ORIGINAL RESEARCH published: 17 March 2020 doi: 10.3389/fnhum.2020.00063 Interhemispheric and Intrahemispheric Connectivity From the Left Pars Opercularis Within the Language Network Is Modulated by Transcranial Stimulation in Healthy Subjects Woo-Kyoung Yoo 1 , Marine Vernet 2,3 , Jeong Hoon Kim 4,5 , Anna-Katharine Brem 2,6,7 , Shahid Bashir 2,8 , Fritz Ifert-Miller 2 , Chang-Hwan Im 5 , Mark Eldaief 2 and Alvaro Pascual-Leone 2,9,10 * 1 Department of Physical Medicine and Rehabilitation, Hallym University Sacred Heart Hospital, Anyang, South Korea, Edited by: 2 Department of Neurology, Harvard Medical School, Boston, MA, United States, 3 ImpAct Team, Lyon Neuroscience Seiki Konishi, Research Center (CRNL), CNRS UMR5292, INSERM, U1028, University Lyon 1, Bron, France, 4 Weldon School of Juntendo University, Japan Biomedical Engineering, Purdue University, West Lafayette, IN, United States, 5 Department of Biomedical Engineering, Reviewed by: Hanyang University, Seoul, South Korea, 6 University Hospital of Old Age Psychiatry, University of Bern, Bern, Switzerland, Koji Jimura, 7 Department of Neuropsychology, Memory Clinic Zentralschweiz, Lucerne Psychiatry, Lucerne, Switzerland, 8 Department of Keio University, Japan Neurophysiology, Neuroscience Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia, 9 Hinda and Arthur Institute Nico Sollmann, for Aging Research and Center for Memory Health, Hebrew SeniorLife, Boston, MA, United States, 10 Guttmann Brain Health Technical University of Munich, Institute, Institut Guttmann de Neurorehabilitation, Universitat Autonoma, Barcelona, Spain Germany Sandro M. Krieg, Technical University of Munich, Neural activity related to language can be modulated within widespread networks Germany following learning or in response to disruption—including the experimental application *Correspondence: of noninvasive brain stimulation. However, the spatiotemporal characteristics of such Alvaro Pascual-Leone apleone@hsl.harvard.edu modulation remain insufficiently explored. The present study combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to explore the modulation Specialty section: This article was submitted to Brain of activity across the language network following continuous theta-burst stimulation Imaging and Stimulation, a section of (cTBS) of the left pars opercularis. In 10 healthy subjects (21 ± 2 years old, four females), the journal Frontiers in Human neuronavigated cTBS was delivered over the left pars opercularis of the frontal operculum Neuroscience (part of the traditional Broca’s area) at 80% of active motor threshold (AMT) stimulation Received: 04 September 2019 intensity. Real cTBS and sham cTBS were performed in two different visits separated Accepted: 10 February 2020 by at least 48 h. Before, immediately, and 10 min after cTBS, 30 single pulses of TMS Published: 17 March 2020 were delivered to the left pars opercularis at 80% of the resting motor threshold (RMT), Citation: Yoo W-K, Vernet M, Kim JH, whereas EEG was simultaneously recorded. We examined the cTBS-induced modulation Brem A-K, Bashir S, Ifert-Miller F, of phase locking values (PLVs) between the TMS-evoked potentials (TEPs) recorded over Im C-H, Eldaief M and Pascual-Leone A the pars opercularis and those recorded over its right-hemispheric homolog area, the left (2020) Interhemispheric and supramarginal area, and the left superior temporal area in different EEG frequency bands Intrahemispheric Connectivity From and different time windows following cTBS. cTBS to the left pars opercularis induced the Left Pars Opercularis Within the Language Network Is Modulated by within the gamma band: (1) a significant increase in TEP phase synchronization between Transcranial Stimulation in Healthy the left and right pars opercularis at an early time window (250–350 ms) following cTBS; Subjects. Front. Hum. Neurosci. 14:63. and (2) significantly increased PLV with the left supramarginal area and the left superior doi: 10.3389/fnhum.2020.00063 temporal area at a later time window (600–700 ms). In the theta and delta band, cTBS to Frontiers in Human Neuroscience | www.frontiersin.org 1 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS the left pars opercularis induced significantly increased phase synchronization of TEPs between the left pars opercularis and the posterior left hemispheric language areas at a late time window. In sham condition, there was a significant decrease in TEP phase synchronization of the high beta band between left pars opercularis and left superior temporal area at 200–300 ms. These results contribute to characterize the dynamics of the language network and may have