Modulation of the dichotic right ear advantage during bilateral but not unilateral transcranial random noise stimulation

Brain and Cognition 123 (2018) 81–88

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Modulation of the dichotic right ear advantage during bilateral but not unilateral transcranial random noise stimulation

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Giulia Prete , Anita D'Anselmo, Luca Tommasi, Alfredo Brancucci Department of Psychological, Health, and Territorial Sciences, ‘G. d’Annunzio’ University of Chieti-Pescara, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords: Auditory cortex Consonant-vowel syllables Dichotic listening Right ear advantage Transcranial Random Noise Stimulation (tRNS)

Transcranial electrical stimulation (tES) has been increasingly adopted to modulate perceptual and cognitive functions, but the effects on auditory perception are still relatively uncharted. Starting from the evidence that a stronger right ear advantage effect (REA) in dichotic listening positively correlates with speech sound processing, the present study was aimed at modulating the REA by means of high-frequency transcranial Random Noise Stimulation (hf-tRNS). Stimulation was applied over the auditory cortex (AC) either unilaterally (Experiment 1, N = 50) or bilaterally (Experiment 2, N = 24) during a verbal dichotic listening task. The results confirmed the REA both during the sham and the tRNS session in both Experiments. Importantly, a significant enhancement of the REA was found during bilateral hf-tRNS with respect to sham (Experiment 1). No modulation was found when hf-tRNS was applied over the left or right AC with the reference electrode placed on the contralateral shoulder, with respect to sham (Experiment 2). This finding is discussed in the light of previous stimulation studies facing the modulation of hemispheric asymmetries. Our results suggest that the effectiveness of bilateral hf-tRNS in modulating basic speech processing mechanisms could be exploited in the treatment of language impairments.

1. Introduction Transcranial electrical stimulation (tES) is a non-invasive method used to modulate human cortical excitability by delivering a low current to the cerebral cortex (Nitsche & Paulus, 2011; Paulus, 2011). Different types of current release characterize different tES techniques: tDCS (transcranial Direct Current Stimulation), tACS (transcranial Alternating Current Stimulation) and tRNS (transcranial Random Noise Stimulation). tRNS is based on the application of a repetitive alternating current through the scalp via two electrodes, in a non-invasive and painless manner (Fertonani, Pirulli, & Miniussi, 2011). Typically, it is applied in three frequency band ranges: entire spectrum, from 0.1 to 640 Hz; low frequency, from 0.1 to 100 Hz (lf-tRNS); and high frequency, from 101 to 640 Hz (hf-tRNS; Terney, Chaieb, Moliadze, Antal, & Paulus, 2008). The current delivered by tRNS affects neuronal membrane potentials by oscillatory electrical stimulation with random normally distributed frequencies, possibly resulting in a frequency spectrum similar to a “white noise” pattern. Unlike tDCS, in which current flows from an active to a reference electrode, tRNS current has a direction but not a stream sense, and this prevents the problem of electrical field polarity. Furthermore, neurons are stimulated regardless of their spatial orientation due to the current variability of tRNS.

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Strong effects of tRNS have been shown both on physiological and behavioural measures (Terney et al., 2008). Specifically, tRNS applied on the primary motor cortex improves motor sequence learning and increases motor cortex excitability (Chaieb, Paulus, & Antal, 2011; Terney et al., 2008). Moreover, a study comparing the effect of tES on the motor cortex corresponding to the leg showed that both hf-tRNS and anodal tDCS significantly increased the excitatory activity of the motor evoked potentials (MEP) with a difference between the two techniques, namely that the excitatory effect of tRNS appeared earlier and lasted longer than that of tDCS (Laczo, Antal, Rothkegel, & Paulus, 2014). Neuromodulatory effects induced by tRNS have been welldocumented in the visual domain (Fertonani et al., 2011; Herpich et al., 2015; Prete, Malatesta & Tommasi, 2017; Van der Groen & Wenderoth, 2016) and in the auditory domain (Vanneste, Fregni, & De Ridder, 2013; Van Doren, Langguth, & Schecklmann, 2014). To our knowledge, no study has been published so far concerning the effects of tRNS in speech sound processing, whereas modulatory effects in the linguistic domain have been obtained applying unilateral tDCS in healthy adults and in aphasic post-stroke patients. Specifically, anodal tDCS over the left prefrontal cortex results in improved naming performance in healthy participants (Fertonani, Rosini, Cotelli, Rossini, & Miniussi, 2010; Iyer et al., 2005) and in aphasic patients (Baker,

Corresponding author at: BLOCCO A, Via dei Vestini 31, I-66013 Chieti, Italy. E-mail address: [email protected] (G. Prete).

https://doi.org/10.1016/j.bandc.2018.03.003 Received 27 October 2016; Received in revised form 28 January 2018; Accepted 9 March 2018 0278-2626/ © 2018 Elsevier Inc. All rights reserved.

