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Keywords:

  • aphasia;
  • Broca;
  • neuronavigation;
  • transcranial magnetic stimulation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

Objectives

This study was undertaken to test the hypothesis that repetitive transcranial magnetic stimulation (rTMS) using a neuronavigational TMS system (nTMS) to the Broca's area would elicit greater virtual aphasia than rTMS using the conventional TMS method (cTMS).

Materials and Methods

Eighteen healthy subjects underwent a randomized crossover experiment to induce virtual aphasia by targeting the Brodmann area 44 and 45 for nTMS, and F3 of international 10–20 system for cTMS. Reaction time for a picture naming task and the reaction duration for a six-digit number naming task were measured before and after each session of stimulation, and compared between the cTMS and nTMS. The stability of the coil positioning on the target was measured by depicting the variability of talairach coordinates (x, y, z) of the sampled stimulation localizations.

Results

At baseline, outcome variables were comparable between cTMS and nTMS. nTMS induced significant delays in reaction time from 944.0 ± 203.4 msec to 1304.6 ± 215.7 msec (p < 0.001) and reaction duration from 1780.5 ± 286.8 msec to 1914.9 ± 295.6 msec (p < 0.001) compared with baseline, whereas cTMS showed no significant changes (p = 0.959 and p = 0.179, respectively). The mean talairach space coordinates of nTMS demonstrated greater consistency of localization of stimulation with the target, and the error range relative to the target was narrower for the nTMS compared with the cTMS (p < 0.001).

Conclusions

nTMS leads to more robust neuromodulation of Broca's area, resulting in delayed verbal reaction time as well as more accurate targeting of the intended stimulation location, demonstrating superiority of nTMS over cTMS for therapeutic use of rTMS in neurorehabilitation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method for activating neuronal circuits in the central and peripheral nervous system [1]. rTMS modulates excitability of the brain [2] and has demonstrated potential therapeutic effects in several psychiatric and neurological illness, as well as in stroke and pain [3]. The conventional method to identify rTMS target sites other than motor cortex is by measuring distances from certain external landmarks or using the international 10–20 electroencephalography (EEG) system. It is challenging to find the optimal location because such approaches do not take into account the interindividual differences in size of the brain, and the anatomy and morphology of cortex [3]. Another critical issue for rTMS applications remains the precise and reliable positioning of the magnetic coil above the cortical region of interest.

Optically tracked navigation in neurosurgical field has expanded to encompass cognitive neuroscience together with rTMS for guidance of the magnetic coil. A neuronavigational TMS system (nTMS) can help identify the optimal brain structures for targeting rTMS [4, 5] and enables guidance of the coil on the base of the individual magnetic resonance imaging (MRI) [6] by providing an online visual feedback of the coil placement with respect to the target brain area [7]. The use of neuronavigation in combination with rTMS has gained increasing importance for very precise positioning in reference to the anatomical landmarks and functional characteristics, over the previous conventional international 10–20 system that may have caused inaccuracy during stimulation due to wrong measurements, unintended movement of the coil or the patient, or both. nTMS is expected to reduce the variability of coil positioning on the target area in comparison to the conventional TMS (cTMS) method using the 10–20 EEG system.

The aim of the current study was to compare the degree of elicited virtual aphasia in terms of delayed verbal reaction time in picture naming and duration in number naming after nTMS adopting individual anatomical mapping area to enhance precision for mapping and targeting of the Broca's area and cTMS using the 10–20 EEG system. So far in the literature, no study has been undertaken to substantiate the superiority of the use of nTMS over the cTMS 10–20 system for therapeutic use of rTMS for the treatment of aphasia.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

Subjects

Eighteen healthy right-handed volunteers participated in the study. All participants were native Korean speakers, had normal or corrected-to-normal vision, and without history of neurological or psychiatric disorders. Two subjects were withdrawn from the study because of intolerance to the discomfort induced by rTMS. All of the remaining 16 participants (eight men and eight women, mean age 34.3 years) gave their written informed consent to the procedure. The study was approved by the institutional review board of a blinded hospital. Participants were reimbursed for their participation.

