NeuroImage 117 (2015) 11–19

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Focalised stimulation using high definition transcranial direct current stimulation (HD-tDCS) to investigate declarative verbal learning and memory functioning 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, Australia St. George Hospital, Sydney, Australia c Faculty of Engineering, University of New South Wales, Sydney, Australia d IMETUM, Technische Universität München, 85748 Garching, Germany b

a r t i c l e

i n f o

Article history: Received 7 January 2015 Accepted 7 May 2015 Available online 15 May 2015 Keywords: High definition transcranial direct current stimulation Declarative verbal memory Left dorsolateral prefrontal cortex Left medial temporal lobe Planum temporale

a b s t r a c t Background: Declarative verbal learning and memory are known to be lateralised to the dominant hemisphere and to be subserved by a network of structures, including those located in frontal and temporal regions. These structures support critical components of verbal memory, including working memory, encoding, and retrieval. Their relative functional 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 learning and memory performance by applying a more focal form of transcranial direct current stimulation, “High Definition tDCS” (HD-tDCS). Additionally, we sought to examine HD-tDCS effects and electrical field intensity distributions using computer modelling. Methods: HD-tDCS was administered to the left dorsolateral prefrontal cortex (LDLPFC), planum temporale (PT), and left medial temporal lobe (LMTL) to stimulate the hippocampus, during learning on a declarative verbal memory task. 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 attention were additionally examined. Results: HD-tDCS to the LDLPFC significantly improved the rate of verbal learning (p = 0.03, η2 = 0.29) and speed of responding during working memory performance (p = 0.02, η2 = 0.35), but not accuracy (p = 0.12, η2 = 0.16). No effect 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 reduced mid-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 working memory may underlie performance effects. This focal method of administrating tDCS has potential for probing and enhancing cognitive functioning. © 2015 Elsevier Inc. All rights reserved.

Introduction New verbal learning is essential for the acquisition of language and auditory information and is known to be subserved by a bilateral network of brain structures with functional processing largely lateralised to the dominant hemisphere (Golby et al., 2001; Vigneau et al., 2006, 2011). Neuropsychological and brain lesion studies have consistently demonstrated that declarative verbal learning and memory is affected when damage occurs to key frontal and temporal regions including the prefrontal cortex and medial temporal lobe (Zola-Morgan et al., 1986, 1994). Functional neuroimaging studies have implicated left ⁎ Corresponding author at: Black Dog Institute, Hospital Road, Randwick NSW 2031, Australia. E-mail address: [email protected] (D.M. Martin).

http://dx.doi.org/10.1016/j.neuroimage.2015.05.019 1053-8119/© 2015 Elsevier Inc. All rights reserved.

lateralised structures in the encoding and retrieval of new memories (Cabeza and Nyberg, 2000), as well as language processing related areas, such as the planum temporale (PT; commonly referred to as Wernicke's area) (Fletcher et al., 1995; Kikyo et al., 2001; López-Barroso et al., 2013). The left dorsolateral prefrontal cortex (LDLPFC), which is functionally involved in the manipulation and organisation of information in verbal working memory (Barbey et al., 2013; Nyberg et al., 2003) and retrieval processes (Cabeza et al., 2002; Kikyo et al., 2001), and the hippocampus, which is important for working memory, encoding and consolidation (Nadel and Hardt, 2011), are theoretically considered to play key roles across the different memory functions of encoding, retention, and retrieval. It is generally thought that new verbal memories are initially maintained and manipulated within working memory (Baddeley, 2000; Gathercole, 1999), encoded and stored via medial temporal structures including the hippocampus (McClelland and Goddard, 1996), and

