|Year : 2020 | Volume
| Issue : 2 | Page : 45-52
Navigated transcranial magnetic stimulation brain mapping: Achievements, opportunities, and prospects
Kai Zhang1, Xuejun Yang2
1 Department of Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
2 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
|Date of Submission||12-May-2020|
|Date of Acceptance||05-Jun-2020|
|Date of Web Publication||27-Jun-2020|
Dr. Xuejun Yang
Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An.shan Road, Heping District, Tianjin 300052
Source of Support: None, Conflict of Interest: None
Maximizing the extent of tumor removal and preserving maximal neurological function are always the fundamental objectives in brain tumor surgery. This has motivated neurosurgeons to try various ways to map brain functions before tumor resection. Navigated transcranial magnetic stimulation (nTMS) is a new noninvasive method for brain mapping, which has produced exceptional results in clinical practice in recent years. However, there are still many deficiencies which need to be addressed to make nTMS more suitable for clinical application and neuroscience research. In this review, we highlight the opportunities provided by nTMS mapping, analyze the shortcomings at a theoretical level, and then emphasize the possibilities and prospects of applying multimodal fusion nTMS.
Keywords: Brain plasticity, brain tumor, fiber tracking, language mapping, motor cortex mapping, navigated transcranial magnetic stimulation
|How to cite this article:|
Zhang K, Yang X. Navigated transcranial magnetic stimulation brain mapping: Achievements, opportunities, and prospects. Glioma 2020;3:45-52
|How to cite this URL:|
Zhang K, Yang X. Navigated transcranial magnetic stimulation brain mapping: Achievements, opportunities, and prospects. Glioma [serial online] 2020 [cited 2022 Dec 8];3:45-52. Available from: http://www.jglioma.com/text.asp?2020/3/2/45/288178
| Introduction|| |
Surgical operation constitutes the beginning of comprehensive treatment for brain tumor. The removal extent of tumor directly determines the prognosis of the patient, while the preservation of neurological function determines the patient's quality of life. However, it is difficult to operate using standard brain anatomy Atlas More Detailses as a reference due to individual anatomical differences, including those induced by the tumor, as well as plasticity such as the shifting of functional areas. Magnetic resonance imaging (MRI) scans present us with anatomical images but cannot provide information about brain function, which may result in confusion between structure and function during the operating procedure. Therefore, intraoperative direct electrical stimulation (DES) is used as a gold standard in brain mapping to avoid unnecessary neurological impairment.
Navigated transcranial magnetic stimulation (nTMS) is a new method of noninvasive brain stimulation with a similar stimulation mechanism to DES and is valuable for both neuroscience research and clinical management. Based on recent research, nTMS can precisely map brain areas associated with motor and/or language function preoperation, evaluate postoperation brain function plasticity, and be applied to promote neurological rehabilitation. nTMS has the advantages of being able to noninvasively produce painless and transient cortical stimulation while still enabling complete and accurate localization of brain functions. Hence, we strive to maximize the advantages of nTMS in order to make it more reliable for clinical application.
| Database Search Strategy|| |
Full-text articles addressing the application of nTMS in brain mapping published between January 2001 and March 2020 were included in this nonsystematic review. The authors searched the PubMed database to identify relevant publications. The following literature search strategy was conducted: One major phrase is that transcranial magnetic stimulation (TMS) was combined with each of: (a) brain tumor, (b) localization, (c) language, and (d) motor. Four queries were obtained. The authors screened the reference list of the included studies to identify other potentially useful studies. After the titles and abstracts were screened, the full texts were searched using the keywords, such as “transcranial magnetic stimulation” and “localization” to determine whether they were potentially suitable. The data extraction focused on the information about brain mapping in neuro-oncology surgery and neuroscience study.
| Principals and Development of Navigated Transcranial Magnetic Stimulation|| |
The fundamental principle of TMS is similar to DES.,,, Both can induce stimulating currents in the cortex of the brain. This produces instantaneous patterns of activity pertaining to excitation or damage, which can be monitored using electrophysiology or recorded through behavioral observations. Since the systematic error of navigation can be corrected to the millimeter level, nTMS technology has made great progress and has several advantages including accurate navigation, real-time display and evaluation, and being noninvasive., When nTMS stimulates the motor cortex, local neurons are excited, evoking contraction of muscles. When areas involved in language function are stimulated, transient impairments of language function can be observed, such as speech arrest, semantic error, and aphasia. This can help us match particular language function with different areas. Hence, we can evaluate brain functions outside of the operating theater pre- or postoperatively and perform nTMS on patients unable to cooperate with examinations.
