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. 2020 May 26;15(5):e0233614. doi: 10.1371/journal.pone.0233614

Ten minutes of transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability

Sabrina Lorenz 1,*, Birte Alex 1, Thomas Kammer 1
Editor: Andrea Antal2
PMCID: PMC7250443  PMID: 32453767

Abstract

Recently, modulatory effects of static magnetic field stimulation (tSMS) on excitability of the motor cortex have been reported. In our previous study we failed to replicate these results. It was suggested that the lack of modulatory effects was due to the use of an auditory oddball task in our study. Thus, we aimed to evaluate the role of an oddball task on the effects of tSMS on motor cortex excitability. In a within-subject-design we compared 10 minutes tSMS with and without oddball task. In one of the two sessions subjects had to solve an auditory oddball task during the exposure to the magnet, whereas there was no task during exposure in the other session. Motor cortex excitability was measured before and after tSMS. No modulation was observed in any condition. However, when data were pooled regarding the order of the sessions, a trend for an increase of excitability was observed in the first session compared to the second session. We now can rule out that the auditory oddball task destroys tSMS effects, as postulated. Our results rather suggest that fluctuations in the amplitudes of single pulse motor evoked potentials may possibly mask weak modulatory effects but may also lead to false positive results if the number of subjects in a study is too low. In addition, there might be a habituation effect to the whole procedure, resulting in less variability when subjects underwent the same experiment twice.

Introduction

Over the past years, several studies have demonstrated that the application of a focal static magnetic field (transcranial static magnetic field stimulation, tSMS) can modulate the excitability of the targeted brain area [e.g., 1, 2–6]. Initially, this method was investigated in the motor system [1]. In their study, a strong permanent magnet was held over the motor region at subject’s scalp for 10 minutes. Reflecting the instantaneous excitability of the motor system [7], the amplitude of motor evoked potentials (MEP) evoked by single pulses of transcranial magnetic stimulation (TMS) was measured before and after tSMS. The result was a decrease in MEPs for 6 minutes after tSMS, indicating reduced excitability of the stimulated cortical area [1]. This effect has been replicated in another study, applying tSMS for 15 minutes [2]. An effect of tSMS on cortical excitability comparable to those evoked by other non-invasive brain stimulation methods such as repetitive TMS [8–10] or transcranial direct current stimulation [11–13], but without the side effects [14, 15] would offer a wide range of possibilities for, i.e., treatment of neurological or psychiatric diseases. Therefore, our group decided to replicate the results of the initial study [1]. Unfortunately, we failed to observe a decrease in MEP amplitudes after tSMS application [16].

Subsequently, it was mentioned [17] that there was a difference between our study [16] and the former one [1], possibly accounting for the different results. To standardize subject’s cognitive activity during magnetic exposure, we used an auditory oddball task. In contrast, there was no special task during exposure in other published tSMS studies.

It was suggested that the use of an oddball task could offer an explanation for the difference in results [17]. Counting mentally could activate the motor cortex due to individual finger counting habits [18], and these habits might manipulate the structure of mental number representations [19]. It has also been observed that productive and perceptive linguistic tasks increase motor cortex excitability bilaterally, indicating that forming number words mentally while counting could cause activation in the hand representation of the motor cortex [20]. Activation of the motor cortex without motor output might therefore interfere with neuroplastic modulation induced by static magnetic fields. In a reply to the letter [17], we discussed the possible effects of the oddball task on the excitability of the motor cortex and also mentioned its role in controlling subject’s attention [21]. However, we opted for a direct experimental comparison as the best way to address this question.

Therefore, in the present study we aimed to test the influence of an acoustic oddball task on the effect of tSMS on motor cortex excitability by directly comparing static magnetic field stimulation with and without oddball task in a within-subject-design.

Material and methods

Subjects

Unfortunately, in the work of Oliviero et al., 2011 no effect size has been reported. Therefore, we based our power estimation (G*Power 3.1.7) on the effect size reported more recently [5]. In their analysis on MEP ratio for the left hand, they observed a significant Time by Group- interaction with an effect size of η2 = 0.163. Together with their sample size of n = 20 (between- group) and an assumed α-error of 0.05, the power of their results was 0.24. Thus, using those values the calculated sample size for our experiment was 22. We decided to recruit 24 subjects to achieve appropriate power. In four cases the experiment could not be completed. Two subjects discontinued the experiment due to an uncomfortable feeling during the experiment. One session had to be cancelled due to MEP amplitudes being too low, even with high TMS intensities up to 66% of maximum stimulator output (MSO). One further session had to be cancelled due to technical difficulties. Therefore, the entire experiment was finished in 20 healthy subjects.

All subjects were right-handed according to a modified version of the Edinburgh Inventory Scale [22] and were screened for neurological and psychiatric disorders, chronic illnesses, previous head surgeries, metal implants in the head region and drug abuse. All subjects gave their written informed consent and were paid for their participation. The study followed the declaration of Helsinki and all experiments were approved by the Ethics Committee of the University of Ulm (231/17).

Measurement of motor cortex excitability

MEPs of the right first dorsal interosseus muscle (FDI) at rest were evoked by monophasic single pulses of TMS using a Magstim 200 stimulator (Magstim Co., Whitland, UK), connected to a figure-of-eight-coil (Double 70mm Alpha Coil, Magstim Co., Whitland, UK).

To identify the motor „hotspot”of the right FDI, suprathreshold TMS pulses were applied to the subjects’ left motor cortex. The coil was held tangentially to the scalp with the handle pointing backwards in an angle of 45° to the sagittal plane. The scalp site with the highest MEP amplitudes was defined as the motor hotspot. To maintain the correct coil position during the experiment and to retrieve the hotspot in the second session, we used a neuronavigation system (PowerMAG View!, MAG & more, Munich, Germany). The hotspot was additionally marked on the scalp using the pointer for correct positioning of the permanent magnet.