implications in the development of noninvasive stimulation protocols to promote the language rehabilitation in aphasia patients. Keywords: noninvasive brain stimulation, TMS-evoked potentials, gamma band, phase synchronization, continuous theta-burst stimulation INTRODUCTION We hypothesized that such an approach, using task-free and externally triggered oscillations, would provide more Language is processed in widely distributed neural networks direct physiological evidence for connectivity mechanisms. including the frontal operculum (Broca’s region) in the dominant Furthermore, synchronization and desynchronization of these hemisphere and its right hemispheric homolog, as well as task-free oscillations in response to the plasticity-inducing parietotemporal areas of the left hemisphere (Pulvermüller, cTBS protocol could provide information relevant to a future 2002; Pulvermüller et al., 2009; Giraud and Poeppel, 2012; noninvasive intervention for the rehabilitation of patients Poeppel et al., 2012). Measuring the information flow between with aphasia (Miniussi and Thut, 2009). Specifically, we those core regions is important for understanding the function hypothesized that cTBS to the left pars opercularis would change of the language network (Singer, 1999; Varela et al., 2001; interhemispheric synchronization of TMS-evoked potential Buzsaki, 2004). Information flow across nodes of a network (TEP) between the left and the right pars opercularis and can be studied by recording synchronizations of spontaneous intrahemispheric interactions between the left pars opercularis cortical oscillations. For instance, a study (Giraud et al., 2007) and the left supramarginal and left superior temporal areas. tried to link auditory structural characteristics of speech and spontaneous brain oscillations within networks important for speech perception and production. Others have examined MATERIALS AND METHODS transient event-related phase synchronizations between two brain areas (Lachaux et al., 1999; Pulvermüller, 2002) or the Participants phase resetting of a cortical oscillation by a perceptual stimulus Ten young, healthy, right-handed adults [the average Edinburgh (Friston et al., 1997; Rizzuto and Kahana, 2001). However, Handedness Inventory (Oldfield, 1971); score, 83] volunteered to sensory stimuli or cognitive task manipulations can affect in participate in the study (21 ± 2 years old; range, 18–24 years parallel several cortical areas. On the other hand, controlled old; four females). None of them had a history of psychiatric perturbations applied directly to well-defined brain regions offer or neurological conditions, and all had normal neurological a superior strategy to gain insights into the casual interactions and medical examinations, and Mini-Mental State Examination between nodes of a given large-scale brain network. Here we scores in the normal range (Miltner et al., 1999; Burgess and applied this strategy to gain insights into the dynamics across the Ali, 2002; Buschman and Miller, 2007; de Diego-Balaguer et al., language network. 2011). Participants visited twice at least 48 h apart for sham We applied single pulses of brain magnetic resonance and real repetitive TMS (rTMS) session; half of the participants imaging (MRI)-guided (neuronavigated) transcranial magnetic started with the sham session first. Participants were not taking stimulation (TMS) to the pars opercularis of the left frontal any medication known to affect motor cortical excitability at the operculum and recorded TMS-evoked cortical responses time of the study and did not have any contraindications to TMS. with electroencephalography (EEG) to gain insights into All tolerated the TMS without any adverse effect or complication. the connectivity dynamics across interhemispheric and All gave their written informed consent to the study, which intrahemispheric connections of the language network. The use followed international guidelines for the use of TMS (Rossi et al., of neuronavigated TMS is important to ensure precise targeting 2009), had been approved by the local institutional review board of a given brain region (Gugino et al., 2001; Bashir et al., 2011). (Beth Israel Deaconess Medical Center, Boston, MA, USA), and We examined the modulation of TMS-evoked cortical responses was conducted in adherence to the Declaration of Helsinki. induced by continuous theta-burst stimulation (cTBS), a noninvasive stimulation protocol that has been shown not only to Experimental Setup decrease the excitability of the targeted area (Huang et al., 2005) All participants underwent a brain MRI using a 3-T GE but also to modulate brain oscillations and