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S. Nikolin et al. / NeuroImage 117 (2015) 11–19

subsequently retrieved through structures similarly engaged during encoding (i.e., left prefrontal and medial temporal regions) (Danker and Anderson, 2010). The PT, whilst functionally important for phonological processing, however, is thought to be more involved in word retrieval (Yagishita et al., 2008). These theoretical assumptions have yet to be directly tested using non-invasive methods which can selectively enhance and/or depress functioning, particularly in deeper regions such as the hippocampus. Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which involves passing a low level current between stimulation and reference electrodes placed upon the scalp (Gandiga et al., 2006). Anodal stimulation, that is, stimulation using a positively charged electrode, increases the rate of spontaneous neural firing in underlying brain regions (Nitsche et al., 2008) and is thought to cause synaptic neuroplastic changes via LTP-like, NMDA receptor-dependent mechanisms that can last up to an hour (Liebetanz et al., 2002; Nitsche et al., 2004). These neuromodulatory effects are considered to underlie tDCS related improvements in learning and memory obtained across various stimulus modalities, including motor (Antal et al., 2004; Nitsche et al., 2003; Reis et al., 2009), visual (Chi et al., 2010; Clark et al., 2012), and verbal (De Vries et al., 2010; Elmer et al., 2009; Flöel et al., 2008; Javadi and Walsh, 2012). These promising findings have helped to establish tDCS as a new technique to modulate and enhance brain functioning, with potential treatment applications in rehabilitation for brain illness or injury (Baker et al., 2010; Monti et al., 2008) and enhancing education and training (Clark et al., 2012; Martin et al., 2013). Previous studies using tDCS to enhance verbal memory have varied in their approach, primarily through focussing on different sites of stimulation (i.e., LDLPFC: Elmer et al., 2009; Javadi et al., 2012; Javadi and Walsh, 2012; Marshall et al., 2004; PT: Fiori et al., 2011; Flöel et al., 2008; Jones et al., 2014; motor cortex: Liuzzi et al., 2010). Correspondingly, findings have varied between studies, with differential facilitatory effects found on specific memory functions, namely encoding (Flöel et al., 2008), retention (Marshall et al., 2004) and retrieval (Javadi et al., 2012; Javadi and Walsh, 2012). For declarative verbal learning and memory, specifically, research has focussed on stimulating the LDLPFC, and similarly, differential effects on memory functions have been reported (Elmer et al., 2009; Javadi et al., 2012; Javadi and Walsh, 2012; Marshall et al., 2004). The optimal tDCS methodology for enhancing specific declarative verbal learning and memory functions therefore remains to be determined. An important limitation to understanding reported effects is the diffuse nature of the stimulatory effects of modern tDCS methods, whereby due to the large electrodes and spacing of these electrodes upon the scalp both the targeted brain region as well as surrounding and interconnected structures are directly affected (Bai et al., 2014; Nathan et al., 1993). Hence it remains unclear whether reported effects are due to stimulation of the targeted cortical region, or surrounding or more distal structures. In the present study we therefore applied a method of tDCS stimulation shown to be more focal in computer modelling studies, high definition tDCS (HD-tDCS), to better localise the effects of stimulation (Datta et al., 2009; Kuo et al., 2013). This focalised method of tDCS using a 4 × 1 ring electrode configuration to stimulate outer cortical regions has been demonstrated to restrict upwards of 30% of the stimulation peak within the perimeter of the ring montage using computer modelling (Edwards et al., 2013). Edwards et al. (2013) have validated their computer modelling experimentally using an identical 4 × 1 ring electrode configuration to deliver supra-threshold stimulation of approximately 500–2000 mA to the motor cortex whilst measuring motor evoked potentials (MEPs) in the hand. More focalised stimulation would therefore allow for improved specificity in determining the relative role of critical cortical areas in subserving the different learning and memory functions. Further, an additional advantage of HD-tDCS is the potential to stimulate the hippocampus through the use of a novel electrode montage developed using

