Protocol for motor and language mapping by navigated TMS in patients and healthy volunteers; workshop report.

INTRODUCTION: Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value. METHODS: The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications. RESULTS: nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here. CONCLUSION: At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping.

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.

A simple magnetoencephalographic auditory paradigm may aid in confirming left-hemispheric language dominance in epilepsy patients.

OBJECTIVE: The intracarotid amobarbital procedure (IAP) is the current "gold standard" in the preoperative assessment of language lateralization in epilepsy surgery candidates. It is, however, invasive and has several limitations. Here we tested a simple noninvasive language lateralization test performed with magnetoencephalography (MEG). METHODS: We recorded auditory MEG responses to pairs of vowels and pure tones in 16 epilepsy surgery candidates who had undergone IAP. For each individual, we selected the pair of planar gradiometer sensors with the strongest N100m response to vowels in each hemisphere and-from the vector sum of signals of this gradiometer pair-calculated the vowel/tone amplitude ratio in the left (L) and right (R) hemisphere and, subsequently, the laterality index: LI = (L-R)/(L+R). In addition to the analysis using a single sensor pair, an alternative analysis was performed using averaged responses over 18 temporal sensor pairs in both hemispheres. RESULTS: The laterality index did not correlate significantly with the lateralization data obtained from the IAP. However, an MEG pattern of stronger responses to vowels than tones in the left hemisphere and stronger responses to tones than vowels in the right hemisphere was associated with left-hemispheric language dominance in the IAP in all the six patients who showed this pattern. This results in a specificity of 100% and a sensitivity of 67% of this MEG pattern in predicting left-hemispheric language dominance (p = 0.01, Fisher's exact test). In the analysis using averaged responses over temporal channels, one additional patient who was left-dominant in IAP showed this particular MEG pattern, increasing the sensitivity to 78% (p = 0.003). SIGNIFICANCE: This simple MEG paradigm shows promise in feasibly and noninvasively confirming left-hemispheric language dominance in epilepsy surgery candidates. It may aid in reducing the need for the IAP, if the results are confirmed in larger patient samples.

Language mapping with navigated transcranial magnetic stimulation in pediatric and adult patients undergoing epilepsy surgery: Comparison with extraoperative direct cortical stimulation.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) is becoming increasingly popular in noninvasive preoperative language mapping, as its results correlate well enough with those obtained by direct cortical stimulation (DCS) during awake surgery in adult patients with tumor. Reports in the context of epilepsy surgery or extraoperative DCS in adults are, however, sparse, and validation of nTMS with DCS in children is lacking. Furthermore, little is known about the risk of inducing epileptic seizures with nTMS in pediatric epilepsy patients. We provide the largest validation study to date in an epilepsy surgery population. METHODS: We compared language mapping with nTMS and extraoperative DCS in 20 epilepsy surgery patients (age range 9-32 years; 14 children and adolescents). RESULTS: In comparison with DCS, sensitivity of nTMS was 68%, specificity 76%, positive predictive value 27%, and negative predictive value 95%. Age, location of ictal-onset zone near or within DCS-mapped language areas or severity of cognitive deficits had no significant effect on these values. None of our patients had seizures during nTMS. SIGNIFICANCE: Our study suggests that nTMS language mapping is clinically useful and safe in epilepsy surgery patients, including school-aged children and patients with extensive cognitive dysfunction. Similar to in tumor surgery, mapping results in the frontal region are most reliable. False negative findings may be slightly more likely in epilepsy than in tumor surgery patients. Mapping results should always be verified by other methods in individual patients.

Effects of navigated TMS on object and action naming.

Transcranial magnetic stimulation (TMS) has been used to induce speech disturbances and to affect speech performance during different naming tasks. Lately, repetitive navigated TMS (nTMS) has been used for non-invasive mapping of cortical speech-related areas. Different naming tasks may give different information that can be useful for presurgical evaluation. We studied the sensitivity of object and action naming tasks to nTMS and compared the distributions of cortical sites where nTMS produced naming errors. Eight healthy subjects named pictures of objects and actions during repetitive nTMS delivered to semi-random left-hemispheric sites. Subject-validated image stacks were obtained in the baseline naming of all pictures before nTMS. Thereafter, nTMS pulse trains were delivered while the subjects were naming the images of objects or actions. The sessions were video-recorded for offline analysis. Naming during nTMS was compared with the baseline performance. The nTMS-induced naming errors were categorized by error type and location. nTMS produced no-response errors, phonological paraphasias, and semantic paraphasias. In seven out of eight subjects, nTMS produced more errors during object than action naming. Both intrasubject and intersubject analysis showed that object naming was significantly more sensitive to nTMS. When the number of errors was compared according to a given area, nTMS to postcentral gyrus induced more errors during object than action naming. Object naming is apparently more easily disrupted by TMS than action naming. Different stimulus types can be useful for locating different aspects of speech functions. This provides new possibilities in both basic and clinical research of cortical speech representations.

A novel approach for documenting naming errors induced by navigated transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is widely used both in basic research and in clinical practice. TMS has been utilized in studies of functional organization of speech in healthy volunteers. Navigated TMS (nTMS) allows preoperative mapping of the motor cortex for surgical planning. Recording behavioral responses to nTMS in the speech-related cortical network in a manner that allows off-line review of performance might increase utility of nTMS both for scientific and clinical purposes, e.g., for a careful preoperative planning. Four subjects participated in the study. The subjects named pictures of objects presented every 2-3s on a computer screen. One-second trains of 5 pulses were applied by nTMS 300ms after the presentation of pictures. The nTMS and stimulus presentation screens were cloned. A commercial digital camera was utilized to record the subject's performance and the screen clones. Delays between presentation, audio and video signals were eliminated by carefully tested combination of displays and camera. An experienced neuropsychologist studied the videos and classified the errors evoked by nTMS during the object naming. Complete anomias, semantic, phonological and performance errors were observed during nTMS of left fronto-parieto-temporal cortical regions. Several errors were detected only in the video classification. nTMS combined with synchronized video recording provides an accurate monitoring tool of behavioral TMS experiments. This experimental setup can be particularly useful for high-quality cognitive paradigms and for clinical purposes.