Study Design

A high-resolution anatomical image was obtained from each participant in a 3-T MR scanner (Achieva 3.0T, Philips Medical Systems, the Netherlands) for use of the BrainsightTM (Rogue Research, Canada). The subjects underwent a randomized crossover experiment to induce virtual aphasia (Fig. 1). Each subject performed their task (block 1) before rTMS was applied and then repeated the task (block 2) immediately after the rTMS. The participants were stimulated with either cTMS or nTMS in random sequence. For those who received nTMS initially, the entire session was repeated with cTMS after a one-week washout period, and vice versa. The sequence of stimulation was counter-balanced across participants.

figure

Figure 1. Depiction of the experimental design. nTMS, neuronavigational TMS; cTMS, conventional TMS.

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Behavioral Tasks

A computer running SuperLab 4.5.1 (Cedrus Corporation, San Pedro, CA, USA) allowed the presentation of stimuli and recording of the responses. One set of tasks comprised 30 number naming tasks and 40 picture naming tasks. The stimuli were presented on a computer screen in front of the participant, in the center of the monitor. Block 1, the baseline task, was performed first, then the subject was given the rTMS stimulation 30 min after the completion of block 1. This was done to lessen the possible learning effect for block 2, which was composed of same materials but in a different sequence of presentation. Participants were instructed to name the presented picture and read out the six-digit numbers as accurately and quickly as possible by responding into a microphone.

Number Naming Task

The six-digit number naming task was randomly manufactured based on the method in a study by Pobric et al. [8], in which the six-digit task was developed to observe the impairment in semantic function after inducing virtual lesion in anterior temporal lobe, with aid of the random number generator program. Each stimulus was given duration of 5000 msec, which was sufficient for the subject to verbally read the presented numbers. The total duration of the six-digit number naming (e.g., 315,682; three hundred fifteen thousand, six hundred eighty-two) was recorded by Praat software program (freely available at home page: http://www.praat.org by Paul Boersma and David Weenink of the Institute of Phonetics Sciences of the University of Amsterdam, Netherlands), which detects the voice waves through a microphone, allowing measurement of the total time duration. Mean pre- and poststimulation reaction durations of number naming for both sessions of nTMS (NNTnpre, NNTnpost) and cTMS (NNTcpre, NNTcpost) were obtained.

Picture Naming Task

Pictures for the picture naming task were extracted from the picture data base of the Korean version of the Boston Naming Test (K-BNT) [9]. All selected pictures had a length of two to three segments (phonemes). Each stimulus was presented for 3000 msec before automatically moving to the next picture. The reaction time from each stimulus presentation to the first sound made by the subject was recorded by a SV-1 Voice Key apparatus (Cedrus, San Pedro, CA, USA) for each picture. Mean pre- and poststimulation reaction times of picture naming for both sessions of nTMS (PNTnpre, PNTnpost) and cTMS (PNTcpre, PNTcpost) were obtained. Because the K-BNT has 100% agreement between the normal subjects, accuracy was discarded from the data analysis [9].

TMS Mapping Protocol

Resting motor threshold (RMT) was measured as follows. The active electrode was placed on the subject's left first dorsal interosseous muscle and stimulated the right M1 area. Each subject's RMT intensity was determined as the minimum TMS intensity that produced at least five peak-to-peak MEP amplitudes of ≥50 μV from 10 consecutive stimulations delivered at an interstimulus interval rate of 4–6 sec [10]. The RMT was calculated only at first visit, and there was no difference between the RMT for nTMS and cTMS sessions. TMS pulses were applied using TAMAS (CR Technology Co., Ltd, Seongnam, South Korea), which has a maximum output of 3.0 Tesla with a power supply of 200–240 Vac 50/60 Hz 5A at a pulse width of 350 μsec. Frequency of 1 Hz stimulation for 10 min, with total of 600 pulses, were delivered at an intensity of 90% of RMT. Figure eight coil was held tangentially to the skull with the coil handle oriented perpendicular to the target on the scalp [11]. The figure eight coil was handheld in all cases without any fixation, to eliminate the biased coil stabilization by use of the fixation arm for nTMS. The Brainsight program was used to transform each subject's brain MR images into a normalized whole brain. This allows specific registration of the target of intended stimulation based on the anatomical mapping for the operator by visual presentation of the brain surface, taking into account the interindividual differences in anatomical brain structures. It also enables sampling of stimulated foci to provide related information including corresponding talairach coordinate and error range, the distance of the stimulated location from the designated target. For nTMS, online visual feedback of the coil placement with its relation to the brain enabled real-time adjustment of the coil. For cTMS, the coil was placed on F3 of the 10-20 system, stimulating with the screen turned away from the operator [12] while sampling by a blinded third party. Localizations of the stimulation were sampled every 30 sec, recording a total of 20 samples at the end of each session of both nTMS and cTMS. The inferior frontal gyrus (IFG) was identified on the surface of normalized brain for stimulation target, on which the coil placement was also visualized. However, because the Brainsight program does not automatically subtract the skull thickness, each sampling records coordinates on the skull and not the penetration of magnetic pulse on the brain surface. For precise localization of the stimulation on the brain surface instead of the skull, the skull thickness was manually deducted by adjusting the crosshair offset in the Brainsight program.

