Navigated repetitive transcranial magnetic stimulation is a highly efficient non-invasive tool for mapping speech-related cortical areas. It helps in designing brain surgery and speeds up the direct cortical stimulation conducted during the surgery. This report describes how to perform speech cortical mapping reliably for preoperative evaluation and research.
The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.
During neurosurgery due to cerebral disease (e.g., epilepsy or a tumor), the extent of resection must be optimized to preserve brain regions that support critical functions. Areas vital for patient integrity and quality of life, such as language-related ones, should be characterized prior to the removal of brain tissue. Typically, they cannot be individually identified merely based on anatomical landmarks1. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which enables the neurosurgeon to understand the organization of the crucial cortical and subcortical structures within each patient2. Although DCS during awake surgery is considered the gold standard of cortical mapping for speech functions, it is limited by its invasiveness, methodological challenges, and the high stress it induces for both the patient and the surgical team. This protocol describes non-invasive speech cortical mapping (SCM) using navigated transcranial magnetic stimulation (navigated TMS or nTMS). Accurate non-invasive mapping aids in surgical planning, and reduces the time, costs, and risks in the operation room (OR). It also provides an alternative for those patients who are not suitable for awake craniotomy3.
Non-invasive imaging methods have already greatly benefited presurgical planning. Anatomical magnetic resonance imaging (MRI) is crucial for locating tumors and brain lesions; in neuronavigation4 and in the navigated TMS mapping5, it guides the operator to the cortical sites of interest. Diffusion-based MRI (dMRI) tractography provides detailed information on the white-matter fiber tracts that connect cortical regions5,6. During the last decade, functional imaging techniques, most notably functional MRI (fMRI) and magnetoencephalography (MEG), have been increasingly used for preoperative motor and speech cortical mapping (SCM)2,8,9. Each method brings benefits to the preoperative mapping procedure, and can, for example, provide information on the functionally related regions outside of the conventional language areas (Broca's and Wernicke's areas). fMRI has been the most commonly used method1 due to its high availability; it has been compared to DCS in the localization of speech-related areas with variable results2,10. However, although functional imaging can identify the involved brain regions, it cannot determine whether these regions are critical for the function to be preserved.
Navigated repetitive TMS (nrTMS) is nowadays used as an alternative to the aforementioned methods for preoperative non-invasive SCM11,12. nrTMS SCM is especially efficient in identifying speech-related cortical areas within the inferior frontal gyrus (IFG), superior temporal gyrus (STG), and supramarginal gyrus (SMG)11,13. An advantage of the method is that the offline analysis of the errors evoked by the stimulation allows the analyzer to be unaware of the stimulation site. It is, thus, possible to judge the error without a priori information of the cortical site's relevance to the speech network. This is enabled by a video recording, which allows the analyzer to distinguish subtle differences in errors, such as semantic and phonological paraphasia, more reliably than during the actual examination11,12. The nrTMS SCM approach currently surpasses the performance of MEG or fMRI speech mapping alone10,14, and additional functional or anatomical information may be used to fine-tune the nrTMS procedure. Preoperative mapping with nrTMS has been demonstrated to shorten operation times and reduce the required size of craniotomy and damage to the eloquent cortex15. It shortens the time of hospitalization and enables a more extensive removal of tumor tissue, thereby increasing patient survival rates15. nrTMS has been validated against intraoperative DCS mapping; specifically, the sensitivity of nrTMS in SCM is high, but its specificity remains low, with excessive false positives compared to DCS13,16.
Currently, presurgical non-invasive SCM with nrTMS can assist in patient selection for operation, help in designing the surgery, and speed up the DCS conducted during the surgery17. Here, a detailed description of how nrTMS SCM can be performed to obtain reliable speech-specific results is provided. After gaining practical experience, the suggested protocol can be tailored to best fit the patient- and site-specific demands. The protocol can be further expanded to certain targets, such as speech production (speech arrest)18,19 or visual and cognitive functions20.
This study was approved by the Hospital District of Helsinki and Uusimaa ethics committee. Informed consent to participate was obtained before the procedure from each subject.