The resting motor threshold (RMT) was measured at the beginning of each session. RMT was defined as the TMS intensity generating an MEP of about 50 μV in at least 5 out of 10 trials.

MEPs were monitored using single TMS pulses. To minimize anticipation and habituation, the pulse frequency jittered randomly between 0.125 Hz and 0.2 Hz (inter-stimulus interval: 5–8 sec).

For probing cortico-spinal excitability, we adjusted stimulation intensity to evoke MEPs with a mean amplitude of about 1mV in the particular subject. 10 single pulses were applied with a given intensity above RMT. If the mean amplitude was not between 0.8 mV and 1.3 mV, the procedure was repeated with an adjusted stimulation intensity, otherwise the tested intensity was defined as 1-mV-intensity.

MEPs of the right FDI were recorded using surface electrodes in a belly-tendon montage. Signals were bandpassed (10–2000 Hz) and amplified using a Toennies universal amplifier (Erich Jaeger GmbH, Hochberg, Germany), sampled with 5000 Hz and online presented, analyzed, and stored on a PC for offline-analysis using DasyLab 13.0 (measX GmbH und Co. KG, Mönchengladbach, Germany).

An acoustic and visual feedback signal was used for online control of relaxation of the FDI during MEP recording.

Static magnetic field stimulation

For tSMS, we used the same magnet as in previous tSMS experiments [1, 2, 16], a cylindrical neodymium magnet (NdFeB) of 30 mm height and 45 mm diameter (model S-45-30-N, Supermagnete, Gottmandingen, Germany). The magnet was held manually on the scalp centered over the previously identified motor hotspot and tSMS was applied for 10 minutes with the south pole pointing to the scalp.

Experimental design

The experiment included two sessions for each subject in a randomized order, which were separated at least by one week. In one session, during tSMS subjects had to perform an acoustic oddball task, whereas in the other session tSMS was applied without any additional activity of the subject. In the oddball task, subjects heard a sequence of two beep tones with different frequencies (300 and 500 Hz, 0.2 s each, every 2.5 seconds) through in-ear-headphones, and were asked to silently count the rare beeps without using their fingers [cf. 16, 23]. The number of rare beeps was adjusted between 20 and 30 in a 10 minutes train. In both sessions, subjects were asked to keep their eyes open and remain calm and silent.

In each session, the subjects were seated in a comfortable chair. The motor hotspot was located as described above before RMT and 1-mV-threshold were determined. Baseline measurement of MEPs (pre tSMS) lasted for 4 minutes. TSMS was then applied for 10 minutes by an additional experimenter. Post measurement started 1 minute after tSMS treatment and lasted 10 minutes.

Data analysis

Statistics were performed using Statistica (V.13, StatSoft GmbH, Hamburg, Germany). Data were visually inspected for spontaneous motor activity 800ms before and after every MEP. MEPs with obvious pre-innervation were excluded. If the excluded data of one subject was above 7% of the subject’s total data, the subject was excluded entirely, leading to the exclusion of two subjects due to numerous pre-innervation. Thus, data of 18 subjects were used for the analysis. Peak-to-peak amplitudes of MEPs of each session were summarized in 2 pre- and 5 post time points, thus each time point reflects the mean amplitude of all MEPs of 2 minutes. Mauchly's sphericity test was applied for repeated-measure data and in case of violation Greenhouse-Geyser correction was used.

Raw data of the 18 subjects included in the analysis can be seen in S1 File.

Results

18 subjects (8 male, mean age 22.78 ± 2.4 years) entered the final analysis.

Main analysis

Mean RMT was 36.9 ± 5.3% of maximum stimulator output (MSO) in the sessions with and 37.1 ± 5.7%MSO in the sessions without oddball task. A paired t-test showed that there was no significant difference in RMT between the two sessions (t = 0.36, p = 0.73), but a high correlation as revealed by correlation analysis (r = 0.89, p<0.001).

Mean TMS intensity to generate MEP amplitudes of about 1 mV was 50.6 ± 9.4% MSO in sessions with and 51.6 ± 10.4% MSO in sessions without oddball task. There was no significant difference between the two sessions (t = 0.77, p = 0.45), but a high correlation (r = 0.87, p<0.001).

In sessions with oddball task, raw baseline MEP amplitude was 1.08 ± 0.49 mV at time point pre1 and 1.13 ± 0.61 mV at time point pre2. In sessions without oddball task, raw baseline MEP amplitude was 1.07 ± 0.39 mV at time point pre1 and 1.11 ± 0.44 mV at time point pre2. There was no difference in MEP amplitudes between the two baseline time points of each session (with oddball task: t = 0.87, p = 0.40; without oddball task: t = 0.58, p = 0.57). Thus, we averaged MEPs of the two baseline time points for each session as premean value. There was no significant difference in premean MEP amplitudes between sessions with and without oddball task (t = 0.07, p = 0.94). However, there was no correlation between premean MEP amplitudes of the two sessions (r = 0.03, p = 0.92).

MEP amplitudes were then normalized for each subject with respect to the premean MEP amplitude of each session, respectively.

Data were analyzed using a two-factor analysis of variance (ANOVA) with the within-factors SESSION (with, without oddball) and TIME (1–7). There was no significant effect for any factor (SESSION: F(1,17) = 0.04, p = 0.84; TIME: F(6,102) = 1.02, p = 0.42) and no interaction (F(6,102) = 0.27, p = 0.95). For graphical illustration of the main analysis see Fig 1.