HDTargets™ (Soterix Medical, New York, NY), a commercially available computer 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 of motor cortex excitability (Caparelli-Daquer et al., 2012; Kuo et al., 2013), however, to-date has not been investigated to probe neuropsychological functioning. The primary aim of this study was therefore to investigate, using facilitatory anodal HD-tDCS, the specific roles of the LDLPFC, PT, as well as the contribution of the hippocampus in subserving different declarative verbal learning and memory functions. A secondary aim was to examine stimulation effects of the different HD-tDCS electrode montages using our own detailed computer modelling to better understand cognitive outcomes. We hypothesised that when given during performance on learning trials, focal tDCS applied to the LDLPFC, and stimulation of left medial temporal region (including the hippocampus) would improve learning and recall relative to sham, whereas HD-tDCS administered to the PT would not. Based on previous tDCS studies (Brunoni and Vanderhasselt, 2014), we also hypothesised that focal LDLPFC 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 on the university website. Handedness was assessed using the Edinburgh Handedness Questionnaire (Oldfield, 1971). Exclusion criteria were concurrent medication likely to affect mental performance (e.g., benzodiazepines or any sedating medications), current history of drug or alcohol abuse or dependence in the last 3 months, any psychiatric or neurological disorder, recent head injury (in the last 3 months), or history of seizure or stroke. All participants were either students of the University of New South Wales or were employed in an English speaking environment. This study was approved by the Human Research Ethics Committee of the University of New South Wales, Sydney, and performed in accordance with the principles outlined in the Australian National Statement of Ethical Conduct in Human Research. Written informed consent was obtained from all participants prior to study commencement. Study design The study used a single blind, intra-individual cross-over, shamcontrolled experimental design. As the current had to be increased and decreased manually, and the montages themselves are easily identifiable, it was not possible for the investigator to be blinded to the stimulation condition for each session. Participants were simply told that four different forms of tDCS were to be given to different brain regions, without further detail of expected effects. The order of stimulation was counterbalanced and randomised across all participants by dividing participants equally into four groups and placing them into a 4 × 4 Latin Square study design. Participants each completed four sessions, with each session separated by an interval of 1 week in order to minimise carry-over effects between sessions. Cognitive tasks Verbal learning and memory were assessed using a modified version of the Rey Auditory Verbal Learning Test (RAVLT; Taylor, 1959), which was administered via computer using a custom-made program developed using E-Prime (Version 2.0; Psychology Software Tools, Pittsburgh, PA). Participants listened to a recording of 15 nouns presented via headphones at a rate of one word every 2 s. The words were presented across three trial blocks; at the end of each trial block participants were asked