synchronizations machine (GE Healthcare, Waukesha WI, USA) with three- (Vernet et al., 2013). CTBS can provide longer-lasting dimensional (3D) modified driven-equilibrium Fourier modulatory effects with shorter stimulation time than traditional transform protocol–prepared fast spoiled gradient echo repetitive TMS, which can have important clinical implications. sequence (0.94 × 0.94 × 1-mm resolution; echo time = 2.9 ms; Frontiers in Human Neuroscience | www.frontiersin.org 2 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS flip angle = 15◦ ) to generate a high-resolution anatomical 3D image to guide TMS. The stimulation setup consisted of a Nexstim stimulator (Nexstim Limited, Helsinki, Finland) for single-pulse TMS and a MagPro stimulator (MagVenture A/S, Farum, Denmark) for the cTBS intervention. The Nexstim eXimia Neuronavigation system was used to ensure that the exact location of the left pars opercularis was targeted as defined by each individual’s brain MRI (Vernet et al., 2013). Motor-evoked potentials (MEPs) induced by single-pulse TMS were recorded using surface electromyography (EMG) with pre-gelled, disposable Ag/AgCl electrodes attached to the skin. The active electrode was placed over the first dorsal interosseus (FDI) muscle, the reference electrode over the metacarpophalangeal joint, and the ground electrode over the wrist. The EMG signal was acquired at 3 kHz, filtered (10–500 Hz), amplified, displayed, and stored for off-line analysis. FIGURE 1 | Post cTBS T0 TEP recorded at the FC5 electrode. cTBS, EEG was recorded with a 60-channel TMS-compatible EEG continuous theta-burst stimulation; TEP, transcranial magnetic stimulation (TMS)-evoked potential. system (eXimia EEG, Nexstim Limited). This system is designed to avoid amplifier saturation after TMS pulse by using a sample-and-hold circuit that keeps the input of the amplifiers in our experimental setup, the interstimulus interval was 240 ms constant from 100 µs prestimulus to 2 ms poststimulus compared to the interstimulus interval of 200 ms in the original (Virtanen et al., 1999). paradigm introduced by Huang et al. (2005). Thus, in our cTBS paradigm, the triplet repetition rate was approximately 4.17 Hz Experimental Session instead of 5 Hz, both frequencies being included in the theta Participants were seated in a comfortable chair, with a headrest, band. Note that previous research from our group has shown that and with their hands supinated and resting on their laps. this cTBS protocol can induce clear changes of oscillations within Participants were monitored for drowsiness and asked to keep the motor cortex (Vernet et al., 2013). their eyes open during TMS (Vernet et al., 2013). Relaxation of Before cTBS, a series of 30 neuronavigated single pulses of the target muscle (FDI muscle) was controlled by continuous TMS was applied to the left pars opercularis to evoke TEPs EMG monitoring. All participants wore earplugs to protect them (Figure 1). These pulses were applied at an intensity of 80% of from possible acoustic trauma (Rossi et al., 2009) and reduce RMT. After cTBS, two series of 30 single pulses were applied to contamination of TEPs by auditory responses to the clicks the same area and at the same intensity, one immediately after produced by the discharge of the TMS coil. cTBS (T0) and one at 10 min later (T10). The left M1 optimal scalp location was determined as the scalp location from which single-pulse TMS induced MEPs of EEG Data Preprocessing After recording EEG, the data were preprocessed using an maximum peak-to-peak amplitude in the right FDI muscle. Once open MATLAB toolbox EEGLAB1 . Data were band-pass filtered this optimal spot was identified, the neuronavigation system between 1 and 50 Hz. Artifacts induced by transient magnetic was used to ensure consistent coil placement and orientation at fields and eye blinks were eliminated using independent the optimal spot. Resting motor threshold (RMT) was defined component analysis. The noise-free data were segmented into as the lowest stimulus intensity of the Nexstim stimulator epochs from 300 ms before the stimulus onset to 1,000 ms after capable of inducing MEPs of ≥50-µV peak-to-peak amplitude the stimulus onset. Epochs were excluded from further analysis in at least 5 out of 10 trials. The RMT was obtained to if they contained significant physiological artifacts (amplitude set the stimulation intensity for subsequent single-pulse TMS. exceeding ±5 µV) in the time range from 50 to 1,000 ms after Active motor threshold (AMT) was defined as the lowest the stimulus onset at any site over all electrodes. stimulus intensity of the MagPro stimulator capable of inducing