Fig 1. Results of the experiment.

Fig 1

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Mean normalized MEP amplitudes are shown pre and post magnet exposure in 2 min intervals. The grey bar represents the exposure (10min) to the permanent magnet. The post measurement started 1 minute after the end of magnet exposure. Error bars show standard error of the mean. No difference between the sessions with and without oddball task was observed, neither was any effect of magnet exposure.

Analysis with respect to session order

To investigate whether the order of the sessions has an impact on our results, we analyzed the data again, sorted by session order.

Mean RMT was 36.5 ± 5.8% of maximum stimulator output (MSO) in the first sessions and 37.5 ± 5.2%MSO in the second sessions. A paired t-test showed that there was no significant difference in RMT between the two sessions (t = 1.73, p = 0.10), but a high correlation as revealed by a correlation analysis (r = 0.91, p<0.001).

Mean TMS intensity to generate MEP amplitudes of about 1 mV was 51.2 ± 10.7% MSO in the first sessions and 50.9 ± 9.1% MSO in the second sessions. There was no significant difference between the two sessions (t = 0.22, p = 0.83) but a high correlation (r = 0.87, p<0.001).

In the first sessions, raw baseline MEP amplitude was 1.04 ± 0.48 mV at time point pre1 and 1.12 ± 0.63 mV at time point pre2. In the second sessions, raw baseline MEP amplitude was 1.10 ± 0.40 mV at time point pre1 and 1.12 ± 0.40 mV at time point pre2.

There was no difference in MEP amplitudes between the two baseline time points of each session (first session: t = 1.04, p = 0.31; second session: t = 0.27, p = 0.79). Thus, we summarized the two baseline time points for each session as premean value. There was no significant difference in pre mean MEP amplitudes between the first and the second sessions (t = 0.15, p = 0.88). However, there was no correlation between premean MEP amplitudes of the two sessions (r = 0.03, p = 0.92).

Normalized MEP data were then analyzed using a two-factor ANOVA with the within-factors SESSION (first, second) and TIME (1–7). There was no significant effect for any factor (SESSION: F(1,17) = 3.90, p = 0.06; TIME: F(6,102) = 1.02, p = 0.42), but a trend towards significant differences between the two sessions as well as a significant SESSION*TIME interaction (F(6,102) = 2.47, p = 0.03, η2 = 0.13). However, since sphericity of the data was violated as revealed by Mauchly's sphericity test, Greenhouse-Geyser correction was applied, resulting in a trend to a significant interaction only (F(3.1,52.2) = 2.47, p = 0.07). For graphical illustration see Fig 2. Inspection of single subject data revealed, that the difference between session 1 and 2 was driven by only 4 out of the 18 subjects (see Fig 3).

Fig 2. Results of the experiment, grouped with respect to session order.

Fig 2

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Mean normalized MEP amplitudes are shown pre and post magnet exposure in 2 min intervals. The grey bar represents the exposure (10min) to the permanent magnet. The post measurement started 1 minute after the end of magnet exposure. Error bars show standard error of the mean. There was a trend towards a significant difference between the first and the second session as well as a trend to increased MEP amplitudes after magnet exposure in the first session.

Fig 3. Individual data.

Fig 3

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Mean normalized MEP amplitudes are shown pre and post magnet exposure in 2 min intervals. The grey bars represent the exposure to the permanent magnet. Visual inspection yielded differences between the sessions only for the subjects 06, 07, 13 and 18, respectively.

Furthermore, a friendly anonymous reviewer encouraged us to report a 3-way ANOVA including the factors SESSION (first/second), INTERVENTION (with/without oddball), and TIME (1–7).

There was a significant effect for the factor SESSION (F(1,224) = 12.35, p<0.001, η2 = 0.05). However, there was no other significant effect for any factor (INTERVENTION: F(1,224)<0.001, p = 0.99; TIME: F(6,224) = 0.66, p = 0.68) nor any statistically significant interaction.

Please note that in this 3-way ANOVA the group of 18 subjects is splitted so that only 9 subjects are averaged for the factors SESSION and INTERVENTION. Furthermore, since our aim was to investigate the influence of the oddball-task on MEP Amplitude (i.e. INTERVENTION*TIME), the question of the influence of session order is a post-hoc question.

Discussion

We evaluated the influence of an acoustic oddball task on the effect of tSMS on motor cortex excitability by directly comparing magnet exposure with and without oddball task. We could not find significant differences for any of the two conditions, indicating that the oddball task was not the reason for our failure to replicate tSMS effects [16], as postulated [17]. Since we again did not observe any modulatory effect of tSMS on excitability, the present study confirms our previous results.

Recent tSMS studies showed short-term modulatory effects up to 6min after application of tSMS for 10 [1] or 15 minutes [2]. In a recent study even long-lasting modulatory effects (at least 30min) on corticospinal excitability have been observed after tSMS applied for 30 minutes [6]. However, in our attempts to replicate tSMS modulatory effects we observed no significant difference in MEP amplitudes before and after 10 minutes of tSMS regardless of the application of the oddball task, which supports the results of our previous tSMS study [16].

A reason for the difference in our results compared to other tSMS studies might be high variability in corticospinal excitability and thus MEP amplitudes. In the present study we observed high intraindividual variabilities in baseline MEP amplitudes between session one and two, although RMTs and 1-mV-intensities correlated between the sessions. A comparable variability in baseline MEP amplitudes together with intersession reliability of RMTs has been reported recently in 27 subjects [24]. The observed variability in our study might mask weak modulatory effects caused by tSMS.