S. Nikolin et al. / NeuroImage 117 (2015) 11–19

to recall as many words as possible in any order. Delayed recall and recognition were assessed following a delay of approximately 20 min. The recognition task included the 15 target words interspersed with 15 novel words sourced from the first and second halves of the RAVLT word list detailed in Shapiro and Harrison (1990), respectively. Four parallel versions of the task were used and presented in a counterbalanced order (Shapiro and Harrison, 1990). The primary outcome measures were: verbal learning, which was calculated using the difference in performance between the first trial block and the best score from the following two trial blocks; total recall score; delayed recall score; retention (calculated using the delayed recall score as a percentage of the best recall trial of the three trial blocks); and correct hits during recognition. Primacy, mid-list and recency learning scores (Ricci et al., 2012) were examined as secondary memory outcome measures. To assess possible additional cognitive effects of anodal LDLPFC tDCS (Coffman et al., 2014), two tasks assessing working memory and sustained attention were administered during the RAVLT 20 minute delay period. Working memory was assessed using a 3-back task which was presented 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 were displayed for 30 ms each at a rate of 2 s per letter. Participants indicated whether the letter currently presented matched one shown three trials previously by pressing the spacebar key on the keyboard. Participants were each presented with 30 possible correct responses, where targets were separated by three to six interposing letters, for an approximate total run time of 5 min. Outcome measures were the percentage of correct responses, response time for correct responses, and A, a measure of sensitivity used in signal detection theory (Zhang and Mueller, 2005). Sustained attention was assessed using an Auditory Continuous Performance Task (ACPT), similar to that described by Benson et al. (2008). Participants were asked to attend to auditory stimuli comprised of three tones of the same frequency (500 Hz), but slightly differing volumes (86, 75, and 67 dB), and told to select the quietest tone by pressing the spacebar key on the keyboard. The ACPT was administered in three 5-minute blocks, each containing 96 stimuli with a random presentation of 24–38 target stimuli per block. The outcome measures for this task were the percentage of correct responses and response time for correct responses. Procedure Participants began each session by practising the 3-back and the ACPT until they reached the criterion of ≥ 50%, and 90% correct responses, respectively, prior to receiving HD-tDCS. The stimulation condition was varied each week using different electrode montages that 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 delay prior to commencing the verbal memory task was included because previous research has suggested significant effects of tDCS on cortical excitability following 5 min of stimulation (Nitsche and Paulus, 2000). The three learning trial blocks were presented over a period of approximately 5 min. Participants then commenced the ACPT, lasting for 15 min, followed by the 3-back task, which lasted approximately 5 min. After the 3-back task, participants then completed the delayed recall and recognition trials of the RAVLT. Fig. 2 shows the experimental timeline for each study session. High definition transcranial direct current stimulation HD-tDCS was delivered at 2 mA continuously for 20 min using commercially 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 been found to elicit no adverse events following 22 min of stimulation (Patel et al., 2009). The current was increased in a ramp-like fashion manually over the course of 30–60 s. During the sham stimulation condition once the 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 to be indistinguishable from active stimulation by study participants (Gandiga et al., 2006; Loo et al., 2012; Nitsche et al., 2005). All adjustments to the current were conducted out of view behind the participants and further precautions were taken to cover the machine in use to obscure any visual indications of the level of current used. Participants received one session each of anodal tDCS in a 4 × 1 electrode configuration to the LDLPFC (F3 according to the 10–20 system), and PT (Cp5), as well as a montage of four electrodes specifically designed to achieve maximal stimulation to the left hippocampus, in addition to a sham condition (see Fig. 1 for the electrode configurations used in this study). Sham stimulation used a montage different to those of the three active conditions so as to preserve participant blinding. HDTargets™ brain modelling software (Soterix Medical, New York, NY) was used to determine the tDCS montage for maximal stimulation to the left medial temporal lobe. HDExplore™ (Soterix Medical, New York, NY) was then used to further refine and reduce the number of electrodes required to achieve maximal stimulation of this region. Computational modelling Sophisticated computational models were also utilised in order to facilitate this study. A 3D head model of a healthy 35-year-old Asian male was reconstructed from T1-weighted 3 T MRI head scans, acquired from Neuroscience Research Australia. Most head model compartments were electrically homogeneous and isotropic, except for the white matter (Bai et al., 2014). The electric potential φ in the head during tDCS was calculated using Laplace's equation: ∇∙(− σ∇φ) = 0, where σ is the electric conductivity tensor. The electric field vector was calculated from the negative gradient of electric potential according to E = −∇φ. Three HD-tDCS montages were simulated: LDLPFC, PT, as well as the LMTL. In each model, the anode delivered a total current of 2 mA through the scalp over a round electrode with a radius of 1 cm, whilst the cathodes, having the same size as the anode, were set as return electrodes sharing the same current intensity across all cathodes (with total amount of return current being − 2 mA). Remaining boundaries of the scalp were set to be electrically insulating, and the bottom of the neck was set to electrical ground (0 V). All simulations were undertaken using the COMSOL Multiphysics (v4.3a, COMSOL AB, Sweden) finite-element software package on a PC workstation (Dell Precision) with 24 G RAM. More detailed methods pertaining to the computational modelling can be found in Bai et al. (2014). Results Declarative verbal learning and memory There was no significant main effect of stimulation condition for any of the primary declarative verbal learning and memory outcome measures. Planned comparisons which examined the effects of each of the three active tDCS conditions compared to sham, however, revealed a 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 results for all primary learning and memory outcome measures. Secondary analyses examined potential stimulation effects on primacy, mid-list, and recency learning (see Table 2). Results similarly showed no significant main effects of condition, although significant differences were found between the LMTL and sham conditions for both recency [F(1,15) = 6.78, p = 0.02, η 2 = 0.31] and mid-list learning [F(1,15) = 8.25, p = 0.01, η 2 = 0.39], though not for the other active conditions.