1. Preparation of the structural images
2. Preparation for neuronavigation
3. Defining the hot spot and motor threshold for M1 stimulation
4. Baseline naming of images
5. Speech cortical mapping
6. Strategy when no naming errors occur
7. Off-line analysis of the evoked naming errors
A navigated transcranial magnetic stimulation system with integrated screens and cameras was used. Figure 1A-C highlights the different TMS-evoked naming errors in one subject during the task at different PTIs (180 ms, 200 ms, and 215 ms). The effect of the timing of the TMS pulses on the number of errors evoked is evident. In other words, TMS-related changes in performance were detected in different areas at different PTIs. The number of errors varied depending on the timing of the TMS pulses even at the same cortical sites, in accordance with MEG studies demonstrating the variation in the timing of activation in different speech-related cortical areas28. A comparison of the results between extraoperative DCS mapping and nrTMS with a fixed PTI at 300 ms in a patient with intractable epilepsy is shown in Figure 2. The data were obtained from a previous publication focusing on epilepsy29.
Figure 1: Results of an nrTMS SCM illustrated over a 3D MRI-based model from a healthy volunteer. (A) PTI of 180 ms. (B) PTI of 200 ms. (C) PTI of 215ms. In addition to the major speech-related areas, the pre-supplementary motor area (pre-SMA) was stimulated as described in the protocol (step 5.7). Most of the errors were evoked in the classical speech areas (IFG, STG, SMG), but also along the path connecting the pre-SMA and Broca's area (the close-to-midline green spots in A and B). Please click here to view a larger version of this figure.
Figure 2: Comparison of the results between extraoperative DCS mapping and nrTMS with a fixed PTI at 300 ms in a patient with intractable epilepsy. (A) Extraoperative grid mapping at the age of 13. The yellow spheres represent all the electrodes on the cortex. The sites of electrode stimulation (2-5 mA) that induced motor responses of the hand and mouth (green circles), naming arrest (anomia; red circles), and interrupting sentence repetition (pink circles) are shown. (B) nrTMS SCM of the same patient at the age of 15. The sites of nrTMS-induced anomias (red dots), semantic and phonological paraphasias (yellow dots), and hesitations (white dots) are shown. The areas with highly reproducible and reliable error induction are circled. The data for this image were taken from the study of Lehtinen et al.29. Please click here to view a larger version of this figure.
Supplementary Figure 1: Examples of images presented in the nrTMS SCM experiment (in Finnish in parentheses). (A) Hanger (Henkari). (B) Scissors (Sakset). (C) Strawberry (Mansikka). Please click here to download this File.
Here, a protocol is presented for nrTMS SCM, which enables practically complete cortical noninvasive mapping of the most important hubs of the speech and language network. Its main advantage is that it can non-invasively simulate the DCS mapping during awake craniotomy30 or extraoperatively29 (see Figure 2). Moreover, it can be applied to language cortical network studies in healthy populations31 and in patients with diseases that are not amenable to surgery32. nrTMS for SCM may also be applied to develop neurorehabilitation strategies such as target selection (e.g., after stroke). The induction of plasticity in speech-related cortical representations by DCS prior to surgery has been studied33 to increase the extent of resection34. The possibilities of nrTMS SCM in such studies should be examined.
In the present results, a relatively large area, including classical speech-related areas and the pre-SMA, was repeatedly stimulated at three different PTIs. Each PTI showed different sensitivity and specificity to errors, but also demonstrated the well-known response variability in non-invasive brain stimulations35. Most errors were induced by the stimulation of the IFG, STG, pre-SMA, and along the frontal aslant tract36. This highlights the power of nrTMS SCM; specifically, in comparison to DCS, the stimulation can be quite flexibly targeted to several areas. We have observed that changing the PTI and recording many sessions does not clearly speed up the reaction times26,29, which would be associated with a learning effect.
The protocol highlights different parameters that can affect the accuracy of nrTMS SCM. The results can be sensitive to the choices made by the TMS operator; the present paper aims to provide a standard guideline with well-tested stimulation parameters. High specificity results from an appropriate choice of several different parameters, including the ISI, PTI, coil location, and rTMS frequency. These parameters affect the specificity of the induced errors, which reflect the functions in the underlying cortical areas; the parameter selection needs to be based on current knowledge on the neurobiology of language.