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when tDCS is used (Galletta et al., 2015), and it is also most effective in sound perception when tRNS is used (Prete, D’Anselmo, Tommasi, & Brancucci, 2017). Considering these findings together with the evidence of a generally stronger efficacy of tRNS with respect to tDCS, in the present study we wanted to determine whether hf-tRNS applied on the auditory cortex with a bilateral or unilateral temporal montage would modulate the size of REA effect. Starting from the structural model exposed above (Kimura, 1967; Sidtis, 1988), we expected that when the temporal cortex of the left and right hemispheres are stimulated together, the left “linguistic” hemisphere should be superior with respect to the right hemisphere in processing linguistic sounds, resulting in a stronger REA effect. If we assume that in “normal condition” (without stimulation), the functional activity of both hemispheres leads to a left-hemispheric dominance which is the base for the REA effect, then the contemporary stimulation of both hemispheres should enhance this asymmetry. This assumption is also based on the evidence of inhibitory inter-hemispheric pathways involved in the REA effect during dichotic listening (Clarke, Lufkin & Zaidel, 1993): it has been shown that callosal size is negatively related to REA, meaning that the ear advantage seems to be associated with inter-hemispheric inhibition mediated by callosal projections. Finally, starting from the results by Nitsche et al. (2007) showing that a smaller active electrode enhances the spatial resolution of tDCS, as well as from positive results obtained in other tRNS studies using electrodes of different sizes (e.g., Fertonani et al., 2011; Pirulli et al., 2013; Terney et al., 2008), we decided to use a bilateral montage with two differently-sized electrodes, even if we did not expect to find differences between the two montages (smaller electrode over the left or right AC), due to the polarity-independent stimulation used which ensures a bilateral temporal stimulation. We hypothesized that hf-tRNS applied bilaterally over the temporal cortices would be effective in modulating the basic hemispheric asymmetry of speech processing. Specifically, we expected to find an increase of the REA during hf-tRNS with respect to the control session (sham stimulation). Moreover, in order to evaluate the effect of electrodes montage on the DL task, a second experiment was performed as a control task. The control experiment was identical to the main experiment, but we exploited a unilateral montage, placing the active electrode either over the left auditory cortex or over the right auditory cortex, and the reference electrode on the contralateral shoulder. Starting from the evidence of (i) a negative correlation between inter-electrode distance and tES efficiency (Moliadze et al., 2010); (ii) stronger effects of bilateral than unilateral tES montage in language rehabilitation (Galletta et al., 2015; Marangolo et al., 2016); and (iii) inter-hemispheric inhibition in REA, we hypothesized to find no modulation in unilateral stimulation with respect to sham.