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S. Nikolin et al. / NeuroImage 117 (2015) 11–19

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 stimulation 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, sham montage (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.

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

η2 = 0.35], but not for the LMTL [F(1,15) = 2.04, p = 0.18] or PT stimulation [F(1,15) = 0.63, p = 0.44]. Sustained attention The main effect of condition was not statistically significant. Further, planned comparisons showed no significant performance differences

Fig. 2. Experimental procedure. The testing session commenced following completion of practice tasks (ACPT and 3-back). RAVLT, Rey Auditory Verbal Learning Task; ACPT, Auditory Continuous Performance Task.

S. Nikolin et al. / NeuroImage 117 (2015) 11–19

*

RAVLT Learning Score

6

15

of the return electrodes. In agreement with preliminary modelling used to calculate electrode montages, further modelling showed that the montage developed for preferential stimulation of the LMTL excited large areas of the left temporal lobe and prefrontal cortex. Electric field magnitude at the left hippocampus was estimated to be approximately 0.16 V·m−1.

5 4 3

Discussion

2

This study investigated the effects of a theoretically more focal form of tDCS (HD-tDCS) applied to critical brain regions which subserve declarative verbal learning and memory functioning. This is the first application of HD-tDCS to probe neuropsychological functioning and examine the effects on different declarative verbal learning and memory functions. Results showed no significant main effects of stimulation condition across either learning and memory or cognitive outcome measures. Secondary analyses, however, revealed that significant cognitive effects occurred in the LDLPFC condition, with focal LDLPFC stimulation shown to increase the rate of verbal learning and speed of working memory functioning compared to sham. To our knowledge only one previous study has directly investigated the effect of LDLPFC tDCS stimulation on learning for declarative verbal memory. 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 methodologically, the current study differed in several key aspects, which may have contributed to the different results. Elmer et al. (2009) used a shorter duration of stimulation, 5 min compared to 20 min in this study, and tDCS was commenced concurrently with verbal learning, whilst in the current study learning was initiated following 5 min of stimulation. The current results, however, are in line with Elmer et al. (2009) in demonstrating that verbal learning can be directly modulated through tDCS stimulation of the LDLPFC. In addition, our results extend this research to suggest that more focal anodal tDCS stimulation of the LDLPFC can be used to increase the rate of verbal learning. Similar to Elmer et al. (2009), we found that these effects were specific to shortterm learning, with no effects on delayed memory or recognition. Other studies have reported significant effects of LDLPFC stimulation on longer-term memory outcomes, with improved recognition accuracy (Javadi et al., 2012; Javadi and Walsh, 2012) and retention (Marshall et al., 2004) previously found following delays ranging from 60 to 90 min. Speculatively, it is possible that the use of different tDCS electrode montages between studies may account for these findings, as both Javadi et al. (2012) and (Marshall et al., 2004) used montages which would have additionally stimulated medial temporal regions

1 0 Sham

LMTL

LDLPFC

PT

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

between any of the active stimulation conditions compared to sham on this cognitive measure. However, LMTL stimulation approached significance 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. Side effects consisted of erythema, two instances of headache (one later in the evening following the LMTL condition, and one following sham stimulation), as well as sensations of mild stinging, itching, and irritation during stimulation. These effects were observed in both active and sham conditions and were transient in nature, resolving on their own with no intervention. One participant reported a “needle-pricking” sensation whist receiving LDLPFC HD-tDCS and subsequently withdrew from the study. Computer modelling Fig. 4 shows the profile of brain electric field magnitude in the head model for the three HD-tDCS montages: LDLPFC, PT, and LMTL. The distribution of brain electrical fields generated using 4 × 1 ring configurations (i.e. for LDLPFC and PT stimulation) was in good agreement with results obtained using the targeting software HDTargets™ (Soterix Medical, New York, NY), and showed localised stimulation with peaks directly beneath the anode and current restricted within the boundaries Table 1 Cognitive test results. Group, means (S.E.M.)