visible twitches in the FDI muscle in half of the trials while Phase Locking Value the participants maintained a contraction of the FDI muscle Phase locking value (PLV) was used to quantify the functional at approximately 20% of the maximal voluntary contraction. connectivity between pairs of regions of interest (ROIs). The AMT was used to set the stimulation intensity for the Phase locking value is a well-known index to measure phase cTBS protocol. synchronization between two time signals acquired from two cTBS was applied to the left pars opercularis with parameters different electrodes in the same time interval and frequency similar to those used by Huang et al. (2005): three pulses at 50 Hz, band (Pulvermüller, 2002). Phase locking value was selected with an interval of 200 ms between the last pulse of a triplet as the functional connectivity measure because it can robustly and the first pulse of a triplet, for a total number of 600 pulses. The intensity was fixed at 80% of AMT. Because of limitations 1 http://sccn.ucsd.edu/eeglab/ Frontiers in Human Neuroscience | www.frontiersin.org 3 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS estimate the interaction between two signals with a constant pars opercularis significantly increased at T0 after real cTBS time delay. Indeed, systematic time delays are expected between compared to baseline (corrected p = 0.009). At a later time the responses to TMS induced at different ROIs. In order to window (600–700 ms), the phase synchronization of TEPs in quantify the degree of phase synchrony between two signals Sx (t) the gamma band between the left pars opercularis and the left and Sy (t), the instantaneous phases ϕx (t) and ϕy (t) were first supramarginal region significantly increased at both T0 and evaluated using the Hilbert transform. The Hilbert transform of T10 compared to baseline (corrected p = 0.022). Similarly, at S(t) is defined as: the same time window (600–700 ms), the phase synchronization of TEPs in the gamma band between the left pars opercularis s(τ ) Z ∞ 1 and the left superior temporal region significantly increased at S̃(t) = P.V. dτ (1) π ∞ t −τ T0 (but not T10) compared to baseline (corrected p = 0.005; Figure 3A). where S̃(t) is the Hilbert transform of the time series S(t), and P.V. denotes the Cauchy principal value. The instantaneous Changes in Theta-Band Synchronization of phase ϕ(t) can then be estimated by: TEP in Real cTBS Condition In the theta band (4–8 Hz) in a 450- to 550-ms time window, the S̃(t) ϕ(t) = arctan (2) phase synchronization of TEPs between the left pars opercularis S(t) and the left supramarginal region significantly increased at The PLV was evaluated using the following definition: T0 after real cTBS compared to baseline (corrected p = 0.037; Figure 3B). PLV = |hej4ϕ(t) i| (3) Changes in Delta-Band Synchronization of where ∆ϕ(t) = ϕx (t) − ϕy (t), and |h·i| is the averaging operator. TEP in Real cTBS Condition The PLV ranges from 0 to 1, where the value close to one In the delta band (1–4 Hz) in a wide time window (350–600 ms), represents that two signals are synchronized with a constant time the phase synchronization of TEPs between the left pars lag and the value close to 0 represents that the two signals are opercularis and the left superior temporal area significantly temporally independent with each other. increased at T10 after real cTBS compared to baseline (corrected In the present study, PLV features were evaluated for three p = 0.009). However, the synchronization of TEPs between the electrode pairs, FC5-FC6, FC5-CP3, and FC5-CP5, where FC5, left pars opercularis and left supramarginal in the delta band FC6, CP3, and CP5 correspond to left pars opercularis, right significantly decreased at an earlier time window (250–350 ms; pars opercularis, left supramarginal area, and left superior Figure 3C). temporal area, respectively. The PLV features were evaluated Changes in Beta2-Band Synchronization of for delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), low beta (13–21 Hz), high beta (21–30 Hz), and gamma (30–50 Hz) TEP in Sham cTBS Condition frequency bands using a sliding window with 100-ms width and In the high beta band (21–30 Hz) in a time window (200–300 ms), 50% overlap. the phase synchronization of TEPs between the left pars opercularis and the left superior temporal area significantly Statistical Analysis decreased at T0 after sham cTBS compared to baseline (corrected We employed a Friedman test to evaluate the difference of PLV p = 0.014; Figure 4). given different conditions, baseline, T0, and T10, for different frequency bands, different time windows, and different pairs of