High variability in MEP amplitudes for single pulse TMS has been observed in other TMS studies. Several phenomena have been considered: spontaneous fluctuations in corticospinal and segmental motoneuron excitability levels [25], variation of synchronization and the number of activated motor units [26], and variability in corticospinal excitability and spinal desynchronization [27]. In the latter study [27], another putative source of variability has been addressed, i.e. the stability of coil position. Variance of MEP amplitudes did not differ comparing navigated and non- navigated TMS in three consecutive measurements each. However, in another study the superiority of navigated TMS over non-navigated TMS has been demonstrated comparing MEP amplitudes [28]. The authors found higher MEP amplitudes combined with a lower variance when TMS was navigated, although MTs were similar with both methods. Since we used navigated TMS, in contrast to other published tSMS studies [e.g., 1, 2, 6], we cannot exclude that the observation of reduced MEP amplitudes in those studies might be due to the non-navigated TMS setup.

Another factor that could possibly influence the reliability of excitability measurements is the number of single TMS pulses averaged to a mean amplitude as dependent variable. Studies suggest the recording of at least 21 MEPs [29], or 26 for male and 30 for female subjects [30] for on optimal consistency in results. In our study we applied an average of 35 pulses (random jitter between 34 and 38) for each baseline measurement, which is above the recommended number. In other tSMS studies, baseline excitability measurements were based on 20 [1] or 30 [2] single TMS pulses. Another study indicates that the first 20 MEPs should not be used for excitability measurements, due to an initial transient-state of corticospinal excitability [31]. However, we observed no systematic difference between the two time points of each baseline measurement, although each time point included an average of only 18 pulses (random jitter between 16 and 19).

The choice of the exposed hemisphere might also contribute to the conflicting results. Whereas in the present study and in some of the previous tSMS experiments [2, 5, 16] the left hemisphere was exposed in right-handed subjects, in the first description of the effect [1] the right hemisphere was chosen. Unfortunately, no information about handedness of the subjects was provided in that study. One could speculate that the dominance of the hemisphere might have an influence on the intensity of putative inhibitory tSMS effects. Applying excitatory protocols, a more pronounced effect for the non-dominant hemisphere has been suggested with andoal tDCS [32, 33] and paired associative stimulation [34]. To our knowledge, there are no data with inhibitory protocols yet. Thus, the influence of hemispheric dominance on tSMS remains to be investigated.

The main independent variable in the present study was presence or absence of an acoustic oddball task during the application of tSMS. We observed no difference in MEP amplitudes in dependence of the oddball task. Moreover, in the subject´s first session, independent of the oddball task, MEPs tended to increase over time post stimulation, whereas there was no change in the subject´s second sessions. The tendency of MEP amplitudes to increase over time in the absence of any intervention was observed before [35–37]. However, in our data this effect is mainly driven by a subsample of four subjects (see Fig 3). Aside from the presence or absence of an acoustic oddball task the procedure in the two sessions of each subject was identical. So far, in all tSMS studies published the effects have not been repeated with the same settings. In addition, although the order of sham and real tSMS sessions was counterbalanced in those studies, their data have not been analyzed with respect to the factor order. Recently, for intermittent theta burst stimulation (iTBS) it was suggested that the modulatory effect might habituate if the same procedure was repeated [24]. In their study, the increase of corticospinal excitability following iTBS was present in a first session, but disappeared when a second, identical session was followed about one week apart. The authors concluded that there is a high interindividual variability as well as a low intraindividual reliability of iTBS effects, and that group results based on only one session should be interpreted with caution [24]. This notion does not only hold for iTBS. In a former study [23] we investigated the effects of transcranial direct current stimulation (tDCS) on visual cortex excitability. Subjects took part in two sessions, which only differed after the tDCS intervention, but included an identical post-stimulation measurement. Only for cathodal tDCS a medium reliability was observed in the post-stimulation measurement, and overall a high variability in response to tDCS was found [23]. Therefore any study investigating the modulatory effect of a cortical stimulation including tSMS would be well advised to repeat the intervention in order to estimate the real effect.

In a study investigating the effects of three different non-invasive brain stimulation techniques on the excitability of the motor cortex, no distinct group effect was observed for either Paired Associative Stimulation, anodal tDCS or iTBS [38]. Instead, cluster analysis revealed a bimodal result pattern for all methods. However, less than half of the subjects responded as expected, and it was suggested that inter-individual variability has to be thoroughly addressed in the field of brain stimulation. Moreover, recently it was shown that cluster analyses based on MEPs might be sensitive for false positive results [37]. In that study, following four different classification techniques a significant number of subjects were classified as responders despite any intervention. Thus, the high variability might sometimes lead to false positive results if MEP amplitudes are used as the dependent variable. This, on the one hand, highlights the importance to unravel the underlying reasons for this variability [39]. On the other hand, since it was shown that neural activity can be regulated volitional [40], better methods have to be established to control for and to standardize brain activity before the application of brain stimulation techniques.

To conclude, we did not observe an inhibitory effect caused by tSMS, nor any influence of the auditory oddball task. However, these results do not exclude a tSMS effect in general. Further studies with adequate statistical power and within-subject replication would clarify this general question. Although there are first attempts for a potential treatment of neurological or psychiatric diseases using tSMS [41], the fundamental research of tSMS is still just at the beginning.

Supporting information

S1 File. Raw data.

File includes all data of the 18 subjects included in the analysis.

(XLSX)

Click here for additional data file. (13.1KB, xlsx)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Andrea Antal

13 Feb 2020

PONE-D-19-34372

Transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability

PLOS ONE

Dear Dr Lorenz,

Thank you for submitting your manuscript to PLOS ONE. I am very sorry for the longer review time, I had difficulties to find reviewers. Your paper was reviewed by two experts on the brain stimulation field, both of them had concerns with regard to the methodology and interpretation of the data. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses all points raised during the review process.