Measure RAVLT Total Learning Delayed recall Retention Recognition 3-Backa A RT (ms) ACPT Target hits (%) RT (ms)

Sham vs. LMTL

Sham vs. LDLPFC

Sham vs. PT

Sham

LMTL

LDLPFC

PT

F

p

F

p

F

p

33.6 (1.4) 3.9 (0.4) 11.1 (0.5) 0.87 (0.03) 13.9 (0.3)

32.3 (1.6) 4.4 (0.5) 11.6 (0.9) 0.90 (0.05) 13.8 (0.5)

32.6 (1.4) 5.2 (0.5) 11.5 (0.7) 0.88 (0.04) 13.6 (0.4)

31.6 (1.9) 4.1 (0.5) 10.8 (0.9) 0.85 (0.04) 13.8 (0.3)

0.70 1.06 0.34 0.56 0.03

0.42 0.32 0.57 0.47 0.88

0.64 6.13 0.48 0.09 0.28

0.44 0.03⁎ 0.50 0.77 0.60

1.67 0.14 0.31 0.33 0.11

0.22 0.72 0.59 0.57 0.74

0.91 (0.02) 729 (33.3)

0.90 (0.02) 730 (42.8)

0.92 (0.02) 698 (45.3)

0.91 (0.02) 729 (48.8)

0.72 2.04

0.41 0.18

2.70 7.51

0.12 0.02⁎

0.50 0.63

0.49 0.44

0.84 (0.03) 876 (48.5)

0.88 (0.03) 814 (37.1)

0.87 (0.03) 847 (45.3)

0.83 (0.03) 869 (49.2)

1.63 3.92

0.22 0.07

2.09 1.71

0.17 0.21

0.09 0.05

0.76 0.83

LMTL, left medial temporal lobe; LDLPFC, left dorsolateral prefrontal cortex; PT, planum temporale; RAVLT, Rey Auditory Verbal Learning Task; ACPT Auditory Continuous Performance Task; RT, response time. a Analysis included order as a covariate. ⁎ p b .05 (uncorrected for multiple comparisons).

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S. Nikolin et al. / NeuroImage 117 (2015) 11–19

Table 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 words recalled were calculated to identify the primacy, mid-list, and recency effects respectively. Group, means (S.E.M.) Sham vs. LMTL

Sham vs. LDLPFC

Sham vs. PT

Measure

Sham

LMTL

LDLPFC

PT

p

p

p

RAVLT Primacy effect Mid-list effect Recency effect

0.385 (0.016) 0.325 (0.009) 0.290 (0.014)

0.361 (0.011) 0.277 (0.020) 0.357 (0.021)

0.376 (0.021) 0.304 (0.015) 0.320 (0.021)

0.373 (0.012) 0.299 (0.022) 0.331 (0.020)

0.12 0.01⁎ 0.02⁎

0.69 0.16 0.17

0.52 0.22 0.15

RAVLT, Rey Auditory Verbal Learning Task; LMTL, left medial temporal lobe; LDLPFC, left dorsolateral prefrontal cortex; PT, planum temporale. ⁎ 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 current study and Elmer et al. (2009) could have resulted in a ceiling effect and thus limited the potential to observe effects on retention or retrieval. Alternatively, the specificity of the current effects on rate of learning could instead suggest a facilitatory role of LDLPFC tDCS on verbal working memory processing. Consistent with this interpretation was the concurrent finding of significantly faster correct working memory response times with focal LDLPFC stimulation. No effect, however, was found on performance accuracy, suggesting a selective benefit on working memory

processing speed or efficiency. These findings are in accordance with previous tDCS research, including a recent meta-analysis evaluating the effect of anodal tDCS given to the LDLPFC showing improved speed, but not performance accuracy (Brunoni and Vanderhasselt, 2014; Zaehle et al., 2011). In addition, no effect was found on sustained attention, indicating that this effect was specific to working memory. Peak functional activation has been shown to occur within the DLPFC during working memory tasks, specifically during continuous updating and temporal order processing (Wager and Smith, 2003). It is therefore possible that increased speed or efficiency of these functions within working memory