Topograhic Data Acquisition and Analysis

Data on the sampling of stimulation including the talairach coordinate as well as the error range from the designated target for both stimulation methods in every subject were collected and analyzed. The accuracy and stability of the coil positioning upon the target were measured by obtaining the mean talairach coordinate (x, y, z) in each subject for cTMS and nTMS together with the distance between the intended target and the actual stimulated spot, the error range, for each sampled stimulation. An average of the 16 mean coordinates was calculated, resulting in one stimulated foci for each stimulation method. The variability of talairach coordinates of the sampled stimulation localizations of target, nTMS, and cTMS were depicted on a single normalized brain using freeware image processing program (MRIcro, http://www.mccauslandcenter.sc.edu/mricro/mricro/index.html).

Statistical Analyses

Statistical analyses were carried out using Wilcoxon signed-rank test and Mann–Whitney test for calculation of differences between the mean pre- and poststimulation values for both behavioral tasks of nTMS and cTMS, and comparison of the differences of post and pre values of cTMS and nTMS. Also, after calculation of the mean error range for each subject, the average mean error range for each group was obtained. Correlations between the mean error range from the target for both cTMS and nTMS were tested using Wilcoxon signed-rank test.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

Behavioral Tasks

Reaction duration for the six-digit number naming task and reaction time for the picture naming task were measured before and immediately after each session of stimulation, and compared between the cTMS and nTMS. At baseline, outcome variables were comparable between cTMS and nTMS (NNTcpre and NNTnpre, 1769.8 ± 277.7 msec and 1780.46 ± 286.8 msec, respectively, p = 0.679; PNTcpre and PNTnpre, 974.6 ± 216.2 msec and 943.9 ± 203.4 msec, respectively, p = 0.352). After cTMS, the reaction duration of NNTc was unchanged (1769.8 ± 277.7 msec to 1782.2 ± 253.9 msec, p = 0.959), whereas after nTMS, the reaction duration of NNTn was significantly increased (1780.46 ± 286.8 msec to 1914.9 ± 295.6 msec, p < 0.001) (Fig. 2a). Likewise, the reaction times of PNTc after cTMS were not changed (974.6 ± 216.2 msec to 892.5 ± 144.2 msec, p = 0.179), whereas the reaction times of PNTn after nTMS were significantly delayed (943.9 ± 203.4 msec to 1304.6 ± 215.7 msec, p < 0.001) (Fig. 2b), suggesting nTMS induced significant delay in reaction duration of NNT and reaction time of PNT compared with the baseline, whereas cTMS showed no significant changes.

figure

Figure 2. Comparison of the effect of the cTMS and nTMS on (a) number naming task and (b) picture naming task. The bars represent the mean reaction time with corresponding standard error caused by rTMS for each of the conventional and navigational stimulation; * p < 0.05. NS, not significant. nTMS, neuronavigational TMS; cTMS, conventional TMS.