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PLOS ONE

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Reviewer #2: No

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: PONE-D-19-34372

Lorenz et al. investigated influence of tSMS on excitability of the primary motor cortex (M1). This is in essence a negative study pointing null effect of tSMS, regardless of inclusion of the oddball task; the only significant change was observed when the order of experimental sessions was taken into consideration. I believe null effects should be made public, as long as the methodology was rigorous and sound. In this regard, I have the following concerns.

1) Initially, the sample size had been calculated based on a certain medium effect size of f = 0.25 (page 5). What if this assumption was not the case? Did the authors calculate? If the actual effect size was smaller, more participants would be needed to detect a difference.

2) The significant effect of SESSION (first, second)*TIME interaction was observed in the second ANOVA with assumed sphericity. I understand this ANOVA was a (so to speak) post-hoc one; nevertheless, a three-way ANOVA could have been conducted first, using SESSION (with and without oddball), ORDER (first, second), and TIME as factors.

3) As a part of conclusion reads “absence of evidence is not evidence of absence (page 17).” I completely agree this statement, but just after that “Further studies with adequate statistical power” were claimed. We might not be able to say something about absence of evidence based on studies without adequate statistical power.

4) In Abstract, the authors argued habituation can be a key factor explaining the results, but this idea was not explicitly dealt in Discussion.

5) (Minor) sagittal “plain (page 6)” should be sagittal “plane.”

Reviewer #2: Review MS Nr. Pone-D-19-34372

This sham-controlled TMS-study was planned in order to examine the influence of cognitive activity (auditory oddball task) on tSMS- induced cortico-spinal excitability (CSE) changes. CSE was assessed via single pulse motor evoked potentials (MEP) in a pre- post experimental design. The results show that a period of 10 min tSMS (sham) did not modulate CSE, and there was no co-modulation from cognitive activity. The authors suggested that fluctuations in MEP amplitude could have masked possible weak modulatory effects. The study has a rationale and is clearly stated. However there are some points limiting its scientific value.

As described in the introduction, this study is a repetition an earlier TMS-study using 10 min tSMS (Kufner et al. 2017). Since after tSMS no effect was found in the earlier study, it is unlikely to find robust tSMS stimulation effects that are useful to clarify the additional influence of cognitive activity. In the introduction of this study I found no discussion how cognitive activity may interact with simultaneous tSMS with respect to pre-post-changes in motor cortical excitability and the formation neuroplasticity.

Although tSMS is described as a new simple form of inhibitory NIBS, and was highlighted a promising tool for brain stimulation, the mechanisms behind the neuromodulatory effects still remain unclear. Reorientation of diamagnetic anisotropic plasma membrane phospholipids (Rosen AD, 2003), coupling of mechanically-activated ion channels to ferromagnetic particles (Dobson et al. 1996) and cryptochromes (Landler & Keays 2018) are in discussion. Thus it should be stated somewhere that the fundamental research on tSMS is still at the beginning, and from this point it appears speculative to speak about treatment of neurological or psychiatric diseases.

Experimental part. The TMS-assessments for such a study are rather minimalistic. To gain more insight into the formation motor cortical plasticity and metaplasticity (tSMS + task) assessments of intracortical circuits by using by paired pulse TMS (SICI, SICF) showed advantageous (Dileone et. al. 2018). In the current study CSE was probed at a stimulation intensity to produce 1 mV MEPs. Here graded stimulation intensities resulting in MEP recruitment curves would provide information about the excitability changes of cortico-spinal circuits over a wider input-output range.

At least an exposure period (10 minutes tSMS) not appears optimal for such a study. Studies have shown that 10 minutes is the minimum, more stable and more long-lasting effect were obtained after periods of 20 and 30 min tSMS. From this point of view it is recommended to repeat the experiments with a longer stimulation period.

Minor points:

The title is no very representative for a study focusing on the influence of cognitive activity

Fig. 1 and Fig.2: the variations (standard error?) in the pre-assessment blocks are much smaller than in the post-assessment blocks. This is quite uncommon for TMS values, and needs explanation

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Reviewer #2: No

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PLoS One. 2020 May 26;15(5):e0233614. doi: 10.1371/journal.pone.0233614.r002

Author response to Decision Letter 0

25 Mar 2020

Reviewer #1: PONE-D-19-34372

Lorenz et al. investigated influence of tSMS on excitability of the primary motor cortex (M1). This is in essence a negative study pointing null effect of tSMS, regardless of inclusion of the oddball task; the only significant change was observed when the order of experimental sessions was taken into consideration. I believe null effects should be made public, as long as the methodology was rigorous and sound. In this regard, I have the following concerns.

1) Initially, the sample size had been calculated based on a certain medium effect size of f = 0.25 (page 5). What if this assumption was not the case? Did the authors calculate? If the actual effect size was smaller, more participants would be needed to detect a difference.

Indeed, if the effect size would have been smaller, the number of participants needed would be higher. Unfortunately, in most of the previous reports on tSMS effects on motor cortex excitability (Oliviero et al., 2011; Silbert et al., 2013, Dileone et al., 2018) no effect size was reported. Thus, our power estimation was based on an assumed medium effect size of 0.25 (following Cohen in case of F-statistics). With an alpha error of 0.05 and a power of 0.8, for a 2 x 7 within factor design the calculated sample size is 18. We recruited 24 subjects and were lucky to be able to analyze exact 18 subjects.