DISCUSSION electrodes. Then, as post hoc test, Wilcoxon signed–rank test was utilized to evaluate the difference of PLV measures between cTBS to the left pars opercularis induced significant changes conditions. The significance level was set to p < 0.05 after in phase synchronization of TEPs evoked from the left pars multiple-comparisons correction using Bonferroni correction. opercularis. Specifically, we found: (1) a significant increase in the gamma frequency between the left and right pars RESULTS opercularis at an early (250–350 ms) time window and a similar increase between the left pars opercularis and the left posterior Figure 2 summarizes the significant results of modulation of TEP language areas at a later time period (600–700 ms); and (2) a synchronization induced by cTBS of the left pars opercularis. significant increase in the theta and delta bands between the Please note that no other significant modulations of TEP left pars opercularis and the posterior language areas. These synchronization across the studied ROIs were found. By EEG results provide novel insights into the interhemispheric and frequency bands, the significant findings were as follows: intrahemispheric dynamics of the language network in healthy young individuals. Changes in Gamma-Band Synchronization cTBS is a TMS protocol that has been primarily used to of TEPs in Real cTBS Condition induce a decrease of excitability in the stimulated area. Indeed, In the gamma band (30–50 Hz) at a 250- to 350-ms time window, it has been shown that cTBS applied over M1 can induce the phase synchronization of TEPs between the left and right depression of the MEPs subsequently evoked by single-pulse Frontiers in Human Neuroscience | www.frontiersin.org 4 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS FIGURE 2 | cTBS was applied on left pars opercularis area with three pulses at 50 Hz, with an interval of 200 ms between the last pulse of a triplet and the first pulse of a triplet, for a total number of 600 pulses. The figure indicates changes in phase synchronization of TEP by real cTBS on left pars opercularis area of the language network. (A) Top view. (B) Left lateral view. Black text: real cTBS condition. Blue text: sham condition. cTBS, continuous theta-burst stimulation; TEP, TMS-evoked potential. TMS (Huang et al., 2005). However, recent studies using TMS Interhemispheric interactions between the left and right pars coupled with EEG, magnetoencephalography (MEG) and/or opercularis regions have been studied as a way to promote magnetic resonance spectroscopy have revealed that cTBS also language function recovery following stroke. Some have argued has an impact on local and remote oscillatory systems, on that a stroke can impair the normal interhemispheric inhibition synchronization, and on inhibitory γ-aminobutyric acid (GABA) balance between the lesioned area and its homolog in the concentration level (Allen et al., 2014; Du et al., 2018). intact hemisphere. If so, decreasing the excitability of the latter Here, we found that cTBS over the left pars opercularis area, for example, with noninvasive brain stimulation, might induced an increase of synchronization in the gamma band decrease the excessive inhibition it exerts on the former area in early TEPs (250 to 350 ms time window) and in late and thus promote recovery. Consistent with such notions, Naeser TEPs (600–700 ms). GABAergic interneurons are known to et al. (2005) observed significant and persistent improvement in be the source of the generation of gamma oscillation (Wang picture-naming abilities in patients with nonfluent aphasia after and Buzsáki, 1996). Our finding of increased gamma-band low frequency rTMS targeting the right frontal operculum. In synchronization after cTBS might be caused by increased activity healthy individuals, similar effects of rTMS on interhemispheric of local inhibitory interneurons subtending the inhibitory inhibitory interactions between homolog areas of the language interaction between the left and right pars opercularis region. network have been shown in studies using positron emission Studies using spinal epidural recordings have shown that tomography (Thiel et al., 2006), functional MRI (Andoh cTBS applied over M1 suppresses the earliest I1-wave (Di and Paus, 2011), and behavioral responses (Cappelletti et al., Lazzaro et al., 2005), which is primarily derived from 2008). In the present study, we show for the first time GABA-related interneuronal circuits within the human motor that such interhemispheric interactions might be subtended cortex (Ziemann et al., 1998). Thus, cTBS might have decreased by synchronization in the gamma