Focalised stimulation using high definition transcranial direct current stimulation (HD-tDCS) to investigate declarative verbal learning and memory functioning

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Focalised stimulation using high definition transcranial direct currentstimulation (HD-tDCS) to investigate declarative verbal learning andmemory functioning

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Stevan Nikolin a, Colleen K. Loo a,b, Siwei Bai c,d, Socrates Dokos c, Donel M. Martin a,⁎a School of Psychiatry, University of New South Wales, Black Dog Institute, Sydney, Australiab St. George Hospital, Sydney, Australiac Faculty of Engineering, University of New South Wales, Sydney, Australiad IMETUM, Technische Universität München, 85748 Garching, Germany

⁎ Corresponding author at: Black Dog Institute, H2031, Australia.

E-mail address: [email protected] (D.M. Mar

http://dx.doi.org/10.1016/j.neuroimage.2015.05.0191053-8119/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Nikolin, S., et al.,investigate declarative verbal learning and m

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Accepted 7 May 2015Available online xxxx

Keywords:High definition transcranial direct current stimulationDeclarative verbal memoryLeft dorsolateral prefrontal cortexLeft medial temporal lobePlanum temporale

Background: Declarative verbal learning andmemory are known to be lateralised to the dominant hemisphere andto be subserved by a network of structures, including those located in frontal and temporal regions. These structuressupport critical components of verbal memory, including working memory, encoding, and retrieval. Their relativefunctional importance in facilitating declarative verbal learning and memory, however, remains unclear.Objective: To investigate the different functional roles of these structures in subserving declarative verbal learningandmemory performance by applying amore focal form of transcranial direct current stimulation, “High DefinitiontDCS” (HD-tDCS). Additionally, we sought to examine HD-tDCS effects and electrical field intensity distributionsusing computer modelling.Methods:HD-tDCSwas administered to the left dorsolateral prefrontal cortex (LDLPFC), planum temporale (PT), andleft medial temporal lobe (LMTL) to stimulate the hippocampus, during learning on a declarative verbal memory

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RRECtask. Sixteen healthy participants completed a single blind, intra-individual cross-over, sham-controlled study
which used a Latin Square experimental design. Cognitive effects on working memory and sustained attentionwere additionally examined.Results:HD-tDCS to the LDLPFC significantly improved the rate of verbal learning (p=0.03, η2=0.29) and speed ofresponding duringworkingmemory performance (p=0.02, η2=0.35), but not accuracy (p=0.12, η2=0.16). Noeffect of tDCS on verbal learning, retention, or retrieval was found for stimulation targeted to the LMTL or the PT.Secondary analyses revealed that LMTL stimulation resulted in increased recency (p=0.02, η2=0.31) and reducedmid-list learning effects (p= 0.01, η2 = 0.39), suggesting an inhibitory effect on learning.Conclusions: HD-tDCS to the LDLPFC facilitates the rate of verbal learning and improved efficiency of workingmemory may underlie performance effects. This focal method of administrating tDCS has potential for probingand enhancing cognitive functioning.

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UNCIntroduction

New verbal learning is essential for the acquisition of language andauditory information and is known to be subserved by a bilateral net-work of brain structures with functional processing largely lateralisedto the dominant hemisphere (Golby et al., 2001; Vigneau et al., 2006,2011). Neuropsychological and brain lesion studies have consistentlydemonstrated that declarative verbal learning and memory is affectedwhen damage occurs to key frontal and temporal regions includingthe prefrontal cortex and medial temporal lobe (Zola-Morgan et al.,1986, 1994). Functional neuroimaging studies have implicated left

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Focalised stimulation using hemory functioning, NeuroIm

lateralised structures in the encoding and retrieval of new memories(Cabeza and Nyberg, 2000), as well as language processing relatedareas, such as the planum temporale (PT; commonly referred to asWernicke's area) (Fletcher et al., 1995; Kikyo et al., 2001; López-Barrosoet al., 2013). The left dorsolateral prefrontal cortex (LDLPFC), which isfunctionally involved in themanipulation andorganisation of informationin verbal working memory (Barbey et al., 2013; Nyberg et al., 2003) andretrieval processes (Cabeza et al., 2002; Kikyo et al., 2001), and the hippo-campus, which is important for working memory, encoding and consoli-dation (Nadel and Hardt, 2011), are theoretically considered to play keyroles across the different memory functions of encoding, retention, andretrieval. It is generally thought that new verbal memories are initiallymaintained and manipulated within working memory (Baddeley, 2000;Gathercole, 1999), encoded and stored via medial temporal structuresincluding the hippocampus (McClelland and Goddard, 1996), and

igh definition transcranial direct current stimulation (HD-tDCS) toage (2015), http://dx.doi.org/10.1016/j.neuroimage.2015.05.019

http://dx.doi.org/10.1016/j.neuroimage.2015.05.019

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subsequently retrieved through structures similarly engaged duringencoding (i.e., left prefrontal and medial temporal regions) (Danker andAnderson, 2010). The PT, whilst functionally important for phonologicalprocessing, however, is thought to be more involved in word retrieval(Yagishita et al., 2008). These theoretical assumptions have yet tobe directly tested using non-invasive methods which can selectivelyenhance and/or depress functioning, particularly in deeper regions suchas the hippocampus.