However, in most of the previous studies less subjects have been investigated (Oliviero et al., 2011: 11 subjects per experiment; Silbert et al., 2013: 10 subjects, Nojima et al., 2015: 10/10/10 per group; Dileone et al., 2018: 10/10/9/14(but 8 real 8 sham)/18(but 9 real 9 sham) for the 5 experiments, respectively). All cited studies demonstrated significant modulatory effects of tSMS. Therefore, it seems unlikely that our sample size was just too small to detect possible changes.

Furthermore, Nojima et al., 2015 reported an effect size of η2= 0.163 for the Time*Group Interaction and of η2= 0.306 in the post hoc analysis for the significant suppression of MEP in the post-0 measurement, directly after tSMS exposure. Both values represent a high effect size, following Cohen (1988) who classified effect sizes above 0.14 as high. From that our assumption of a medium effect size is a conservative estimation.

2) The significant effect of SESSION (first, second)*TIME interaction was observed in the second ANOVA with assumed sphericity. I understand this ANOVA was a (so to speak) post-hoc one; nevertheless, a three-way ANOVA could have been conducted first, using SESSION (with and without oddball), ORDER (first, second), and TIME as factors.

Indeed, a three-way ANOVA including the factors SESSION (first, second, your “ORDER”), INTERVENTION (without and with oddball, your “SESSION”), and TIME can be conducted. See the analysis here:

Please note that in the manuscript, we used the factor named SESSION both for intervention type as well as for order.

In this 3-way ANOVA the group of 18 subjects is splitted so that only 9 subjects are averaged for the factors SESSION and INTERVENTION, reducing the power compared to the approach presented in the manuscript. Furthermore, since our aim was to investigate the influence of the oddball-task on MEP Amplitude (i.e. SESSION (intervention)*TIME), we think that a 3-way ANOVA is not appropriate as first statistical attempt. The question of the influence of session order was a post-hoc question which should not be addressed in the first place. Therefore, we feel that the way we present the data is the appropriate one in a scientific sense.

3) As a part of conclusion reads “absence of evidence is not evidence of absence (page 17).” I completely agree this statement, but just after that “Further studies with adequate statistical power” were claimed. We might not be able to say something about absence of evidence based on studies without adequate statistical power.

Thank you for this sophisticated hint. Indeed, without adequate statistical power neither evidence nor the absence of evidence can be stated. This does not touch the core problem, i.e. the generation of evidence of absence, which cannot be reached regardless the adequacy of power.

We changed the passage in the conclusion section . It now reads: ”However, these results do not exclude a tSMS effect in general. Further studies with adequate statistical power and within-subject replication would clarify this general question.”

4) In Abstract, the authors argued habituation can be a key factor explaining the results, but this idea was not explicitly dealt in Discussion.

Thank you for indicating this discrepancy. It was not in our intention to postulate habituation as a key factor explaining our results. In the abstract, we only stated: “there might be a habituation effect to the whole procedure, resulting in less variability when subjects underwent the same experiment twice.”

We tried to include the habituation argument in this passage of the discussion: “Recently, for intermittent theta burst stimulation (iTBS) it was suggested that the modulatory effect might habituate if the same procedure was repeated [24]. In their study, the increase of corticospinal excitability following iTBS was present in a first session, but disappeared when a second, identical session was followed about one week apart. The authors concluded that there is a high interindividual variability as well as a low intraindividual reliability of iTBS effects, and that group results based on only one session should be interpreted with caution [24].” (page 15f.).

Since the difference between session 1 and 2 in our study is mainly driven by a subsample of 4 subjects (see Fig.3), a putative habituation on the whole procedure plays more a secondary role and was therefore not dealt with more attention. In fact, individual variability in MEP amplitudes seems to be smaller in the subject´s second sessions (which can be seen in the smaller standard errors in Fig. 2 as well), and we just argued that this might be due to a kind of habituation to the procedure.

5) (Minor) sagittal “plain (page 6)” should be sagittal “plane.”

We corrected this spelling mistake.

Reviewer #2: Review MS Nr. Pone-D-19-34372

This sham-controlled TMS-study was planned in order to examine the influence of cognitive activity (auditory oddball task) on tSMS- induced cortico-spinal excitability (CSE) changes. CSE was assessed via single pulse motor evoked potentials (MEP) in a pre- post experimental design. The results show that a period of 10 min tSMS (sham) did not modulate CSE, and there was no co-modulation from cognitive activity. The authors suggested that fluctuations in MEP amplitude could have masked possible weak modulatory effects. The study has a rationale and is clearly stated. However there are some points limiting its scientific value.

As described in the introduction, this study is a repetition an earlier TMS-study using 10 min tSMS (Kufner et al. 2017). Since after tSMS no effect was found in the earlier study, it is unlikely to find robust tSMS stimulation effects that are useful to clarify the additional influence of cognitive activity. In the introduction of this study I found no discussion how cognitive activity may interact with simultaneous tSMS with respect to pre-post-changes in motor cortical excitability and the formation neuroplasticity.

Thank you for this request. We tried to explain the putative interaction between tSMS and cognitive activity introduced by the auditory oddball task. In the introduction, we wrote:

"It was suggested that the use of an oddball task could offer an explanation for the difference in results [17]. Counting mentally could activate the motor cortex due to individual finger counting habits [18], and these habits might manipulate the structure of mental number representations [19]. It has also been observed that productive and perceptive linguistic tasks increase motor cortex excitability bilaterally, indicating that forming number words mentally while counting could cause activation in the hand representation of the motor cortex [20]." (page 3f.)

We now added the following sentence: "Activation of the motor cortex without motor output might therefore interfere with neuroplastic modulation induced by static magnetic fields."

We think that this passage now clarifies both, the putative interaction of tSMS in the motor system and a cognitive activity involving motor cortex as well as the motivation for the study.