Rorden, & Fridriksson, 2010). Moreover, tDCS over the inferior frontal gyrus induces a facilitation of auditory perceptual learning (Sehm et al., 2013). In a similar way, tDCS applied on the posterior temporal region enhances language performance in a picture naming task (Sparing, Dafotakis, Meister, Thirugnanasambandam, & Fink, 2008), and facilitates word retrieval as well as verbal learning in healthy participants and non-fluent aphasic patients (Fiori et al., 2011; Flöel, Rösser, Michka, Knecht, & Breitenstein, 2008). The stimulation effect has also been demonstrated at 1 and 3 weeks after the end of the treatment in aphasic patients (for overview see (Monti et al., 2013). Considering the positive results obtained in linguistic tasks using tDCS, together with the evidence of stronger outcomes of tRNS than tDCS in some cognitive domains (i.e., Herpich et al., 2015; Vanneste et al., 2013), we aimed here to investigate the impact of hf-tRNS on auditory speech perception. In particular, we wanted to evaluate the effects of tES applied over the auditory cortex while participants performed a dichotic listening (DL) task. We chose to apply online-hf-tRNS because it has been shown that it is more effective in inducing facilitatory effects than offline-hf-tRNS (Pirulli, Fertonani, & Miniussi, 2013). Moreover, it has also been found that high frequency tRNS induces stronger effects than low frequency tRNS (Terney et al., 2008). In this way, we intended to explore the possibility to modulate the mutual involvement of the hemispheres which is at the basis of the right ear advantage (REA). DL consists in presenting two different auditory stimuli simultaneously, one at the left and the other at the right ear (Brancucci, D’Anselmo, Martello, & Tommasi, 2008; Brancucci & San Martini, 1999, 2003; Bryden, 1988; D'Anselmo, Marzoli, & Brancucci, 2016; D'Anselmo, Reiterer, Zuccarini, Tommasi, & Brancucci, 2013; Hugdahl et al., 1999; Tervaniemi & Hugdahl, 2003). Generally, participants are faster and more accurate in reporting speech stimuli presented at the right ear, compared to the left ear (Kimura, 1961). The REA effect can be explained referring to the so-called “structural model” (Kimura, 1967; Sidtis, 1988) assuming that the contralateral auditory inputs are strongly represented in the hemispheres, whereas the ipsilateral inputs are inhibited. This causes the input from the right ear to reach mainly the left auditory cortex. However, passing first through the left auditory cortex and then via the corpus callosum, it can reach, somewhat attenuated, the right auditory cortex (Brancucci et al., 2004; Della Penna et al., 2007; Kimura, 1967). An alternative explanation of the REA effect is the attentional model proposed by Kinsbourne (1970, 1973, 1975, 1980), according to which asymmetries in the perception of verbal material are attributable to the greater activation of the left hemisphere, which results in a contralateral attentional bias, toward the right side. These theories have been supported by neuroimaging findings, demonstrating that verbal dichotic stimuli induce stronger cortical responses in the left auditory cortex (Della Penna et al., 2007; Hugdahl et al., 1999), and a similar REA was also found in a verbal imaginative task in which no acoustic information has been presented (Prete, Marzoli, Brancucci, & Tommasi, 2016). Finally, it has been shown that an imbalance of this inter-hemispheric asymmetry could be at the basis of some linguistic impairments, both during development and in adulthood (e.g., Asbjørnsen, Helland, Obrzut, & Boliek, 2004; Krause & Cohen Kadosh, 2013; Obrzut & Mahoney, 2011; Turkeltaub, 2015). Thus, a strengthening of the REA effect might foster an improvement in linguistic skills (Asbjørnsen & Helland, 2006), such as language comprehension (Asbjørnsen & Helland, 2006), word recognition and spelling, which are often impaired in people who are poorly lateralized (Kershner & Morton, 1990). In a previous study we did not find effects in the REA modulation by applying either anodal or cathodal tDCS over the auditory cortex using an extra-cephalic montage (D'Anselmo, Prete, Tommasi, & Brancucci, 2015). However, it has been previously demonstrated that a negative correlation exists between the inter-electrodes distance and the magnitude and duration of the tES effects (Moliadze, Antal, & Paulus, 2010). Moreover, it has also been shown that a bilateral montage is most effective than an asymmetrical montage in language rehabilitation

2. Experiment 1: bilateral hf-tRNS 2.1. Materials and methods 2.1.1. Participants Fifty healthy volunteers took part in the study (31 females, mean age: 22.79 ± 0.41). Handedness scores were assessed at the end of the experimental procedure, by using the Edinburgh Handedness Inventory (Oldfield, 1971), according to which the handedness score ranges from −100 (totally left handed) to +100 (totally right handed): 4 male participants were excluded (3 left-handers: scores < 0, and 1 without a laterality preference: score = 0). The mean handedness score of the remaining 46 participants was 63.45 ( ± 3.27). Starting from the wellknown effect of handedness on the cerebral lateralization for linguistic skills, as well as from the reversed ear advantage during dichotic listening in persons with a right-hemispheric superiority for language (Van der Haegen, Westerhausen, Hugdahl, & Brysbaert, 2013), a male participant was excluded because his handedness score was more than 2 standard deviation lower that the mean of the group, showing a weak right preference (score = 13.04). Participants were enrolled if they did 82

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dichotic stimuli were obtained presenting one CV-syllable to the left ear and at the same time one different CV-syllable to the right ear. Syllables were paired with each other, yielding a total of 30 temporally aligned pairs to achieve simultaneous onset of the initial consonants, using GoldWave (V.5.08, GoldWaveInc.) software. All of the possible combinations of pairs were presented and reversed between the left and the right ear (e.g., /ba/ to the left ear and /da/ to the right ear; /da/ to the left ear and /ba/ to the right ear).

not show auditory impairments. An audiometric functional assessment was performed in which participants had to press a button when a complex tone of 264 or 395 Hz, presented via earphones repeatedly with increased intensities (steps of 2.5 dBA), became perceivable (Brancucci, Babiloni, Rossini, & Romani, 2005). Participants were recruited when no different hearing thresholds were present between left and right ear ( ± 5 dBA). All participants declared to be native Italian speakers and free from psychiatric or neurological disorders. They selfreported normal or corrected-to-normal vision, and no implanted metal objects. Participants gave their written consent before beginning the experiment. The whole procedure was carried out in accordance with the principles of the Declaration of Helsinki, and the protocol was approved by the Local Ethical Committee.