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Talairach Coordinates

The exported data of the talairach coordinates of stimulated locations for the cTMS and nTMS were arranged and then averaged to calculate the mean coordinate per person for each session. The mean talairach coordinates for the target of 16 subjects were x = −45.9, y = 20.4, z = 8.2 for the target; x = −42.1, y = 10.5, z = 28.1 for the cTMS; and x = −46.3, y = 20.9, z = 8.2 for the nTMS. Figure 3 depicts the MRIcro drawing of the talairach coordinates; 1) 16 cTMS; 2) 16 targets; and 3) 16 nTMS. Because some overlapped completely, they were eclipsed by others with the exactly the same coordinate. The Brodmann area for the target and the nTMS ranged from 44 to 47, with 44 being the most commonly targeted Brodmann area (n = 7), while Brodmann area 45 was the most commonly stimulated area (n = 7) with the nTMS. The Brodmann areas for the cTMS were 6, 8, 9, 41, and 44, with 9 being the most commonly stimulated area (n = 7). The mean talairach space coordinates of nTMS demonstrated greater consistency of localization of stimulation with the target, compared with the cTMS. The error range from the target was 11.3–47.3 mm for the cTMS and 0.3–1.7 mm for the nTMS. Mean error ranges of the cTMS and nTMS were 33.4 ± 14.7 mm and 0.8 ± 0.5 mm, respectively. The error range relative to the target was significantly narrower for the nTMS compared with the cTMS (p < 0.001) (Fig. 4).

figure

Figure 3. The mapping area and repeated stimuli of 16 subjects are presented for (a) cTMS (green), (b) target (red), and (c) nTMS (purple).

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figure

Figure 4. Comparison of mean error ranges of cTMS and nTMS. Bar represents standard error; *p < 0.05. nTMS, neuronavigational TMS; cTMS, conventional TMS.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

The main finding of this study comparing nTMS vs. cTMS is that nTMS leads to more robust neuromodulation of Broca's area in healthy subjects as compared with cTMS adopting 10–20 EEG system. More specifically, our study shows that application of nTMS over the Broca's area results in an increase in reaction time for the picture naming task and reaction duration for the number naming task. In contrast, stimulation with cTMS did not have a significant effect on these behavioral tasks. Our results confirm that the optically tracked nTMS reduces the variability of the coil positioning, eliciting more profound virtual lesions compared with the non-neuronavigated method.

TMS is widely used both in basic research and in clinical practice [13]. Low frequency rTMS has a neuromodulatory effect on cortical excitability, and this physiologic influence can offer a valuable therapeutic effect on the recovery from stroke [10]. Several studies have demonstrated that rTMS can induce a change in behavioral performance by transiently disrupting neural processing or virtual lesioning [14]. For example, when applied on the functionally relevant area for language, it could provide information on the functional role of targeted brain area engaged in various language tasks [11]. However, when the target is inaccurately located or stimulated, this desired effect will be diluted or will not occur. Therefore, our hypothesis of this study was that rTMS using neuronavigational system to the Broca's area would elicit greater virtual aphasia than rTMS using the conventional method.

In some previous studies, the high interindividual variance in the brain anatomy was not taken into account, and rTMS application site was defined by anatomical landmarks on the surface scalp or standardized coordinates, instead of considering individual anatomical brain map [11]. The largest source of variability in TMS application is inaccurate coil positioning or misplacement of the coil, rendering stimulation of a different cortical area from where the operator originally intended to stimulate. Therefore, minimizing such sources of variability and accurate targeting of the magnetic pulses to the desired cortical area to maximize the rTMS effect are paramount requisites for the clinical and research applications of rTMS. The reliability of the magnetic coil positioning on the precise cortical region is a critical issue in rTMS application, and optically tracked rTMS could be the answer by optimizing the stability of the coil positioning [15]. Even minor changes in coil location and orientation could affect the area being stimulated, hence, significantly changing the effect of the magnetic field in the brain [12]. The external fixation device for stabilization of coil positioning has been previously suggested; however, it was found uncomfortable [3] for both the operator and the patient.

To solve this problem of inappropriate coil positioning, an nTMS guiding the coil on the base of the individual MRI has been developed. This system provides an online visual feedback of the coil positioning with respect to the target area by utilizing individual MR images, allowing more reliable rTMS pulses reaching certain anatomical structures [15]. The high precision of neuronavigation enables the stimulated magnetic field to be focused within a range of several millimeters.