Transcranial direct current stimulation (tDCS) is a neuromodulatorytechnique which involves passing a low level current between stimula-tion and reference electrodes placed upon the scalp (Gandiga et al.,2006). Anodal stimulation, that is, stimulation using a positively chargedelectrode, increases the rate of spontaneous neural firing in underlyingbrain regions (Nitsche et al., 2008) and is thought to cause synapticneuroplastic changes via LTP-like, NMDA receptor-dependent mecha-nisms that can last up to an hour (Liebetanz et al., 2002; Nitsche et al.,2004). These neuromodulatory effects are considered to underlie tDCSrelated improvements in learning and memory obtained across variousstimulus modalities, including motor (Antal et al., 2004; Nitsche et al.,2003; Reis et al., 2009), visual (Chi et al., 2010; Clark et al., 2012), andverbal (De Vries et al., 2010; Elmer et al., 2009; Flöel et al., 2008;Javadi andWalsh, 2012). These promisingfindings have helped to estab-lish tDCS as a new technique to modulate and enhance brain function-ing, with potential treatment applications in rehabilitation for brainillness or injury (Baker et al., 2010; Monti et al., 2008) and enhancingeducation and training (Clark et al., 2012; Martin et al., 2013).

Previous studies using tDCS to enhance verbal memory have variedin their approach, primarily through focussing on different sites ofstimulation (i.e., LDLPFC: Elmer et al., 2009; Javadi et al., 2012; Javadiand Walsh, 2012; Marshall et al., 2004; PT: Fiori et al., 2011; Flöelet al., 2008; Jones et al., 2014; motor cortex: Liuzzi et al., 2010). Corre-spondingly, findings have varied between studies, with differentialfacilitatory effects found on specific memory functions, namely encoding(Flöel et al., 2008), retention (Marshall et al., 2004) and retrieval (Javadiet al., 2012; Javadi and Walsh, 2012). For declarative verbal learning andmemory, specifically, research has focussed on stimulating the LDLPFC,and similarly, differential effects on memory functions have been report-ed (Elmer et al., 2009; Javadi et al., 2012; Javadi and Walsh, 2012;Marshall et al., 2004). The optimal tDCS methodology for enhancingspecific declarative verbal learning and memory functions thereforeremains to be determined.

An important limitation to understanding reported effects is thediffuse nature of the stimulatory effects of modern tDCS methods,whereby due to the large electrodes and spacing of these electrodesupon the scalp both the targeted brain region as well as surroundingand interconnected structures are directly affected (Bai et al., 2014;Nathan et al., 1993). Hence it remains unclear whether reported effectsare due to stimulation of the targeted cortical region, or surrounding ormore distal structures. In the present study we therefore applied amethod of tDCS stimulation shown to bemore focal in computermodel-ling studies, high definition tDCS (HD-tDCS), to better localise theeffects of stimulation (Datta et al., 2009; Kuo et al., 2013). This focalisedmethod of tDCS using a 4 × 1 ring electrode configuration to stimu-late outer cortical regions has been demonstrated to restrictupwards of 30% of the stimulation peak within the perimeter ofthe ring montage using computer modelling (Edwards et al., 2013).Edwards et al. (2013) have validated their computer modelling experi-mentally using an identical 4 × 1 ring electrode configuration to deliversupra-threshold stimulation of approximately 500–2000 mA to themotor cortex whilst measuring motor evoked potentials (MEPs) in thehand.

More focalised stimulation would therefore allow for improvedspecificity in determining the relative role of critical cortical areas insubserving the different learning and memory functions. Further, anadditional advantage of HD-tDCS is the potential to stimulate the hippo-campus through the use of a novel electrode montage developed using

Please cite this article as: Nikolin, S., et al., Focalised stimulation using hinvestigate declarative verbal learning and memory functioning, NeuroIm

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HDTargets™ (Soterix Medical, New York, NY), a commercially availablecomputer modelling software package.