2.1.4. Procedure Participants were tested individually and they were asked to wear headphones (Philips e SHP5400). Written instructions were presented, in which participants were informed that during the task they would choose a target syllable, described as the syllable heard first or best, after the dichotic presentation. They were also asked to pay attention to both ears simultaneously, without favouring one ear (Hugdahl et al., 2000), and to maintain their gaze on the fixation cross presented in the center of the screen. Each session (tRNS and Sham) was composed of 2 blocks of 30 trials each. The initial position of the headphones was counterbalanced across participants and, during the pause between the two sessions, the orientation of the headphones (left and right ear) was inverted, in order to control for possible output differences in the earpieces. A trial started with the presentation of a dichotic stimulus, during which a fixation cross was presented on the computer screen, followed by a response phase in which the fixation cross was replaced by the 6 syllables written on the screen. The participant was asked to indicate which CV-syllable was heard better, by mouse-clicking on the corresponding syllable on the display, without time limits. The experiment was completely automated using a software written in Microsoft Visual Basic and lasted about 15 min.

2.1.2. tRNS and general procedure tRNS was delivered by a battery-driven, constant current stimulator (DC-Stimulator, NeuroConn GmbH, Germany) through a pair of surface saline-soaked sponge electrodes, one measuring 5 cm × 9.5 cm and the other measuring 5 cm × 5 cm, kept firm by elastic bands. A random noise current with intensity 1.5 mA and with 0 mA offset was applied for 20 min, resulting in a current density of 0.032 mA/cm2 for the largest electrode of the two and 0.06 mA/cm2 for the smaller one. Current was discharged at random frequencies ranging from 100 to 640 Hz (high frequency), according to safety guidelines (Poreisz, Boros, Antal, & Paulus, 2007), with a ramping period of 15 s both at the beginning and at the end of the stimulation. A bilateral montage was used in order to stimulate the left and right temporal lobes, placing the electrodes on T3 and T4 sites of the 10–20 EEG positioning system, thus ensuring that the auditory cortex was stimulated (Zaehle, Beretta, Jäncke, Herrmann, & Sandmann, 2011). In order to avoid the disadvantage of having possible unwanted excitability due to the bipolar montage with equally sized electrodes, and from the evidence of a better spatial resolution of the target area obtained by using a smaller active electrode, the size of electrodes was arranged in order to be asymmetrical (Nitsche et al., 2007). Thus, when the 5 × 9.5 cm2 electrode was placed over T3, the 5 × 5 cm2 electrode was placed over T4 (24 participants received this montage), and vice versa. The long side of the larger electrode was oriented in anteriorposterior direction, in order to target AC. Each participant took part in 2 different sessions (tRNS and Sham), separated by at least 2 h. In the Sham session the current was turned off after 15 s, ensuring that there was no effective current delivery (Ambrus, Antal, & Paulus, 2010). The order of sessions was counterbalanced across participants, and the task started 5 min after the beginning of the stimulation. In each session, participants sat comfortably at a distance of approximately 80 cm from the computer screen, in a dark and silent room and they were informed that they could stop the experiment at any time by asking the experimenter, who stood behind them. At the end of each session, participants were required to report any possible sensation attributable to the stimulation, and at the end of the second session they were asked whether they believed to have distinguished the real stimulation (tRNS) from the control stimulation (sham). None of the participants reported having distinguished the two sessions, and the majority of them stated that they had felt no sensation, or only a very weak itch under the electrodes at the beginning of both sessions.

2.2. Results Data analysis was based on the number of correctly reported syllables, for the left ear and for the right ear. A response was considered as correct if one of the two dichotically presented syllables was reported, and the number of correct response for each ear was calculated. These values were transformed to percentage of correct responses for the left ear and for the right ear, in both tRNS and Sham sessions, separately. Four participants were excluded because their scores differed more than 2 standard deviations from the mean in one or more of the conditions (3 females), thus statistical analyses were carried out on the responses of 41 participants (smaller electrode applied over the left temporal cortex: 21 participants). As specified in the introduction, two differently-sized electrodes were used in order to increase the focality of the stimulation: in order to control for the possible effect of the different montage (smaller electrode positioned over T3 or T4), the electrodes position was considered in the analysis, even if we did not have specific hypotheses concerning this manipulation. Data were analyzed by means of a 2 × 2 × 2 analysis of variance (ANOVA), with the percentage of correct responses as the dependent variable, with Position of the smaller electrode (left, right temporal cortex) as the between-subjects factor, and with Stimulation (tRNS, sham) and Ear (left, right) as within-subjects factors. Post-hoc comparisons were carried out by means of t-tests. When needed, FDR correction for multiple comparisons was applied (Benjamini & Hochberg, 1995) with ɑ = 0.05. Both uncorrected p-values and corrected p-values (q-values) are reported. The ANOVA revealed a main effect of Ear (F(1, 39) = 35.52, p < 0.001, ηp2 = 0.48), confirming the expected Right Ear Advantage (left ear: 35.06% ± 1.05; right ear: 49.45% ± 0.98). The interaction between Ear and Stimulation was significant (F(1, 39) = 5.12, p = 0.029, ηp2 = 0.12; see Table 1). As shown in Fig. 1, and confirmed by paired t-tests, the REA was increased during tRNS with respect to sham (t(40) = 2.16; p = 0.037;

