The residual effects of single and repetitive tDCS remain to be explored in further studies.
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