HD-tDCS has previously been investigated as a form of analgesia(Borckardt et al., 2012; Villamar et al., 2013) and for the evaluation ofmotor cortex excitability (Caparelli-Daquer et al., 2012; Kuo et al.,2013), however, to-date has not been investigated to probe neuropsycho-logical functioning.

The primary aim of this study was therefore to investigate, usingfacilitatory anodal HD-tDCS, the specific roles of the LDLPFC, PT, aswell as the contribution of the hippocampus in subserving differentdeclarative verbal learning and memory functions. A secondary aimwas to examine stimulation effects of the different HD-tDCS electrodemontages using our own detailed computer modelling to better under-stand cognitive outcomes. We hypothesised that when given duringperformance on learning trials, focal tDCS applied to the LDLPFC, andstimulation of leftmedial temporal region (including the hippocampus)would improve learning and recall relative to sham, whereas HD-tDCSadministered to the PT would not. Based on previous tDCS studies(Brunoni and Vanderhasselt, 2014), we also hypothesised that focalLDLPFC would improve the speed of working memory.

Materials and methods

Participants

Sixteen healthy right-handed participants (age 21.8 years ± 2.4;8 females) were recruited through a study advertisement placed onthe university website. Handedness was assessed using the Edin-burgh Handedness Questionnaire (Oldfield, 1971). Exclusioncriteria were concurrent medication likely to affect mental perfor-mance (e.g., benzodiazepines or any sedating medications), currenthistory of drug or alcohol abuse or dependence in the last 3 months,any psychiatric or neurological disorder, recent head injury (in thelast 3 months), or history of seizure or stroke. All participants wereeither students of the University of New SouthWales orwere employedin an English speaking environment. This study was approved by theHuman Research Ethics Committee of the University of New SouthWales, Sydney, and performed in accordancewith the principles outlinedin the Australian National Statement of Ethical Conduct in HumanResearch. Written informed consent was obtained from all participantsprior to study commencement.

Study design

The study used a single blind, intra-individual cross-over, sham-controlled experimental design. As the current had to be increasedand decreased manually, and the montages themselves are easilyidentifiable, it was not possible for the investigator to be blinded tothe stimulation condition for each session. Participants were simplytold that four different forms of tDCS were to be given to differentbrain regions, without further detail of expected effects. The order ofstimulation was counterbalanced and randomised across all partici-pants by dividing participants equally into four groups and placingthem into a 4 × 4 Latin Square study design. Participants each complet-ed four sessions, with each session separated by an interval of 1 week inorder to minimise carry-over effects between sessions.

Cognitive tasks

Verbal learning andmemorywere assessed using amodified versionof the Rey Auditory Verbal Learning Test (RAVLT; Taylor, 1959), whichwas administered via computer using a custom-made program devel-opedusing E-Prime (Version 2.0; Psychology Software Tools, Pittsburgh,PA). Participants listened to a recording of 15 nouns presented via head-phones at a rate of oneword every 2 s. Thewordswere presented acrossthree trial blocks; at the end of each trial block participants were asked



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to recall as many words as possible in any order. Delayed recall andrecognition were assessed following a delay of approximately 20 min.The recognition task included the 15 target words interspersed with 15novel words sourced from the first and second halves of the RAVLTword list detailed in Shapiro and Harrison (1990), respectively. Four par-allel versions of the task were used and presented in a counterbalancedorder (Shapiro and Harrison, 1990).

The primary outcome measures were: verbal learning, which wascalculated using the difference in performance between the first trialblock and the best score from the following two trial blocks; total recallscore; delayed recall score; retention (calculated using the delayedrecall score as a percentage of the best recall trial of the three trialblocks); and correct hits during recognition. Primacy, mid-list andrecency learning scores (Ricci et al., 2012) were examined as secondarymemory outcome measures.

To assess possible additional cognitive effects of anodal LDLPFCtDCS (Coffman et al., 2014), two tasks assessing working memoryand sustained attention were administered during the RAVLT20 minute delay period.

Working memory was assessed using a 3-back task which was pre-sented via computer using Inquisit 3 software (Millisecond Software,Seattle, WA). The task used was similar to that described elsewhere(Mull and Seyal, 2001). Briefly, a set of ten letters from A–J weredisplayed for 30ms each at a rate of 2 s per letter. Participants indicatedwhether the letter currently presented matched one shown three trialspreviously by pressing the spacebar key on the keyboard. Participantswere each presented with 30 possible correct responses, where targetswere separated by three to six interposing letters, for an approximatetotal run time of 5 min. Outcomemeasures were the percentage of cor-rect responses, response time for correct responses, and A, a measure ofsensitivity used in signal detection theory (Zhang and Mueller, 2005).