2.1.3. Stimuli Dichotic pairs of consonant-vowel syllables were used as stimuli. Syllables were recorded with a microphone from a natural voice of an Italian female native speaker. The sample rate was 44.1 kHz and the amplitude resolution was 16 bit. The peak level was 70 dB and the mean duration of the consonant-vowel (CV) syllables was about 450 ms (allowing for differences in voice-onset time length for unvoiced and voiced syllables). Each syllable consisted of one of the 6 stop-consonants /b/, /d/, /g/, /p/, /t/, /k/, followed by the vowel /a/. The 83

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Table 1 Descriptive values (mean ± standard deviation) of percentage number of correct responses for Sham and hf-tRNS condition for the left ear and for the right ear. EAR

Sham tRNS

Left

Right

36.54 ± 10.15 33.58 ± 8.77

47.89 ± 9.95 51.02 ± 7.83

Fig. 3. The graph shows for each participant the Laterality Index (LI) obtained during the tRNS session subtracted to the LI obtained during the Sham session. Positive values indicate an increased REA and negative values indicate a decreased REA, during stimulation compared to sham, for Experiment 1 (bilateral temporal stimulation).

over the left temporal cortex (t(20) = 1.95; p = 0.065; right temporal cortex: t(19) = −1.30; p = 0.209). The other main effects and interactions failed to reach statistical significance. In order to further confirm the effect of the tRNS on the REA, a laterality index (LI) was calculated on the percentage of Left ear and Right ear responses, using the formula LI = (R − L)/(R + L) × 100, according to which positive values correspond to the REA effect, and it was used as the dependent variable. First of all, the existence of a REA effect was confirmed by comparing the LI obtained in the sham session (13.55 ± 3.60) and in the tRNS session (20.89 ± 2.98) with the value of 0 (absence of asymmetry). The results of the single sample t-tests confirmed the significant REA effect in both the sham session (t(40) = 3.77, p < 0.001; q = 0.050) and the tRNS session (t(40) = 7.00, p < 0.001; q = 0.025). Then a t-test was carried out, comparing the LI obtained in the tRNS session and in the sham session: the result was significant (t(40) = 2.30, p = 0.027), confirming an enhanced LI (REA effect) in the tRNS session with respect to the sham. Fig. 3 shows the LI in the tRNS session subtracted to the LI in the Sham session (REA effect), for each participant.

Fig. 1. Percentage of correct responses for the Left ear (left panel) and for the Right ear (right panel), during Sham (white columns) and hf-tRNS (gray columns). Bars represent standard errors and asterisks show the significant comparisons (p < 0.001).

q = 0.050), whereas the percentage of left ear responses was lower during tRNS than during sham (t(40) = −2.25; p = 0.030; q = 0.025). The interaction between Stimulation and Position of the smaller electrode was significant (F(1, 39) = 5.01, p = 0.031, ηp2 = 0.11). As shown in Fig. 2, the percentage of correct responses slightly increased when the smaller electrode was positioned over the left temporal cortex with respect to the sham, and it slightly decreased when the smaller electrode was positioned over the right temporal cortex with respect to the sham. Nevertheless, t-tests revealed that the difference tended to the statistical significance only when the smaller electrode was applied

3. Experiment 2: unilateral hf-tRNS 3.1. Materials and methods 3.1.1. Participants Twenty-four healthy volunteers took part in the study (12 females, mean age: 24.42 ± 0.46). None of them took part in Experiment 1. All participants were right-handers, with a mean handedness score of 68.40 ( ± 3.64), as measured by the Edinburgh Handedness Inventory (Oldfield, 1971). Participants were enrolled if they did not present auditory impairments and different hearing thresholds ( ± 5 dBA) between left and right ears, as measured by an audiometric functional assessment (Brancucci et al., 2005). All participants were native Italian speakers free from psychiatric or neurological disorders, had normal or corrected-to-normal vision and no implanted metal objects. Participants gave their written consent before taking part in the experiment. The whole procedure was carried out in accordance with the principles of the Declaration of Helsinki, and the protocol was approved by the Local Ethical Committee. 3.1.2. tRNS and general procedure Stimuli, general procedure and stimulation parameters were the same as those used in Experiment 1, with the following exceptions: (i) participants carried out 3 separate sessions, in 3 different days (3 sessions in 3 days in a row for 87.5% of the sample – the remaining 3

Fig. 2. Percentage of correct responses for the montage in which the smaller electrode was positioned over the Left temporal cortex (left panel) and for the montage in which it was positioned over the Right temporal cortex (right panel), during Sham (white columns) and hf-tRNS (gray columns). Bars represent standard errors.