Cincotta et al. demonstrated the increased reliability of handheld focal coil positioning with the optically tracked neuronavigation by comparing the TMS-induced electrical field between nTMS and the cTMS [16]. Bashir et al. compared the effects of navigated and non-navigated rTMS in the motor cortex of 10 healthy subjects, and found that navigated rTMS leads to more robust modulation in terms of physiologic and behavioral effects [10]. For motor cortex stimulation, motor evoked potential can be an indirect marker for optimal coil position. However, for stimulation on areas other than motor cortex, such as language cortex or cortex engaged in cognitive process, such markers are not available. Therefore, more profound differences in the neuromodulatory effect could be expected between navigated and non-navigated rTMS. That is one of our reasons for selecting the Broca's area as the target on the cortex to be stimulated. Schuhmann et al. studied the temporal characteristics of activation of Broca's area by applying event-related TMS to Broca's area after picture presentation. They found TMS at 300 msec after picture presentation led to an increased picture naming latency and concluded that Broca's area is involved in the process of syllabification during overt speech production [11]. Therefore, we applied rTMS to the Broca's area to elicit virtual aphasia in terms of delayed verbal reaction time.

The Brainsight software allows adjustment of the coil position by correcting the misdirected coil-head relationship in real-time, which maximizes the consistency of stimulation on the specific anatomical area of the brain and enhances the physiologic effect of rTMS. The software also localizes and records the stimulated areas in talairach or Montreal Neurological Institute (MNI) coordinates, enabling the operator to redirect the coil positioning as the coil or the target is displaced or moved. Furthermore, because this system takes into account the spatial parameters of previous stimuli, it can be stored and used as reference for repeated stimulations and measurements.

To stimulate Brodmann area 44/45, targets were registered based on anatomical mapping of individual brain instead of referring to the talairach coordinate corresponding to the Brodmann area 44/45 (x = −49.5, y = 12.83, z = 24.83) [11]. Our results revealed mean target coordinate as x = −45.9, y = 20.4, z = 8.2. In a previous study comparing cTMS and nTMS in patients with chronic pain and depression, the M1 target was shown to be more posterior, dorsolateral premotor cortex target more superficial, and the dorsolateral prefrontal cortex target was more anterior, lateral, and deeply located when using the neuronavigation guidance compared with the standard procedure [17], suggesting that target determination using the 10–20 EEG system can be quite different from that of the nTMS based on anatomical mapping. Our mapping of coordinates (Figs. 3 and 4) for stimulation demonstrated that stimulation loci based on the international 10–20 EEG system were more superiorly, posteriorly, and widely distributed and dispersed on the cortex. This compelling finding may be valuable for clinicians who utilize rTMS, especially in targeting of the Broca's area, for treatment of aphasia using a 10–20 EEG system. The dispersion and variability seen in cTMS can be explained by various skull sizes and contours among individuals, and such errors can be, as shown by our results, reduced with the guide of the nTMS.

In our study, the targets were registered based on the brain surface anatomy by the operator, rendering some variability between the subjects, naturally followed by inevitable variability of the coordinates in nTMS. Stimulation over the Brodmann area 45 involves both the pars opercularis and pars triangularis. This rather nonspecific stimulation may be responsible for the dispersion within target and reduced virtual lesioning effect. More precise targeting over the pars opercularis or pars triangularis would have reduced variability and induced more pronounced effect.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

In conclusion, our findings suggest that neuronavigated rTMS leads to more robust neuromodulation of Broca's area resulting in delayed verbal reaction time, as well as more accurate targeting of the intended stimulation location, demonstrating superiority of the utilization of neuronavigation system for therapeutic neurorehabilitation in clinical setting. Expanding the study on the patients with aphasia would further delineate the superiority of the therapeutic use of the neuronagivation guided rTMS, which will contribute to advancement in the treatment of aphasia.

Authorship Statements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References

Drs. Kim, Min, Yang, and Paik designed and conducted the study, including patient recruitment, data collection, and data analysis. Dr. Kim prepared the manuscript draft with important intellectual input from Dr. Paik. All authors approved the final manuscript. Ministry of Health & Welfare of the Republic of Korea provided funding for the study. Drs. Kim, Yang, and Paik had complete access to the study data.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Authorship Statements
  9. References
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