Sustained attention was assessed using an Auditory ContinuousPerformance Task (ACPT), similar to that described by Benson et al.(2008). Participants were asked to attend to auditory stimuli comprisedof three tones of the same frequency (500 Hz), but slightly differingvolumes (86, 75, and 67 dB), and told to select the quietest tone bypressing the spacebar key on the keyboard. The ACPTwas administeredin three 5-minute blocks, each containing 96 stimuli with a randompresentation of 24–38 target stimuli per block. The outcome measuresfor this task were the percentage of correct responses and responsetime for correct responses.

Procedure

Participants began each session by practising the 3-back and theACPT until they reached the criterion of ≥ 50%, and 90% correctresponses, respectively, prior to receiving HD-tDCS. The stimulationcondition was varied each week using different electrode montagesthat resulted in stimulation to the left medial temporal lobe (LMTL);LDLPFC; left PT; and a sham montage (see Fig. 1).

At each session participants were stimulated using tDCS for 20 min,beginning 5 min prior to the commencement of the RAVLT. This delayprior to commencing the verbal memory task was included becauseprevious research has suggested significant effects of tDCS on corticalexcitability following 5 min of stimulation (Nitsche and Paulus, 2000).The three learning trial blocks were presented over a period of approx-imately 5 min. Participants then commenced the ACPT, lasting for15 min, followed by the 3-back task, which lasted approximately5 min. After the 3-back task, participants then completed the delayedrecall and recognition trials of the RAVLT. Fig. 2 shows the experimentaltimeline for each study session.

High definition transcranial direct current stimulation

HD-tDCSwas delivered at 2mA continuously for 20 min using com-mercially available equipment (Soterix Medical, New York, NY). This


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resulted in a current density of ~3.2 A·m−2, which has previously beenfound to elicit no adverse events following 22 min of stimulation (Patelet al., 2009). The current was increased in a ramp-like fashion manuallyover the course of 30–60 s. During the sham stimulation condition oncethe current reached approximately half of the active stimulation value(i.e., 1 mA) it was ramped back down over 30 s and then switched off.A similar procedure has been shown to elicit minimal discomfort and tobe indistinguishable from active stimulation by study participants(Gandiga et al., 2006; Loo et al., 2012; Nitsche et al., 2005). All adjust-ments to the current were conducted out of view behind the participantsand further precautions were taken to cover the machine in use toobscure any visual indications of the level of current used. Participantsreceived one session each of anodal tDCS in a 4 × 1 electrode configura-tion to the LDLPFC (F3 according to the 10–20 system), and PT (Cp5), aswell as a montage of four electrodes specifically designed to achievemaximal stimulation to the left hippocampus, in addition to a shamcondition (see Fig. 1 for the electrode configurations used in this study).Sham stimulation used a montage different to those of the three activeconditions so as to preserve participant blinding. HDTargets™ brainmodelling software (Soterix Medical, New York, NY) was used to deter-mine the tDCSmontage formaximal stimulation to the leftmedial tempo-ral lobe. HDExplore™ (Soterix Medical, New York, NY) was then used tofurther refine and reduce the number of electrodes required to achievemaximal stimulation of this region.

Computational modelling

Sophisticated computational models were also utilised in order tofacilitate this study. A 3D head model of a healthy 35-year-old Asianmalewas reconstructed fromT1-weighted 3 TMRI head scans, acquiredfromNeuroscience Research Australia. Most headmodel compartmentswere electrically homogeneous and isotropic, except for the white mat-ter (Bai et al., 2014). The electric potential φ in the head during tDCSwas calculated using Laplace's equation: ∇∙(−σ∇φ) = 0, where σ isthe electric conductivity tensor. The electric field vector was calculatedfrom the negative gradient of electric potential according to E = −∇φ.Three HD-tDCS montages were simulated: LDLPFC, PT, as well as theLMTL. In each model, the anode delivered a total current of 2 mAthrough the scalp over a round electrode with a radius of 1 cm, whilstthe cathodes, having the same size as the anode, were set as returnelectrodes sharing the same current intensity across all cathodes (withtotal amount of return current being −2 mA). Remaining boundariesof the scalp were set to be electrically insulating, and the bottom ofthe neck was set to electrical ground (0 V). All simulations were under-taken using the COMSOL Multiphysics (v4.3a, COMSOL AB, Sweden)finite-element software package on a PC workstation (Dell Precision)with 24 G RAM.More detailedmethods pertaining to the computationalmodelling can be found in Bai et al. (2014).