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participants carried out the last session after 3, 4 and 6 days from the first session, respectively). (ii) In each session they received (1) hf-tRNS over the left temporal cortex (T3), (2) hf-tRNS over the right temporal cortex (T4), and 3) sham stimulation (order of sessions was balanced among participants). The smaller electrode was placed over the left/ right temporal cortex in the left/right stimulation sessions respectively, and the larger reference electrode was placed on the contralateral shoulder. (iii) At the end of each session, participants were asked to complete a questionnaire in which they were invited to rate the sensations experienced during the stimulation (Fertonani, Ferrari, & Miniussi, 2015). The majority of them stated that they had felt no sensation, or only a very weak itch under the electrodes at the beginning of the stimulation. Moreover, they were invited to refer what kind of stimulation they believed to have received among the three options: real stimulation, placebo, I do not know. Two participants were excluded because they correctly recognized real stimulation and sham session (1 female receiving sham during the second session, and 1 male receiving sham in the third session).

Fig. 5. The graph shows for each participant the Laterality Index (LI) obtained during the left-tRNS session subtracted to the LI obtained during the Sham session (empty circles), and the LI obtained during the right-tRNS session subtracted to the LI obtained during the Sham session (black triangles). Positive values indicate an increased REA and negative values indicate a decreased REA, during stimulation compared to sham, for Experiment 2 (unilateral temporal stimulation).

3.2. Results The same analyses as those described in Experiment 1 were carried out in the present Experiment. In particular, the percentage of correctly recognized syllables for the left and right ear in each session was considered as the dependent variable in an ANOVA in which Stimulation (sham, left-tRNS, right-tRNS) and Ear (left, right) were used as withinsubjects factors. Two participants were excluded because their scores differed more than 2 standard deviations from the mean in one or more of the conditions (1 female), thus statistical analyses were carried out on the responses of 20 participants. The ANOVA revealed a main effect of Ear (F(1, 19) = 25.88, p < 0.001, ηp2 = 0.58), confirming the expected Right Ear Advantage (left ear: 32.72% ± 1.45; right ear: 54.50% ± 1.39). The interaction between Ear and Stimulation was not significant (F(2, 38) = 1.09, p = 0.347; see Fig. 4). In order to further explore the effect of the tRNS on the REA, the laterality index (LI: positive values correspond to the REA effect) was used as the dependent variable. LI obtained in the sham session (29.29 ± 4.51), in the left-tRNS session (23.99 ± 6.22) and in the right-tRNS session (22.23 ± 5.63) was compared to 0 (absence of asymmetry), by means of single sample t-tests. Results confirmed a significant REA effect in each session (sham: t(19) = 6.50, p < 0.001, q = 0.017; right-tRNS: t(19) = 3.95, p < 0.001, q = 0.033; left-tRNS:

t(19) = 3.86, p = 0.001, q = 0.050). Moreover, LI obtained in the lefttRNS session and in the right-tRNS session was compared to LI obtained in the sham session by means of t-tests: the results further confirmed the absence of difference between stimulation and sham sessions (left-tRNS: t(19) = −0.96, p = 0.351; right-tRNS: t(19) = −1.46, p = 0.161). Fig. 5 shows the difference between the LI in the tRNS sessions and the LI in the Sham session, for each participant.