band, and that appears cortical excitability in the left pars opercularis and increased possible to modulate it by noninvasive stimulation of the left inhibition, which led to a change in TMS-evoked EEG gamma pars opercularis. synchronization. Alternatively, the increase of gamma coherence Beyond interhemispheric interactions, our results confirm the might be related to the gamma frequency (50 Hz) embedded in relevance of interregional gamma band synchronization within the cTBS pattern. brain networks previously shown in cognition and perception Interesting deficits of gamma oscillations have been reported (Sarnthein et al., 1998; Rose and Büchel, 2005; Buschman in patients with schizophrenia. Ferrarelli et al. (2008) showed and Miller, 2007) and language learning (de Diego-Balaguer that gamma activity evoked by single-pulse TMS applied et al., 2011). For instance, Miltner et al. (1999) showed that over the dorsolateral prefrontal cortex was significantly intrahemispheric coherence in the gamma band increased during decreased within the first 100 ms after TMS in schizophrenic the formation of percepts and memory, linguistic processing, patients compared to healthy controls. In such patients, and other behavioral and perceptual functions. Another study spontaneous gamma activity did not show any differences showed a greater functional connectivity between the frontal between patients and healthy controls, emphasizing the and parietal cortices within the gamma band during successful utility of TMS and specifically the use of TMS–EEG to reveal recollection, as opposed to merely experiencing a feeling of physiological abnormalities. familiarity (Burgess and Ali, 2002). In the language network, an Frontiers in Human Neuroscience | www.frontiersin.org 5 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS FIGURE 3 | Changes of phase locking value (PLV) by real cTBS on the left pars opercularis. cTBS, continuous theta-burst stimulation. FC5, FC6, CP3, and CP5 correspond to left pars opercularis, right pars opercularis, left supramarginal area, and left superior temporal area, respectively. *p < 0.05, **p < 0.01. (A) Gamma band changes. (B) Theta band changes. (C) Delta band chnages. MEG study by Duesburg et al. (2012) reported that a covert verb be functionally linked in temporal synchrony with distant generation task increased gamma band synchronization among modules via lower frequency theta and gamma band regulation. regions activated during the task, in particular, the inferior Bastiaansen et al. (2005) showed that the left hemisphere frontal gyrus and the medial frontal gyrus. A similar result of theta activity might be related to the processing of words gamma band phase locking was observed during a silent reading with extensive semantic stores. The present results, showing task (Hirata et al., 2010). Our results provide further support for increases of gamma TEP synchronization in a late time window the relevance of phase coherence among gamma rhythms within (600–700 ms) between the left pars opercularis and the left the language network. supramarginal area, may be related to local processes associated It is also worth noting that local cell assemblies in the with feature binding (Gray and Singer, 1989; Tallon-Baudry cortex are thought to form functional units through synchronous et al., 1998), whereas the increases in TEP synchronization activation in the gamma range (Engel and Singer, 2001; in the theta band at the 450 to 550 ms time window Bastiaansen and Hagoort, 2013). Oscillations may function between the left pars opercularis area and left supramarginal as nested sets, where lower-frequency activity binds higher- area might serve as a long-range synchronization between frequency activity (Lisman and Buzsáki, 2008). Theta bursts frontal and parietal cortices (von Stein and Sarnthein, 2000; occur during the up-phase of delta activity (Lakatos et al., Mellem et al., 2013). 2005), and gamma bursts occur during the up-phase of Delta oscillations, on the other hand, have been mainly theta activity (Lisman and Buzsáki, 2008). Thus, it has been associated with slow-wave sleep and anesthesia, which are states suggested that local modules of high-frequency gamma can without conscious awareness. However, delta oscillations might Frontiers in Human Neuroscience | www.frontiersin.org 6 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS using a single-session cTBS protocol with usual intensity (such as the one used in the present study) have been reported to last its effects approximately only 20–60 min (Huang et al., 2005; Chung et al., 2016). Study Limitations The present study has a number of limitations