Results

Declarative verbal learning and memory

There was no significant main effect of stimulation condition forany of the primary declarative verbal learning and memory outcomemeasures. Planned comparisons which examined the effects of each ofthe three active tDCS conditions compared to sham, however, revealeda significant effect on rate of learning only in the LDLPFC condition[F(1,15) = 6.13, p = 0.03, η2 = 0.29; Fig. 3]. Table 1 shows the resultsfor all primary learning and memory outcome measures.

Secondary analyses examined potential stimulation effects on prima-cy, mid-list, and recency learning (see Table 2). Results similarly showedno significant main effects of condition, although significant differenceswere found between the LMTL and sham conditions for both recency[F(1,15) = 6.78, p = 0.02, η2 = 0.31] and mid-list learning [F(1,15) =8.25, p= 0.01, η2 = 0.39], though not for the other active conditions.



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Fig. 1.Montages used during stimulation, derived from HDExplore™ and HDTargets™ software: A, anodal stimulation to the LDLPFC (anode: F3; cathodes: AF3, F5, FC, FC3). B, Anodal stimu-lation to the PT (anode: Cp5; cathodes: C5, TP7, Cp3, P5). C, Electrode configuration resulting in anodal stimulation of the LMTL (anode: P9; cathodes: Fp1, Fp2, FC4); D, shammontage (anode:F4; cathodes: Cp4, Cp6). E, Model simulation using HDExplore™ of the pattern of current strength associated with the LMTL montage designed to maximally stimulate the left hippocampus.


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The main effect of condition was not statistically significant for anyof the working memory outcome measures. The main effect of orderwas at trend significance and therefore was included as a covariate.Significantly faster response times for correct responses were foundwith LDLPFC stimulation compared to sham [F(1,15) = 7.51, p = 0.02,

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Fig. 2.Experimental procedure. The testing session commenced following completionof practice taPerformance Task.


η2 = 0.35], but not for the LMTL [F(1,15) = 2.04, p = 0.18] or PTstimulation [F(1,15) = 0.63, p = 0.44].

Sustained attention

Themain effect of condition was not statistically significant. Further,planned comparisons showed no significant performance differences

sks (ACPT and3-back). RAVLT, ReyAuditoryVerbal Learning Task; ACPT, Auditory Continuous



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Sham LMTL LDLPFC PT

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Fig. 3. Verbal learning scores, as calculated by the difference between final and initialblocks of the Rey's Auditory Verbal Learning Test (RAVLT), for each stimulationcondition.*p b .05.

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between any of the active stimulation conditions compared to sham onthis cognitive measure. However, LMTL stimulation approached signifi-cance for reduced response times in comparison to sham stimulation[F(1,15) = 3.92, p = 0.07].

Side effects

All but one of the participants tolerated the stimulation well. Sideeffects consisted of erythema, two instances of headache (one later inthe evening following the LMTL condition, and one following shamstimulation), as well as sensations of mild stinging, itching, and irrita-tion during stimulation. These effects were observed in both activeand sham conditions and were transient in nature, resolving on theirownwith no intervention. One participant reported a “needle-pricking”sensation whist receiving LDLPFC HD-tDCS and subsequently withdrewfrom the study.

Computer modelling

Fig. 4 shows the profile of brain electric field magnitude in the headmodel for the three HD-tDCS montages: LDLPFC, PT, and LMTL. Thedistribution of brain electrical fields generated using 4 × 1 ring config-urations (i.e. for LDLPFC and PT stimulation) was in good agreementwith results obtained using the targeting software HDTargets™ (SoterixMedical, New York, NY), and showed localised stimulation with peaksdirectly beneath the anode and current restrictedwithin the boundaries

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Table 1Cognitive test results.

Group, means (S.E.M.)

Measure Sham LMTL LDLPFC PT

RAVLTTotal 33.6 (1.4) 32.3 (1.6) 32.6 (1.4) 31.6Learning 3.9 (0.4) 4.4 (0.5) 5.2 (0.5) 4.1Delayed recall 11.1 (0.5) 11.6 (0.9) 11.5 (0.7) 10.8Retention 0.87 (0.03) 0.90 (0.05) 0.88 (0.04) 0.85Recognition 13.9 (0.3) 13.8 (0.5) 13.6 (0.4) 13.8

3-Backa

A 0.91 (0.02) 0.90 (0.02) 0.92 (0.02) 0.91RT (ms) 729 (33.3) 730 (42.8) 698 (45.3) 729

ACPTTarget hits (%) 0.84 (0.03) 0.88 (0.03) 0.87 (0.03) 0.83RT (ms) 876 (48.5) 814 (37.1) 847 (45.3) 999

LMTL, left medial temporal lobe; LDLPFC, left dorsolateral prefrontal cortex; PT, planum tempoTask; RT, response time.

a Analysis included order as a covariate.⁎ p b .05 (uncorrected for multiple comparisons).