4. Discussion The present study showed that hf-tRNS applied bilaterally over the auditory cortex enhances the REA effect. Increased excitability of cortical areas targeted by hf-tRNS had already been shown previously (Terney et al., 2008). It has been already shown that the left temporal cortex superiority in speech sound processing is at the basis of the REA effect (Bryden, 1988; Della Penna et al., 2007). We have here demonstrated that tRNS delivered bilaterally to the temporal cortices is sufficient to positively modulate the left-hemispheric superiority, as measured with DL (stronger REA). Starting from this premise, one should expect that hf-tRNS applied over the left temporal cortex enhances the REA, and that hf-tRNS applied over the right temporal cortex decreases the REA, when compared to sham. The results of the second experiment described here, however, disconfirmed these expectations, showing that unilateral stimulation does not influence the ear advantage in a DL task. The involvement of the left auditory cortex in the REA effect has been widely shown in a number of studies (e.g., Eichele, Nordby, Rimol, & Hugdahl, 2005; Hirnstein, Westerhausen, Korsnes, & Hugdahl, 2013; Oltedal & Hugdahl, 2017; Van der Haegen et al., 2013), and our control data (sham sessions) confirmed the expected REA effect in absence of tES in two groups of healthy right-handed participants. Moreover, the fact that the overall performance of participants in the first experiment slightly improved when the smaller electrode was positioned over the left temporal cortex would further confirm the involvement of speech abilities – lateralized to the left hemisphere – in the DL task: in this case, in fact, the smaller size of the electrode induced a higher spatial resolution of tES on the auditory areas in the left hemisphere, leading to a higher percentage of correct responses. This speculation is further confirmed by an exploratory analysis carried out including left-handed, mixed-handed and weak right-handed participants during bilateral stimulation (Experiment 1). Also in this case we confirmed a REA and we also found an increased REA when tRNS was applied. The only difference with respect to the main analysis concerned the interaction

Fig. 4. Percentage of correct responses for the Left ear (left panel) and for the Right ear (right panel), during Sham (white columns), Left-tRNS (gray columns) and Right-tRNS (black columns). Bars represent standard errors. To note that the depicted interaction between Ear and Stimulation is not significant.

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who found an improvement in the processing of time critical auditory information following stimulation. It is known that the left hemisphere is specialized in rapid temporal processing of auditory stimuli (Brancucci et al., 2008; Zatorre, Belin, & Penhune, 2002), and this leads us to speculate that high frequency stimulation may have a greater impact than low frequency tRNS in the processing of rapidly changing temporal cues, which are crucial in speech processing. However, to test this attractive hypothesis in a proper way, future studies should test whether tRNS delivered at several different frequencies around the one mainly involved in the auditory task, thanks to the effect of electrical resonance (Ge & Liu, 2016), is suitable to change the working frequency of auditory neurons. A large number of studies have shown the direct relationship between REA effect and linguistic abilities, so that the lack of REA in the DL task is considered as a sign of neurological or cognitive disorders, as aphasia (Kershner & Morton, 1990; Moore & Papanicolaou, 1988), developmental stuttering (Foundas, Corey, Hurley, & Heilman, 2004), attentional deficits in learning disabilities (Obrzut, Hynd, Obrzut, & Pirozzolo, 1981), and so on. Thus, it was proposed that the REA effect found by means of DL can be considered as a marker of the typical development of some cognitive functions, at least in the linguistic domain (Asbjørnsen et al., 2004; Asbjørnsen & Helland, 2006; for a review see Obrzut & Mahoney, 2011). As a consequence, the results of the present study suggest that hf-tRNS applied for 20 min over the auditory cortex bilaterally enhances linguistic sound processing. As mentioned above, in a previous study in which anodal and cathodal tDCS were applied over left/right auditory cortex with an extra-cephalic reference electrode (D'Anselmo et al., 2015) we failed to find significant modulation of the REA effect, using the same DL paradigm as that used in the present study. The present results are in line with those we found by means of tDCS, showing that tES applied over the temporal cortex unilaterally is not efficient in modulating cerebral asymmetries involved in the REA effect. Concerning this point it has to be highlighted that a negative correlation had been shown between the inter-electrode distance and the magnitude and duration of the stimulation effects (Moliadze et al., 2010). Furthermore, Galletta et al. (2015) have recently found that a bilateral electrode montage is most effective in language rehabilitation than an asymmetrical montage. Marangolo et al. (2016) showed that anodal tDCS applied over Broca’s area in aphasic patients, together with cathodal stimulation over the contralateral cortex, induced stronger resting state functional connectivity – as measured by means of fMRI – compared to sham. Using a graph-theoretical analysis to weight the relative importance of nodes within a network they found enhanced connectivity in a network of left hemispheric areas, including premotor cortex, anterior cingulate cortex, precuneus and cerebellum. These findings support the conclusion that bilateral tES is efficient at modulating linguistic processing. Nevertheless, Wang, Wu, Chen, Yuan, and Zhang (2013) showed that anodal tDCS applied over the left perisylvian region and Broca’s area improved language performance in patients with non-fluent progressive aphasia, showing that unilateral tDCS can influence linguistic sound processing. However, You, Kim, Chun, Jung, and Park (2011) found that cathodal tDCS applied over the right superior temporal gyrus, but not anodal tDCS over the contralateral gyrus, improved verbal comprehension in non-fluent post-stroke aphasic patients (for a review, see Sandars, Cloutman, & Woollams, 2016). We can conclude that different tES setups lead to different effects depending on the specific task and the specific cognitive demand. The present results together with previous evidence (D'Anselmo et al., 2015) suggest that the hemispheric asymmetry in language perception (REA effect), as measured by using the DL task, can be strengthened by applying hf-tRNS over the temporal cortices bilaterally.