However, we should also note that the stimulation depth of TMS is less than 3 cm, limiting it to the level of the cortex, and meaning that it cannot be used to directly stimulate subcortical fiber tracts., DES, therefore, remains the only feasible way to stimulate and locate subcortical structures with real-time intraoperative display and cannot currently be replaced by noninvasive technology.
| Language Function Area Mapping|| |
Brain tumors, especially gliomas, have diffuse infiltrating growth patterns which make it difficult to distinguish the border of tumor. When the tumor is located in an eloquent area, the risk of loss of neurological function will increase during surgical resection. Thus, researchers focus on evaluating the risk of operating and the precise location of functional brain areas. As a specific advanced cognitive function, the process of language formation and output is complex, and different functional areas perform different tasks with complex interactions. Nevertheless, current research all follows the theoretical basis that cognitive systems are highly modular, making it difficult to locate and judge the role of different brain regions during language formation using a single method. TMS-induced speech arrest was first reported in 1991 in an epilepsy patient after stimulation with a 25-Hz high-frequency pattern. However, the pain and the risk of seizure limited its clinical application. In 1996, speech arrest and dysarthria were successfully induced using low-frequency TMS to lateralize the suppression of speech output, with clear distinction between speech arrest and dysarthria due to the tonic contraction of cranial muscles. Stimulation at 4 Hz was recommended for its safety and effectiveness, making it possible to use TMS in the study of language function. In 2012, Lioumis et al. used nTMS to accurately locate the language function area during a picture-naming task. They recorded and analyzed the types of speech errors to show that noninvasive mapping of language function is possible. In some brain tumor cases, tumor-induced oxygenation changes can impair the accuracy of blood oxygen level dependent functional MRI (BOLD-fMRI), prompting researchers to develop new noninvasive methods for mapping brain functions. To improve the feasibility and reliability of nTMS brain mapping, teams from Germany and America studied various stimulation tasks, patterns, sequences, onset times, and protocols in both healthy controls and brain tumor patients.,, They compared outcomes with nTMS mapping to those with preoperative BOLD-fMRI and intraoperative DES during awake surgery and obtained reliable results. They then produced preliminarily unified stimulus parameters and protocols, leading to gradual adoption in clinical practice. Researchers have also tried using nTMS as a novel research method. Hauck et al. designed a mapping study comparing nTMS and fMRI in healthy controls, while they performed different tasks including object naming, pseudoword reading, verb generation, and action naming. The results from the two methods were comparable. However, it should be noted that patients with preexisting aphasia or severe cognitive impairment made significantly more mistakes during nTMS mapping than nonaphasic patients, raising the need for further study to determine whether the procedure is reliable in this patient group. Interestingly, neither age nor pain caused by the examination biased the results. In general, as a clinical brain mapping method, nTMS has a sensitivity of more than 90%, but a low specificity in comparison to DES,, the gold standard. Work is required to improve task design and develop stimulation patterns to further increase the reliability.
Protocols for localization of language function areas using DES and nTMS both involve stimulus-interference methods, through direct or indirect stimulation of the cortex., They are used to interfere with language task execution and disturb normal language function in order to identify a direct causal relationship between the structure and function of the stimulated cortex and, therefore, locate the essential language function areas. In contrast, fMRI, magnetoencephalography, and electroencephalography are activation-observation methods which require individuals to complete specific tasks in order to activate corresponding functional brain areas.,, Simultaneously, electromagnetic signals of the whole brain are collected. However, further offline data processing is required to determine the distributions of brain functions by analyzing the difference between task-related and rest-state data. While they have the benefit of being noninvasive, these methods cannot be used to identify the direct causality of language tasks and activated brain areas and, therefore, are not sufficiently accurate to satisfy clinical demands. Hence, the potential advantage of using nTMS for localization of language function in brain tumor patients is the higher rate of true negatives when stimulating negative stimulation sites. This makes it useful for judging whether the removal of nonessential functional brain areas will affect the language function, which allows better functional prognosis, and reduces the brain mapping range as well as the exposure range of craniotomy.