The reviewer is right with the notion that we did not find a tSMS effect in our previous study (Kufner et al. 2017). However, the problem here was that we only measured in combination with the auditory oddball task. Therefore, indeed, this cognitive task could have interacted with the modulatory influence of tSMS, destroying the putative tSMS effect. This exactly was postulated in a letter by Foffani et al. (2017). We cannot follow the argument of the reviewer that is unlikely to find robust tSMS effects in the light of our previous results (Kufner et al. 2017), since a replication of the study by Oliviero et al. (2011), without any additional cognitive task, should yield tSMS effects.

Although tSMS is described as a new simple form of inhibitory NIBS, and was highlighted a promising tool for brain stimulation, the mechanisms behind the neuromodulatory effects still remain unclear. Reorientation of diamagnetic anisotropic plasma membrane phospholipids (Rosen AD, 2003), coupling of mechanically-activated ion channels to ferromagnetic particles (Dobson et al. 1996) and cryptochromes (Landler & Keays 2018) are in discussion. Thus it should be stated somewhere that the fundamental research on tSMS is still at the beginning, and from this point it appears speculative to speak about treatment of neurological or psychiatric diseases.

We agree that fundamental research on tSMS is at the beginning. Since other groups already published applications of tSMS in the context of neurological diseases, we stated in the introduction: " An effect of tSMS on cortical excitability comparable to those evoked by other noninvasive brain stimulation methods such as repetitive TMS [8-10] or transcranial direct current stimulation [11-13], but without the side effects [14, 15] would offer a wide range of possibilities for, i.e., treatment of neurological or psychiatric diseases." (page 3). However, in order to clarify our view on the early state of tSMS research, we added the following passage in the discussion: “Although there are first attempts for a potential treatment of neurological or psychiatric diseases using tSMS [41], the fundamental research of tSMS is still just at the beginning.”(page 17).

Experimental part. The TMS-assessments for such a study are rather minimalistic. To gain more insight into the formation motor cortical plasticity and metaplasticity (tSMS + task) assessments of intracortical circuits by using by paired pulse TMS (SICI, SICF) showed advantageous (Dileone et. al. 2018). In the current study CSE was probed at a stimulation intensity to produce 1 mV MEPs. Here graded stimulation intensities resulting in MEP recruitment curves would provide information about the excitability changes of cortico-spinal circuits over a wider input-output range.

We agree that besides MEP amplitude other parameters are suitable for measuring changes in cortico-spinal excitability. Since paired pulse TMS paradigms (SICI, ICF) show only moderate to poor test-retest-reliability whereas that for MEP amplitudes is better (i.e. Hermsen et al., 2016, J Neurol Sci 362), those measurements may not be that suitable to detect such small changes possibly caused by tSMS, although there was an effect reported by Dileone et al., 2018. However, all published data so far report a suppression effect of tSMS on MEP amplitude. Furthermore, the aim of the present study was explicitly to clarify the issue of putative interference of a cognitive task which was hypothesized to cancel the tSMS effect. Therefore, we chose MEP amplitude as the only dependent variable.

At least an exposure period (10 minutes tSMS) not appears optimal for such a study. Studies have shown that 10 minutes is the minimum, more stable and more long-lasting effect were obtained after periods of 20 and 30 min tSMS. From this point of view it is recommended to repeat the experiments with a longer stimulation period.

We agree with the reviewer that a longer exposure of tSMS might increase the modulatory effect, as recent publications demonstrate. However, the aim of the study was to replicate the original finding, as well as to answer the question concerning the impact of the additional cognitive task, as raised by Foffani and Dileone (2017). Therefore, we did not prolong the exposure time. The main question of the study, namely whether the inhibitory effect of 10min tSMS reported by Oliviero et al., 2011 is abrogated if an acoustic oddball task was used during stimulation, would not be answered by using a prolonged stimulation time.

Minor points:

The title is no very representative for a study focusing on the influence of cognitive activity

Thank you for this claim. Indeed, the title would not be appropriate for a study focusing on the influence of cognitive activity. However, in the present study we do not focus on the influence of cognitive activity. Instead, we focus on the reliability of putative tSMS effects on motor cortex excitability, trying to replicate former results and to investigate the reasons for replication failures. Therefore, we think that the title focusses on the main aspects of the manuscript.

Fig. 1 and Fig.2: the variations (standard error?) in the pre-assessment blocks are much smaller than in the post-assessment blocks. This is quite uncommon for TMS values, and needs explanation

We show normalized values. The normalization took place on the pre-assessment blocks. If we would average the two pre time points together to one single time point, no variation at all would be found since each and any subject, by definition, would have the value of 1. Only the fact that we kept the time resolution with two aggregation states in the pre-assessment blocks allowed us to include these two time points into the inference analysis.

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Decision Letter 1

Andrea Antal

9 Apr 2020

PONE-D-19-34372R1

Transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability

PLOS ONE

Dear Dr. Lorenz,

Thank you for submitting your manuscript to PLOS ONE. Your paper was reevaluated by the same Reviewers, they found that the manuscript has improved a lot, however, minor corrections/additions should be made before acceptance.  After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses all points raised during the review process.

We would appreciate receiving your revised manuscript by 10 of May, 2020. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

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  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Andrea Antal, PhD

Academic Editor

PLOS ONE

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1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to thank the authors for the elaboration and revision. The responses to my previous comments are in principle satisfactory. Please include the ideas described in the comments in the main text.

More specifically,

1) Please report the effect size, as well as the p-values. Methods states that the power analysis was performed based on the f-value as an indicator for the effect size, whereas in the response to the comments eta-squared was presented. In the main text, please also be congruent.

2) Please describe explicitly why the authors considered the three-way ANOVA inappropriate in this study. Without a priori assumption it would be the first analysis.