between the position of the smaller electrode and the type of stimulation (tRNS and Sham) which did not reach statistical significance, confirming the left-hemispheric involvement in this task in participants with a possibly stronger left-hemispheric superiority for linguistic processing (those with a stronger right-hand preference). These supplementary results held true either when all of the participants were included in the analyses, and when outliers were excluded. Nevertheless, the bilateral montage used in the first experiment ensured that both left and right temporal cortices were stimulated simultaneously, and thus the REA was enhanced independently of the positioning of each electrode. In fact, we decided to stimulate both hemispheres in order to amplify the effects of tRNS (Moliadze et al., 2010), based on the assumption that if both auditory areas are stimulated together, the spontaneous cerebral asymmetries present in right-handers should provide a hemispheric imbalance, favoring the “linguistic hemisphere”. Our results confirm this expectation, showing that the bilateral stimulation enhanced the REA. This speculation has been confirmed by the evidence of null effects obtained by means of unilateral tRNS. The difference between unilateral and bilateral stimulation could be explained making reference to the stronger stochastic resonance induced by bilateral than unilateral stimulation. Stochastic resonance is a welldocumented phenomenon according to which the detection of weak signals can be improved by adding noise to the main signal (e.g., Wiesenfeld & Moss, 1995). It has been largely documented at a perceptual level, and it is of interest in the field of tES studies. It has been proposed, in fact, that the biological noise induced by tES – and in particular by tRNS – can be intended as neuronal noise which can improve the responsiveness of the stimulated neurons, at least at a cortical level. Moreover, it has been found that spontaneous noise exists within the auditory nervous system of mammalian, which seems to be at the basis of the spontaneous neuronal activity in the auditory areas in absence of external physical stimulation (Liberman, 1978). In line with this evidence, it has also been shown that human hearing can be enhanced by adding noise into the acoustic stream (Zeng, Fu, & Morse, 2000). Similarly, stochastic resonance has been hypothesized to be the basis of tRNS effects (Van Doren et al., 2014). It has been shown, for instance, that 2 mA hf-tRNS applied for 20 min over the auditory cortices bilaterally (as in the first experiment of the present study) increased auditory steady state responses, as measured by means of EEG. This evidence has been attributed to the stochastic resonance induced by tES (for a review, see Miniussi, Harris, & Ruzzoli, 2013; Moss, Ward, & Sannita, 2004). Moreover, a number of neuroimaging studies revealed that the cortical activity related to dichotic listening extends across both the left and the right hemispheres: for example in a fMRI study Westerhausen, Kompus and Hugdahl (2014) tested a wide sample of right-handed participants during a consonant-vowel DL task. The results showed the involvement of a bi-hemispheric network including temporal, parietal and frontal sites, with just some areas showing a clear lateralization. This evidence, considered together with the finding of inter-hemispheric inhibitory pathways involved in DL (Brancucci et al., 2004; Clarke et al., 1993; Della Penna et al., 2007) lead us to conclude that both hemispheres are involved in the REA effect. The present results provide support for this hypothesis, showing that the stimulation of both left and right temporal cortices improves the REA effect with respect to sham. It has also to be highlighted that the large electrodes used in the present study do not allow us to exclude that the effect of stimulation affected further areas besides AC, and thus we can speculate that the stronger effects found with the bilateral montage can also be attributable to wider cortical stochastic resonance, extending beyond temporal cortices (possibly extending to the main language cortical sites, such as Wernicke’s and Broca’s areas). All these findings seem to suggest that a bilateral stimulation activates a stochastic resonance mechanism, making the temporal cortex more sensitive to auditory stimulation. Finally, the efficacy of bilateral tRNS applied at high frequency in the modulation of auditory cortex has also been demonstrated recently by Rufener, Ruhnau, Heinze, and Zaehle (2017),

5. Conclusion tES techniques represent a potential tool for implementing non86

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invasive protocols for the treatment of cognitive functions. Due to the high number of possible tES setups, further studies are needed in order to clarify their potential, and comparative studies among different techniques, montages and stimulation parameters are desirable to disentangle their strengths and limits. Starting from the evidence available to date, we suggest that hf-tRNS applied bilaterally over the auditory cortex might be taken into consideration in the field of neurorehabilitation, at least for the assessment and treatment of language impairments. Further studies are needed in this domain, in order to find the optimal setups for specific linguistic therapies.

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