Research and clinical application of nTMS started relatively late in China; early on, there was only preliminary study into language function lateralization using nonnavigational TMS. In 2014, Yang's team began to explore tasks and stimulation models suitable for the Chinese language and was the first to complete function mapping using nTMS for the Chinese language, producing several preliminary results. For the Chinese language, Zhang et al. and Lin et al. mapped the essential and participating functional areas, analyzed the neural pathway in the posterior inferior frontal gyrus, and located positive sites using nTMS. They also further discussed the neural fiber redundancy mechanism by tracing the arcuate fasciculus with combined BOLD-fMRI and diffusion tensor imaging (DTI) methods. Nevertheless, more research is required into the combination of nTMS and DES for operation guidance and stimulation protocols and evaluation standards for nTMS for the Chinese language.
| Motor Function Area Mapping|| |
Early on, the main application of TMS was to judge the integrity of neural pathways. In 1997, Krings et al. completed the first localization of motor function areas with TMS using a frameless robotic arm system, but this was not applied to clinical use due to limitations of the navigation. In 2011, Picht's group localized motor function areas in brain tumor patients with nTMS and obtained consistent results to those from intraoperative DES mapping outcomes, showing that nTMS was viable for clinical application. In task-related BOLD-fMRI brain mapping, the completion of the task requires the active participation of the individuals, which contrasts with nTMS in several ways.,, First, if the patient suffering from paralysis, then they may be unable to complete the motor task required for fMRI mapping, resulting in greater errors in the mapping outcomes., With nTMS localization, so long as the integrity of neural pathway is not compromised, the relationship between muscles and functional areas in the cortex can be monitored by EMG without participant cooperation., Second, the motor tasks used in fMRI, such as finger movements, always involve multiple muscle groups. The localization results, therefore, reflect the brain function mapping results from the muscle groups required to complete the specific task. In contrast, nTMS responses depend on the excitability of positive sites in the motor cortex and their relationship with all corresponding muscles.,, Third, since fMRI analysis is actually a kind of probabilistic analysis which requires manual setting of data thresholds, data errors will occur during processing., nTMS results can be observed directly, which reduces the occurrence of similar errors. Therefore, nTMS can locate major muscle groups with more accurate outcomes than fMRI with good credibility.,,
The individual resting motion threshold has important implications for the accuracy of localization of functional areas with nTMS. With this in mind, Sollmann et al. conducted a multiple regression analysis on the data of nTMS motor cortex mapping in 100 patients with brain tumors, exploring 14 clinical factors that may cause variation in the resting motion threshold between individuals. The results showed that gender, preoperative cerebral edema, antiepileptic drugs, tumor location, and dyskinesia are all factors which affect the individual resting motion threshold, which is deserving of attention from neurosurgeons and neuroscience researchers. As well as helping neurosurgeon to understand the relationship between the tumor and the surrounding functional areas, the use of preoperative nTMS motor cortex mapping has also enabled more thorough treatment and removal of the tumor while preserving maximal neurological function. Rosenstock et al. have established an nTMS-based risk stratification model by examining whether the results of nTMS mapping and its neurophysiological data predict postoperative motor outcome in glioma surgery. They retrospectively analyzed 113 glioma patients by performing multiple ordinal logistic regression analysis and showed that no new permanent deficit was observed when the distance between tumor and the corticospinal tract was greater than 8 mm and the precentral gyrus was not infiltrated. The risk stratification model enables clinicians to better counsel patients about the risk of functional deterioration or the potential for recovery based on objective functional-anatomical and neurophysiological measures. Another prospective study has shown that preoperative motor mapping by nTMS can help improve the surgeon's awareness of the high-risk areas of the operation, thereby changing the surgical approach and, in some cases, even the preplanned resection range. At the same time, nTMS motor mapping has good reproducibility, and therefore retest reliability,,, and can be applied to a wider range of patients than traditional preoperative functional area positioning technology. The nTMS mapping procedure can even be completed in patients with paralysis, cognitive dysfunction, or in children as young as three. In general, methods and procedures for preoperative motor mapping with nTMS in glioma patients are relatively mature,,,,, and there have been no great technical breakthroughs or developments in recent years. More research has been focused on the evaluation of curative effects and the cost–benefit analysis of nTMS as a new preoperative mapping method for brain tumor patients. In 2018, Ille et al. applied nTMS motor and language localization in order to determine the dominant hemisphere for the surgical treatment of arteriovenous malformations. This is an example of a scenario where nTMS plays a more objective role, acting as a useful supplement to the Spetzler-Martin classification.