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of the return electrodes. In agreement with preliminary modelling usedto calculate electrode montages, further modelling showed that themontage developed for preferential stimulation of the LMTL excitedlarge areas of the left temporal lobe and prefrontal cortex. Electricfield magnitude at the left hippocampus was estimated to be approxi-mately 0.16 V·m−1.

Discussion

This study investigated the effects of a theoretically more focal formof tDCS (HD-tDCS) applied to critical brain regions which subservedeclarative verbal learning and memory functioning. This is the firstapplication of HD-tDCS to probe neuropsychological functioning and ex-amine the effects on different declarative verbal learning and memoryfunctions. Results showed no significant main effects of stimulation con-dition across either learning andmemory or cognitive outcomemeasures.Secondary analyses, however, revealed that significant cognitive effectsoccurred in the LDLPFC condition, with focal LDLPFC stimulation shownto increase the rate of verbal learning and speedofworkingmemory func-tioning compared to sham.

To our knowledge only one previous study has directly investigatedthe effect of LDLPFC tDCS stimulation on learning for declarative verbalmemory. Using a similar experimental paradigm to the current study,Elmer et al. (2009) found that cathodal tDCS inhibited verbal learning,although there was no effect of anodal tDCS. Although similar method-ologically, the current study differed in several key aspects, which mayhave contributed to the different results. Elmer et al. (2009) used ashorter duration of stimulation, 5 min compared to 20 min in thisstudy, and tDCS was commenced concurrently with verbal learning,whilst in the current study learning was initiated following 5 min ofstimulation. The current results, however, are in line with Elmer et al.(2009) in demonstrating that verbal learning can be directly modulatedthrough tDCS stimulation of the LDLPFC. In addition, our results extendthis research to suggest that more focal anodal tDCS stimulation of theLDLPFC can be used to increase the rate of verbal learning. Similar toElmer et al. (2009), we found that these effects were specific to short-term learning, with no effects on delayed memory or recognition.

Other studies have reported significant effects of LDLPFC stimulationon longer-termmemory outcomes,with improved recognition accuracy(Javadi et al., 2012; Javadi and Walsh, 2012) and retention (Marshallet al., 2004) previously found following delays ranging from 60 to90 min. Speculatively, it is possible that the use of different tDCS elec-trode montages between studies may account for these findings, asboth Javadi et al. (2012) and (Marshall et al., 2004) used montageswhich would have additionally stimulated medial temporal regions

Sham vs. LMTL Sham vs. LDLPFC Sham vs. PT

F p F p F p

(1.9) 0.70 0.42 0.64 0.44 1.67 0.22(0.5) 1.06 0.32 6.13 0.03⁎ 0.14 0.72(0.9) 0.34 0.57 0.48 0.50 0.31 0.59(0.04) 0.56 0.47 0.09 0.77 0.33 0.57(0.3) 0.03 0.88 0.28 0.60 0.11 0.74

(0.02) 0.72 0.41 2.70 0.12 0.50 0.49(48.8) 2.04 0.18 7.51 0.02⁎ 0.63 0.44

(0.03) 1.63 0.22 2.09 0.17 0.09 0.76(136) 3.92 0.07 1.71 0.21 0.93 0.35

rale; RAVLT, Rey Auditory Verbal Learning Task; ACPT Auditory Continuous Performance



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t2:1Q2 Table 2t2:2 Results for secondary learning outcome measures. The proportion of words recalled in the first, middle, or final thirds of the RAVLT word list compared to the total number of wordst2:3 recalled were calculated to identify the primacy, mid-list, and recency effects respectively.

t2:4 Group, means (S.E.M.)

t2:5 Sham vs. LMTL Sham vs. LDLPFC Sham vs. PT

t2:6 Measure Sham LMTL LDLPFC PT p p p

t2:7 RAVLTt2:8 Primacy effect 0.385 (0.016) 0.361 (0.011) 0.376 (0.021) 0.373 (0.012) 0.12 0.69 0.52t2:9 Mid-list effect 0.325 (0.009) 0.277 (0.020) 0.304 (0.015) 0.299 (0.022) 0.01⁎ 0.16 0.22t2:10 Recency effect 0.290 (0.014) 0.357 (0.021) 0.320 (0.021) 0.331 (0.020) 0.02⁎ 0.17 0.15

t2:11 RAVLT, Rey Auditory Verbal Learning Task; LMTL, left medial temporal lobe; LDLPFC, left dorsolateral prefrontal cortex; PT, planum temporale.t2:12 ⁎ p b .05 (uncorrected for multiple comparisons).


involved in memory consolidation and retrieval processes. In addition,the relatively shorter delay period (i.e., 20 min) used both in the currentstudy and Elmer et al. (2009) could have resulted in a ceiling effect andthus limited the potential to observe effects on retention or retrieval.