Reviewer #2: The authors only made minor changes in the new version of the manuscript. Not all suggestions were replied, for example the use recruitment curves was recommended in the first review to test pre- post changes in motor cortex excitability (MCE)

The authors stated in their response that “aim of this study was to replicate the original finding…… as rised by Foffani and Dileone (2017)”. Thus the intention of this study was not to evaluate the effect of tSMS on MCE in relation to the previous research in this field. This would include longer stimulation times and additional TMS protocols. However the current title of their study suggests that tSMS per se produces no modulatory effect on MCE.

As solution to this problem a more result oriented title is proposed, for example: “Ten minutes of tSMS does not reliable modulate MCE”

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: rev2_Phone-D-19-34372R2.docx

Click here for additional data file. (11.9KB, docx)
PLoS One. 2020 May 26;15(5):e0233614. doi: 10.1371/journal.pone.0233614.r004

Author response to Decision Letter 1

30 Apr 2020

Reviewer #1: I would like to thank the authors for the elaboration and revision. The responses to my previous comments are in principle satisfactory. Please include the ideas described in the comments in the main text.

More specifically,

1) Please report the effect size, as well as the p-values. Methods states that the power analysis was performed based on the f-value as an indicator for the effect size, whereas in the response to the comments eta-squared was presented. In the main text, please also be congruent.

Thank you for this hint. For the significant SESSION*TIME interaction in the analysis with respect to session order, we now added the missing effect size as η2 value (page 11). Furthermore, we rigorously checked all results of inference statistics reported with respect to completeness.

Since our experiment was based on the first study by Oliviero et al., 2011 without reporting any effect sizes, in our former version of the manuscript we decided to estimate a medium effect size for power analysis, based on the f-value reported. However, due to the fact that in a more recent paper (Nojima et al., 2015) real effect sizes were reported and in line with our own calculation, we now decided to include a power analysis on the basis of the reported η2 values instead. We changed the passage in the methods section. It now reads:

“Unfortunately, in the work of Oliviero et al., 2011 no effect size has been reported. Therefore, we based our power estimation (G*Power 3.1.7) on the effect size reported more recently (Nojima et al., 2015). In their analysis on MEP ratio for the left hand, they observed a significant Time by Group- interaction with an effect size of η2=0.163. Together with their sample size of n=20 (between- group) and an assumed α-error of 0.05, the power of their results was 0.24. Thus, using those values the calculated sample size for our experiment was 22. We decided to recruit 24 subjects to achieve appropriate power.”

2) Please describe explicitly why the authors considered the three-way ANOVA inappropriate in this study. Without a priori assumption it would be the first analysis.

We included the following passage in the results section:

“Furthermore, a friendly anonymous reviewer encouraged us to report a 3-way ANOVA including the factors SESSION (first/second), INTERVENTION (with/without oddball), and TIME (1-7).

There was a significant effect for the factor SESSION (F(1,224)=12.35, p<0.001, η2= 0.05). However, there was no other significant effect for any factor (INTERVENTION: F(1,224)<0.001, p=0.99; TIME: F(6,224)=0.66, p=0.68) nor any statistically significant interaction.

Please note that in this 3-way ANOVA the group of 18 subjects is splitted so that only 9 subjects are averaged for the factors SESSION and INTERVENTION. Furthermore, since our aim was to investigate the influence of the oddball-task on MEP Amplitude (i.e. INTERVENTION*TIME), the question of the influence of session order is a post-hoc question.”

Reviewer #2: The authors only made minor changes in the new version of the manuscript. Not all suggestions were replied, for example the use recruitment curves was recommended in the first review to test pre- post changes in motor cortex excitability (MCE)

Thank you for indicating this. We are sorry for skipping a response to the topic recruitment curves. Indeed, recruitment curves seem to be more informative regarding modulation excitability in the motor system. However, it is more time-consuming to apply recruitment curves with respect to MEP recordings with a fixed intensity. Since we aimed to replicate several previous results, we restricted our dependent variable to MEP amplitudes.

The authors stated in their response that “aim of this study was to replicate the original finding…… as rised by Foffani and Dileone (2017)”. Thus the intention of this study was not to evaluate the effect of tSMS on MCE in relation to the previous research in this field. This would include longer stimulation times and additional TMS protocols. However the current title of their study suggests that tSMS per se produces no modulatory effect on MCE.

As solution to this problem a more result oriented title is proposed, for example: “Ten minutes of tSMS does not reliable modulate MCE”

Since the reviewer is right with his or her argument, we changed the title of the manuscript. It now reads “Ten minutes of transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability”.

Attachment

Submitted filename: Response_to_reviewers_R2.docx

Click here for additional data file. (15.5KB, docx)

Decision Letter 2

Andrea Antal

11 May 2020

Ten minutes of transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability

PONE-D-19-34372R2

Dear Dr. Lorenz,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Andrea Antal, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors have nicely addressed all previous comments!

I have no further comments

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Acceptance letter

Andrea Antal

14 May 2020

PONE-D-19-34372R2

Ten minutes of transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability

Dear Dr. Lorenz:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Dr. Andrea Antal

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Raw data.

    File includes all data of the 18 subjects included in the analysis.

    (XLSX)

    Click here for additional data file. (13.1KB, xlsx)
    Attachment

    Submitted filename: Response_to_Reviewers_final.docx

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    Attachment

    Submitted filename: rev2_Phone-D-19-34372R2.docx

    Click here for additional data file. (11.9KB, docx)
    Attachment

    Submitted filename: Response_to_reviewers_R2.docx

    Click here for additional data file. (15.5KB, docx)

    Data Availability Statement

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