To date, in China, there have been no systematic reports on the application of nTMS motor mapping in brain tumor patients, and only a few conference papers have mentioned the preliminary application of this technology. Recently, Yang's group completed a preliminary study of nTMS to locate the hand area of the motor cortex and discussed relevant algorithms with which to judge the accuracy of determination of motor cortex shift. To summarize, nTMS has been used to successfully map the motor cortex,,, supplementary motor cortex, and nonprimary motor area in healthy controls and patients. We suspect that robot-assisted nTMS will further develop on the basis of existing equipment, making automated mapping possible.
| Navigated Transcranial Magnetic Stimulation-Based Fiber Tracking|| |
In recent years, the combined application of nTMS and noninvasive subcortical fiber tracking technology has attracted increasing attention. Studies have shown the value of using the results of nTMS mapping as the region of interest (ROI) for DTI fiber tracking. Through data analysis, it is then possible to establish a direct anatomical-functional subcortical fiber relationship,, or function-specific tractography, which can accurately display subcortical fibers and related functions. This method is more accurate than the classic anatomical atlas positioning method, especially for brain tumor patients, and DTI analysis based on MRI data often causes artifacts. Rosenstock et al. performed nTMS mapping on patients with eloquent-located high-grade glioma and tracked the corticospinal tract using DTI based on nTMS motor positive cortical seeds and a second subcortical ROI in the caudal pons defined by the color-coded anisotropic fraction map. The results showed that lower average anisotropic fraction values within the affected corticospinal tract and higher average apparent diffusion coefficient values are significantly associated with postoperative motor function deterioration. This method provided a novel proposal for improving the fiber tracking quality and showed improved predictive power for postoperative motor outcome based on nTMS. Negwer et al. compared nTMS-based DTI fiber tracking with cubic ROI tractography in patients with left-sided perisylvian lesions. As the most reproducible protocol in language pathways, the cubic ROI protocol showed better results in arcuate fasciculus tracking, but the nTMS protocol provided superior results in the visualization of other language-related fiber tracts.
By comparing nTMS language-positive sites and arcuate fasciculus fiber tracking results in healthy controls, Lin et al. provided the first data on the relationship between essential language sites and the arcuate fasciculus among different brain regions through the generation of two probabilistic maps. The indicated redundancy of the arcuate fasciculus may represent both the potential and limitation of neuroplasticity at the white-matter level, which may be useful when selecting surgical strategies within language-eloquent areas. The nTMS-based DTI fiber tracking approach has been widely applied in clinical practice. Studies have shown that for patients with eloquent-located glioma, the tracking results of the inferior fronto-occipital fasciculus, frontal aslant tract, superior longitudinal fasciculus, and the arcuate fasciculus were related to the degree of aphasia at preoperative, postoperative, and long-term follow-up after surgery. Similar results,,, have indicated that nTMS-based language fiber tacking has high specificity and may become an indicator for evaluating aphasia related to tumor surgery.
| Brain Plasticity Evaluation and Exploration of Brain Function|| |
Since nTMS and DES are relatively consistent for brain mapping, researchers have started to apply nTMS for evaluating the postoperative rehabilitation of brain tumor patients. In 2013, Boudreau et al. used nTMS to locate the cortical area for the tongue to explore the remolding trend of tongue muscles after exercise in healthy controls. Conway et al. used nTMS to map cortical motor representation in patients with gliomas affecting the precentral gyrus preoperatively and 3–42 months postoperatively. The study provided a method for preliminarily judgment of cortical functional reorganization. They showed that the reshaping trend was different for the relative position between tumor and Rolandic region, which confirmed that nTMS can be used to noninvasively detect plastic reorganization in brain tumor patients. Another study showed that in motor area glioma patients, nTMS motor mapping 1 and 3 weeks postoperatively can be used to evaluate upper-extremity motor function recovery. They showed that those with longer distances between hotspots, lesions, and positive motor-evoked potentials have prognostic values of better recovery and can, therefore, be used as prognostic predictors for functional recovery.