Alternatively, the specificity of the current effects on rate of learningcould instead suggest a facilitatory role of LDLPFC tDCS on verbal workingmemory processing. Consistent with this interpretation was the concur-rent finding of significantly faster correct working memory responsetimes with focal LDLPFC stimulation. No effect, however, was found onperformance accuracy, suggesting a selective benefit onworkingmemory

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Fig. 4. Computational simulation results of three HD-tDCSmontages: LDLPFC (left), PT (middle)m) in the brain. Red, white and black arrows indicate the locations of the LDLPFC, PT and the l


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previous tDCS research, including a recent meta-analysis evaluating theeffect of anodal tDCS given to the LDLPFC showing improved speed, butnot performance accuracy (Brunoni and Vanderhasselt, 2014; Zaehleet al., 2011). In addition, no effect was found on sustained attention, indi-cating that this effect was specific to working memory. Peak functionalactivation has been shown to occur within the DLPFC during workingmemory tasks, specifically during continuous updating and temporalorder processing (Wager and Smith, 2003). It is therefore possible thatincreased speed or efficiency of these functions within working memory

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and LMTL (right). The figure presents the distribution of electric field magnitude (unit: V/eft hippocampus respectively.



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may therefore account for the significantly faster rate of learning observedon the declarative verbal memory task.

Unexpectedly, no effect of LMTL stimulation was found on anydeclarative verbal learning and memory outcome measure. This isdespite observations of improved list learning rates in subjects withlarger intracranial proportions of the medial temporal lobe (Fernaeuset al., 2013), and conversely, impaired encoding and storage of verbalinformation in patients presenting with medial temporal lobe atrophy(Boon et al., 2011). Increased LMTL functional activity has furtherbeen demonstrated during word encoding in imaging studies (Leubeet al., 2001; Parsons et al., 2006; Powell et al., 2005).

The LMTL montage was initially adopted in order to stimulate the lefthippocampus, as a large body of evidence from both lesion and neuroim-aging research indicated that the hippocampi, specifically the left hippo-campus, are functionally important for verbal learning and recall(Breitenstein et al., 2004; Grasby et al., 1993; Meinzer et al., 2010; Opitzand Friederici, 2003). A possible explanation for this negative result isthat the montage used did not adequately stimulate the hippocampus.The experimental tDCS montage chosen to target the left hippocampuswas based on computer modelling which is yet to be physiologicallyvalidated. Indeed, results from the more detailed computer modellingshowed that the hippocampal montage, rather than focally targeting theleft hippocampus, additionally stimulated large portions of the left tem-poral lobe aswell as the prefrontal cortex. Thismodelling further estimat-ed stimulation at the left hippocampus to be modest, only 0.16 V·m−1,approximately half the electric field magnitude observed elsewhere inthe brain (notably posterior left perisylvian areas) using the same mon-tage. Notwithstanding, the degree of stimulation observed in the medialleft temporal lobe shown with the detailed modelling, and the relativelylarge volume of the hippocampus (approximately 7.5 cm3 in healthyyoung adults (Raz et al., 2005)) together suggest that some hippocampalstimulation was achieved.

This interpretation is supported by the results of analyses of learningeffects which revealed significant recency and reduced mid-list effectsspecific to the LMTL stimulation condition. It is possible that greaterrecency effects may have occurred due to improved retrieval of thelater items in the word list from hippocampal stimulation, as increasedactivation has been previously shown duringworkingmemory retrieval(Öztekin et al., 2009). Alternatively, recency effects have also been welldocumented to occur in patients with mild cognitive impairment andAlzheimer's dementia (Martín et al., 2013; Orru et al., 2009), both ofwhich present with hippocampal atrophy (Visser et al., 2002). In addi-tion, reduced recall performance on the middle portion of word listtasks has been found to occur with partial resection of the left anteriortemporal lobe (Hermann et al., 1992). This pattern of results maytherefore be interpreted to suggest an inhibitory effect of left hippo-campal stimulation, which in turn disrupted the pattern of learning.Further research is therefore required both to confirm this result andto investigate potential effects on declarative verbal memory out-comes using alternative timing of stimulation (e.g., during retentionor retrieval).