The images for the naming task should be selected so that they do not induce erroneous naming by themselves (Supplementary Figure 1). Here, the images were chosen from a standardized image bank and controlled for various naming parameters25,37. For example, the pool of images was restricted to items with similar complexity and frequency in everyday use, as well as high name agreement. The choice of images can vary based on the needs of each surgical center38, the population under investigation39, the native language of the tested subject40,41 and the used task42. As presented in the protocol, the baseline image selection is finally individualized for each subject, as on-spot naming is subjective.
The stimulation frequency needs to be defined individually, because it may determine the distribution of errors during navigated transcranial magnetic brain stimulation43. The presented choice, 4-8 Hz, is based on the rTMS work by Epstein et al.44. The initial stimulation frequency is set to 5 Hz. If no errors are detected, the stimulation frequency is increased to 7 Hz. Higher frequencies may reduce nrTMS-induced pain and increase the specificity of naming errors45. Higher frequencies also have the advantage of limiting the pulses to a short and more specific time interval. They may, however, affect functions related to, for example, speech motor execution44,46, which are not the main target of the present protocol.
It is recommended to vary the PTI between 150-400 ms. This is an important time window for word retrieval during the object naming task28,47. The protocol aims at speech specificity by avoiding the interference of basic visual processing, which occurs during the first 150 ms after image presentation and may affect object naming but is unrelated to speech production. The recommended upper limit for the PTI is based on typical response latencies in picture naming in the same subject28,48, and individual variation in the optimal values between subjects can be expected (see Figure 1). The PTI selection should ideally be based on personalized measures, although this may be logistically demanding in a clinical setting. Helsinki University Hospital protocols usually start with a 300 ms PTI. It may also be useful to change the PTI based on the stimulated area12,13,49, as indicated by several language studies28,47,50. Nevertheless, PTIs outside the above-mentioned window may also induce naming errors that are useful for presurgical evaluation (for a comparative study, see Krieg et al.49 using PTIs of 0-300 ms).
The cortical speech network is widespread and varies among individuals, particularly in patients with tumors and epilepsy29,30,39. nrTMS induces language disturbance with great variability across individuals, analogous to those observed during awake craniotomy stimulations27,51. The information obtained from fMRI50, DTI52,53,54, and MEG55 can direct the nTMS user and result in a procedure that is tailored for each individual and is, thus, more specific and accurate. The objective in nrTMS SCM is to increase the specificity, reduce the number of non-responders, guide the DCS reliably, or replace it when the resources and conditions do not allow a team of highly specialized experts to perform it. In the future, multilocus TMS (mTMS) could be applied in the procedure to stimulate different parts of the cortex without physically moving the stimulation coil56.
The present protocol can be performed with several types of naming tasks42,57 or other cognitive tasks (calculations, decision making, etc.)58. The video recording can disclose crucial features of the task performance (e.g., grimaces by the subject indicating that no motor speech arrest is induced) that can go unobserved during the stimulation. The setup also allows for asking the subject about the nrTMS-induced experiences and sensations by jointly viewing the video recording. This can help in distinguishing pain-induced errors from the true effects of nrTMS. Finally, the protocol can be easily modified to different subject groups (e.g., bilingual individuals31) and to serve the needs of each surgical or research team.
The authors have nothing to disclose.
Pantelis Lioumis has been supported by an HUS VTR grant (TYH2022224), Salla Autti by the Päivikki and Sakari Sohlberg Foundation, and Hanna Renvall by the Paulo Foundation and Academy of Finland (grant 321460).
Neurology surface electrodes | Ambu A/S | Ambu Neuroline Ground | |
Neurology surface electrodes | Ambu A/S | Ambu Neuroline 720 | |
Off-line speech error analyzer | Nexstim Ltd | NexSpeech 2.1.0 | |
Single patient surface electrode | Ambu A/S | Ambu Neuroline 700 | |
Stimulator | Nexstim Ltd | NBS 4.3 |