Fig. 4. Computational simulation results of three HD-tDCS montages: LDLPFC (left), PT (middle) and LMTL (right). The figure presents the distribution of electric field magnitude (unit: V/m) in the brain. Red, white and black arrows indicate the locations of the LDLPFC, PT and the left hippocampus respectively.

S. Nikolin et al. / NeuroImage 117 (2015) 11–19

may therefore account for the significantly faster rate of learning observed on the declarative verbal memory task. Unexpectedly, no effect of LMTL stimulation was found on any declarative verbal learning and memory outcome measure. This is despite observations of improved list learning rates in subjects with larger intracranial proportions of the medial temporal lobe (Fernaeus et al., 2013), and conversely, impaired encoding and storage of verbal information in patients presenting with medial temporal lobe atrophy (Boon et al., 2011). Increased LMTL functional activity has further been demonstrated during word encoding in imaging studies (Leube et al., 2001; Parsons et al., 2006; Powell et al., 2005). The LMTL montage was initially adopted in order to stimulate the left hippocampus, as a large body of evidence from both lesion and neuroimaging research indicated that the hippocampi, specifically the left hippocampus, are functionally important for verbal learning and recall (Breitenstein et al., 2005; Grasby et al., 1993; Meinzer et al., 2010; Opitz and Friederici, 2003). A possible explanation for this negative result is that the montage used did not adequately stimulate the hippocampus. The experimental tDCS montage chosen to target the left hippocampus was based on computer modelling which is yet to be physiologically validated. Indeed, results from the more detailed computer modelling showed that the hippocampal montage, rather than focally targeting the left hippocampus, additionally stimulated large portions of the left temporal lobe as well as the prefrontal cortex. This modelling further estimated stimulation at the left hippocampus to be modest, only 0.16 V·m−1, approximately half the electric field magnitude observed elsewhere in the brain (notably posterior left perisylvian areas) using the same montage. Notwithstanding, the degree of stimulation observed in the medial left temporal lobe shown with the detailed modelling, and the relatively large volume of the hippocampus (approximately 7.5 cm3 in healthy young adults (Raz et al., 2005)) together suggest that some hippocampal stimulation was achieved. This interpretation is supported by the results of analyses of learning effects which revealed significant recency and reduced mid-list effects specific to the LMTL stimulation condition. It is possible that greater recency effects may have occurred due to improved retrieval of the later items in the word list from hippocampal stimulation, as increased activation has been previously shown during working memory retrieval (Öztekin et al., 2009). Alternatively, recency effects have also been well documented to occur in patients with mild cognitive impairment and Alzheimer's dementia (Martín et al., 2013; Orru et al., 2009), both of which present with hippocampal atrophy (Visser et al., 2002). In addition, reduced recall performance on the middle portion of word list tasks has been found to occur with partial resection of the left anterior temporal lobe (Hermann et al., 1992). This pattern of results may therefore be interpreted to suggest an inhibitory effect of left hippocampal stimulation, which in turn disrupted the pattern of learning. Further research is therefore required both to confirm this result and to investigate potential effects on declarative verbal memory outcomes using alternative timing of stimulation (e.g., during retention or retrieval). Similarly, no significant effects on declarative verbal learning and memory were found with focal stimulation of the PT. This is in contrast to previous tDCS research showing improved learning and retrieval on verbal memory tasks (Fiori et al., 2011; Flöel et al., 2008), and neuroimaging work showing temporal regions, including the PT, as particularly active during semantic processing (Vigneau et al., 2006). There are two possible explanations that may account for this result. Firstly, the PT itself might not be important for verbal memory performance; rather, diffuse stimulation of nearby or more distal regions may be responsible for the previously observed improvements in cognitive functioning. Anodal tDCS to the left posterior parietal cortex, a region further posterior to the PT, has been demonstrated to improve the rate of list learning and delayed recall using a similar declarative verbal memory list learning task (Jones et