Similarly, no significant effects on declarative verbal learning andmemory were found with focal stimulation of the PT. This is in contrastto previous tDCS research showing improved learning and retrieval onverbal memory tasks (Fiori et al., 2011; Flöel et al., 2008), and neuroim-aging work showing temporal regions, including the PT, as particularlyactive during semantic processing (Vigneau et al., 2006). There aretwo possible explanations that may account for this result. Firstly, thePT itself might not be important for verbal memory performance; rather,diffuse stimulation of nearby or more distal regions may be responsiblefor the previously observed improvements in cognitive functioning. An-odal tDCS to the left posterior parietal cortex, a region further posteriorto the PT, has been demonstrated to improve the rate of list learningand delayed recall using a similar declarative verbal memory list learningtask (Jones et al., 2014). Past studies using standard tDCS electrodesplaced at the location of the PT (Cp5) could have activated similar


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posterior regions, whereas with HD-tDCS, due to its high spatial resolu-tion, stimulation is far more specific. For example, Flöel et al. (2008)employed standard 5 × 7 cm electrodes spaced widely apart whereas inthe current study the anode and other electrodes were approximately2 cm in diameter and arranged in a 4 × 1 montage, which has been sug-gested by computer modelling to produce much more focal, and lessdeeply penetrating, cortical stimulation (Datta et al., 2009). The PT isknown to behighly interconnectedwith frontal cortical regions via the ar-cuate fasciculus, whose integrity has been found to be important for newverbal learning (López-Barroso et al., 2013). The focal stimulation of thePT achieved in the current study therefore may not have been sufficientto modulate this network and thus cause effects on either learning or re-call. Alternatively, the placement of the anode used in the PT montagemay also have not been optimal to achieve effects on memory.Caparelli-Daquer et al. (2012) showed using a series of HD-tDCS comput-er simulations that, in comparisonwith standard tDCS electrode position-ing, small deviations fromoptimal placement can result in vastly differentresponses from participants due to the highly focal nature of the stimula-tion. Future studies may benefit from using neuroimaging andneuronavigational software to account for inter-individual neuroanatom-ical variability andmore accurately identify the precise location of regionsof interest for focal tDCS stimulation.

There were several limitations to our study. Firstly, findings mayhave been limited by ceiling effects on the declarative verbal learningtask. For example, results showed that by the third learning trial onthe task, 6/16 participants had reached a ceiling level of performancein the LDLPFC condition compared to the other conditions (3/16 in thePT condition, and 2/16 in both sham and LMTL conditions). Hence, theeffect size calculated for the LDLPFC condition on rate of verbal learning,although large, may have been an underestimate as further learningmay have occurred had there been greater number of stimuli. Previousstudies which have used the same declarative verbal memory test in acomparable cohort of young and educated participants have similarlyobserved ceiling effects (Uttl, 2005; Van Der Elst et al., 2005). Futurestudies may benefit from the use of a greater number of stimuli andlonger delay periods to avoid such effects. Further, the administrationof additional trials to assess learning rates should be considered, aslearning rate calculations may be affected by limited trials due tounderperformance on the first trial block. Lastly, the computer model-ling software used to develop the electrode montages employed in thecurrent study was based on commercially available software and thefocal targeting of subcortical regions, including the hippocampus, isyet to be physiologically validated. Thus, both inter-individual differ-ences in brain anatomy coupled with potential inaccuracies in themodelling may have affected outcomes.

Conclusions

In conclusion, to our knowledge this research represents the firstattempt to probe the functional roles of critical brain structuressubserving declarative verbal learning and memory functioningusing a more focal form of tDCS (HD-tDCS). Previously, HD-tDCS hadonly been explored for use in pain management (Borckardt et al.,2012; Villamar et al., 2013) and evaluating motor cortex excitability(Caparelli-Daquer et al., 2012; Kuo et al., 2013). The current resultsshow initial support for the utility of HD-tDCS to probe neuropsycho-logical functioning of focal cortical regions; however, additional workis required to further develop this method to achieve effective stimula-tion of deeper brain regions, such as the hippocampus. Large effect sizesfound for HD-tDCS LDLPFC stimulation on the rate of declarative verballearning and speed of working memory functioning, however, indicatethat HD-tDCS when given to the LDLPFCmay be beneficial for cognitiveenhancement and remediation purposes. Further investigation istherefore warranted to evaluate the cognitive enhancing potential ofHD-tDCS.



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Acknowledgments

The authorswould like to thank SoterixMedical for providing accessto HD-tDCS software (HDExplore™ and HDTargets™) necessary toconduct this study. The efforts of Dr Abhishek Datta are acknowledgedfor assistance in developing the montages used.

Conflict of interestColleen Loo was provided with tDCS equipment from Soterix for a

clinical trial unrelated to this study. The remaining authors declare nocompeting financial interests.

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Focalised stimulation using high definition transcranial direct current stimulation (HD-tDCS) to investigate declarative verbal learning and memory functioning

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