that should be considered when interpreting the results. Most importantly, we did not explore the functional correlation of TMS-induced oscillations with language testing. Therefore, it is not possible to experimentally assess whether these oscillation patterns are related to speech production. The left pars opercularis area is well known to be part of the network for speech function. Thus, it seems reasonable to assume that it has a functional role in language, which might be subtended by oscillatory activity similar to the observed TMS-induced oscillations. Nonetheless, this hypothesis awaits future experimental evaluation. In addition, it is important to note that our number of subjects is small, and they were all quite young. Further studies are needed to assess the relevance of the present findings for older adults and elderly individuals. Similarly, we have fewer females than males and an insufficient number of participants to look at gender effects. This too would warrant further studies. Finally, the relevance of our findings to patients with a stroke that might have caused aphasia needs to be examined. CONCLUSION FIGURE 4 | Changes of phase-locking value (PLV) by sham cTBS. FC5 and Our results provide novel insights into the interhemispheric CP5 correspond to left pars opercularis and left superior temporal area, respectively. *p < 0.05. and intrahemispheric dynamics of activity across nodes of the language network and illustrate the potential of using noninvasive brain stimulation for their controlled modulation. Such findings may have implications for the future development also play a role during wakefulness. For instance, high delta of noninvasive stimulation protocols to promote recovery (approximately 3 Hz) appears to organize gamma oscillations of aphasia. during memory retrieval tasks (Burgess and Ali, 2002). Thus, the dissociation of changes in PLV induced by real cTBS within the delta band might be related to different functions and also DATA AVAILABILITY STATEMENT warrant further study. We also found a significant decrease in phase synchronization The datasets generated for this study are available on request to of high beta band in sham condition only between left pars the corresponding author. opercularis and left superior temporal areas at T0. Although the PLV was relatively low compared to real cTBS condition, this decrease might have been related to functional changes in ETHICS STATEMENT this network. There was some evidence that shows decreased The studies involving human participants were reviewed and coherence in beta band coherence after stimulation of the motor approved by Beth Israel Deaconess Medical Center, Boston, MA, cortex with inhibitory protocol (Mima et al., 2003; Tamura et al., USA. The patients/participants provided their written informed 2005), but also after periods of rest (Fuggetta et al., 2007). Recent consent to participate in this study. evidence also showed a decrease in beta wave at 100–200 ms after sham cTBS (Opitz et al., 2015), in congruence with our sham result. Thus, the decrease in high beta coherence we observed AUTHOR CONTRIBUTIONS in the sham condition could be related either to a placebo effect of the stimulation, or to the fact that the participants were W-KY, SB, and AP-L designed the study. A-KB, FI-M, ME, at rest during the stimulation. We cannot entirely exclude the and MV collected the data. W-KY and JK analyzed the data. possible influence of the previous stimulation session due to W-KY, MV, JK, A-KB, FI-M, ME, SB, and AP-L wrote the main relatively short washout period (at least 48 h), although studies manuscript text. All authors reviewed the manuscript. Frontiers in Human Neuroscience | www.frontiersin.org 7 March 2020 | Volume 14 | Article 63 Yoo et al. Language Network Modulation by cTBS FUNDING by the Fyssen Foundation (France). Dr. W-KY was supported by a National Research Foundation of Korea grant funded by This work was supported in part by grants from CIMIT (Dr. the Korean Government MEST, Basic Research Promotion Fund AP-L), the National Center for Research Resources: Harvard (NRF-2013R1A1A2012562). Clinical and Translational Science Center (UL1 RR025758). Dr. AP-L serves on the scientific advisory boards for Nexstim, ACKNOWLEDGMENTS Neuronix, Starlab Neuroscience, Neosync, and Novavision, and is a listed inventor on issued and pending patents on the real-time We thank Andrea Vatulas, Cara Burzynski and Ann Connor for integration of TMS with EEG and MRI. Dr. MV was supported their administrative support. REFERENCES cortex in schizophrenia patients: a TMS/EEG study. Am. J. 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