al., 2014). Past studies using standard tDCS electrodes placed 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 resolution, stimulation is far more specific. For example, Flöel et al. (2008) employed standard 5 × 7 cm electrodes spaced widely apart whereas in the current study the anode and other electrodes were approximately 2 cm in diameter and arranged in a 4 × 1 montage, which has been suggested by computer modelling to produce much more focal, and less deeply penetrating, cortical stimulation (Datta et al., 2009). The PT is known to be highly interconnected with frontal cortical regions via the arcuate fasciculus, whose integrity has been found to be important for new verbal learning (López-Barroso et al., 2013). The focal stimulation of the PT achieved in the current study therefore may not have been sufficient to modulate this network and thus cause effects on either learning or recall. Alternatively, the placement of the anode used in the PT montage may also have not been optimal to achieve effects on memory. Caparelli-Daquer et al. (2012) showed using a series of HD-tDCS computer simulations that, in comparison with standard tDCS electrode positioning, small deviations from optimal placement can result in vastly different responses from participants due to the highly focal nature of the stimulation. Future studies may benefit from using neuroimaging and neuronavigational software to account for inter-individual neuroanatomical variability and more accurately identify the precise location of regions of interest for focal tDCS stimulation. There were several limitations to our study. Firstly, findings may have been limited by ceiling effects on the declarative verbal learning task. For example, results showed that by the third learning trial on the task, 6/16 participants had reached a ceiling level of performance in the LDLPFC condition compared to the other conditions (3/16 in the PT condition, and 2/16 in both sham and LMTL conditions). Hence, the effect size calculated for the LDLPFC condition on rate of verbal learning, although large, may have been an underestimate as further learning may have occurred had there been greater number of stimuli. Previous studies which have used the same declarative verbal memory test in a comparable cohort of young and educated participants have similarly observed ceiling effects (Uttl, 2005; Van Der Elst et al., 2005). Future studies may benefit from the use of a greater number of stimuli and longer delay periods to avoid such effects. Further, the administration of additional trials to assess learning rates should be considered, as learning rate calculations may be affected by limited trials due to underperformance on the first trial block. Lastly, the computer modelling software used to develop the electrode montages employed in the current study was based on commercially available software and the focal targeting of subcortical regions, including the hippocampus, is yet to be physiologically validated. Thus, both inter-individual differences in brain anatomy coupled with potential inaccuracies in the modelling may have affected outcomes.

Conclusions In conclusion, to our knowledge this research represents the first attempt to probe the functional roles of critical brain structures subserving declarative verbal learning and memory functioning using a more focal form of tDCS (HD-tDCS). Previously, HD-tDCS had only 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 results show initial support for the utility of HD-tDCS to probe neuropsychological functioning of focal cortical regions; however, additional work is required to further develop this method to achieve effective stimulation of deeper brain regions, such as the hippocampus. Large effect sizes found for HD-tDCS LDLPFC stimulation on the rate of declarative verbal learning and speed of working memory functioning, however, indicate that HD-tDCS when given to the LDLPFC may be beneficial for cognitive enhancement and remediation purposes. Further investigation is therefore warranted to evaluate the cognitive enhancing potential of HD-tDCS.

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S. Nikolin et al. / NeuroImage 117 (2015) 11–19

Acknowledgments The authors would like to thank Soterix Medical for providing access to HD-tDCS software (HDExplore™ and HDTargets™) necessary to conduct this study. The efforts of Dr Abhishek Datta are acknowledged for assistance in developing the montages used. Conflict of interest Colleen Loo was provided with tDCS equipment from Soterix for a clinical trial unrelated to this study. The remaining authors declare no competing financial interests.

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