In addition, Ille et al. mapped arithmetic processing with nTMS in patients with parietal brain tumors and correlated the nTMS-positive sites with postoperative outcome. Result showed that nTMS might be a useful tool for preoperative mapping of arithmetic processing, but the reliability of the results should be evaluated in a larger series and by intraoperative mapping data. nTMS has also been applied to mapping different brain functions, such as visual-spatial attention, and writing function. Currently, these are all still in the stage of exploring appropriate methods in healthy volunteers. The future goal is to use nTMS to map the distribution of various function areas for both neuroscience research and preoperative brain tumor mapping.
| Perspective|| |
In terms of central nervous system tumors, surgical resection of tumor is always the beginning of comprehensive treatments which directly affect the prognosis of patients. Mapping eloquent area of the brain is a crucial procedure in neurosurgical clinical work as localization of functional cortices determines the choice of surgical approach, the extent of surgical resection, and may also affect the postoperative recovery and prognosis. Multimodal imaging fusion technology can combine data from three-dimensional reconstructions of brain anatomical structure, vascular pathways, cortical function, and metabolic levels, as well as subcortical fiber connection. Therefore, its application has extended the boundaries of neurosurgical concepts and promoted the surgical philosophy of “maximizing the extent of tumor removal while maximizing the preservation of neurological function.” Lesions in noneloquent areas can be completely resected or even extended resected, but if the lesion is located in the eloquent areas, the benefits and risks of operation should be evaluated prudently.
nTMS is a new noninvasive method for brain mapping, which has shown potential for application in preoperative localization of brain function, and may be a useful supplement for radiotherapy planning. However, due to the complexity of the language formation process and the brain network connection, its application in preoperative localization of language function area is still unstable. Further study is, therefore, required into stimulation models, task selection, result determination methods, and behavioral data objectification. Only by improving the sensitivity and specificity of nTMS brain mapping can it become a reliable method for preoperative localization of brain functions. This requires both profound researches into the methodology, as well as updates in data processing and analysis methods and multimodal image fusion technology., Our ultimate goal is to achieve the accurate fusion of nTMS mapping information with fMRI, PET-CT, and other multimodal imaging. From this, we can formulate delicate tumor resection plans according to the tumor extent, cortical and subcortical functional boundary, and tumor metabolic range. Increases in the judgment of true-negative stimulation sites can be useful for the determination of nonfunction areas, which may shorten the process of intraoperative DES mapping, narrow the craniotomy range, and further reduce the surgical trauma. The stability of judgments of negative sites is more challenging and more valuable than the judgment of positive sites.
Although the combination of nTMS language/motor function mapping and DTI fiber tracking has shown good efficacy in glioma surgery in a previous study, there was no control group in this study, which needs to be addressed in the future. Therefore, nTMS is effective, reliable, safe, and noninvasive,,, though in current clinical practice, it is still only supplementary to intraoperative DES localization and preoperative multimodal imaging fusion in neuro-oncology surgery.
At present, there is an urgent need for a combined software and hardware systems which can accurately integrate technologies to promote the clinical application of nTMS. For nTMS to become an independent technique for brain function mapping in the future, further research is required into localization accuracy, repeatability, and operation protocol. In particular, research is required into the correction of navigation parameters after brain shifting during operation to obtain more reliable results.,, Only in this way can nTMS become a conventional tool that neurosurgeons can use in brain tumor surgery to help patients obtain more satisfactory results. We anticipate great progress in the application of nTMS technology.
Financial support and sponsorship
The work was funded by the National Key Research and Development Program of China (No. 2018YFC0115603) and Clinical Medicine Research Project of Tianjin Medical University of China (No. 2018kylc001).
Conflicts of interest
There are no conflicts of interest.
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