-supplementary files only-

Protocol for Motor and Language Mapping by Navigated TMS in Patients

and Healthy Volunteers; workshop report

The navigated TMS workshop group; Helsinki Meeting 2016

Sandro M. Krieg, MD, MBA1; Pantelis Lioumis, PhD2; Jyrki P. Mäkelä, MD, PhD2;

Juha Wilenius, MD 3; Jari Karhu, MD, PhD4; Henri Hannula, MSc4,5; Petri

Savolainen, MSc4; Carolin Weiss Lucas, MD6; Kathleen Seidel, MD7; Aki Laakso,

MD, PhD8; Mominul Islam, MD, PhD9; Selja Vaalto, MD, PhD3; Henri Lehtinen,

Lic. Psych, MSc10; Anne-Mari Vitikainen, PhD2; Phiroz E. Tarapore, MD11;

Thomas Picht, MD12

all authors contributed equally to this work

1 Department of Neurosurgery, Klinikum rechts der Isar, Technische Universität

München, Germany,2 BioMag Laboratory, HUS Medical Imaging Center, University of Helsinki and

Helsinki University Hospital, Helsinki, Finland,3 Department of Clinical Neurophysiology, HUS Medical Imaging Center,

University of Helsinki and Helsinki University Hospital, Helsinki, Finland4 Nexstim Plc, Helsinki, Finland.

5 Department of Biomedical Engineering and Computational Science, Aalto

University, Espoo, Finland,6 Center of Neurosurgery, University Hospital Cologne, Germany.7 Department of Neurosurgery Inselspital, Bern University Hospital University of

Berne, Switzerland,8 Department of Neurosurgery, Helsinki University Hospital and Clinical

Neurosciences, Neurosurgery, University of Helsinki, Helsinki, Finland,9 Department of Clinical Neurophysiology (R2:01), Karolinska University Hospital,

Solna, Stockholm, Sweden,10 Epilepsy Unit, Department of Pediatric Neurology, Helsinki University Central

Hospital, Helsinki, Finland, 11 Department of Neurological Surgery, University of California, San Francisco,

CA, USA,

12 Department of Neurosurgery, Charité–Universitätsmedizin Berlin, Germany.

Address for correspondence:Sandro M. Krieg, MD, MBA Sandro.Krieg@tum.de

Department of Neurosurgery, Klinikum rechts der Isar

Technische Universität München

Ismaninger Str. 22, 81675 Munich, Germany

Phone: +49 89 4140 9482, Fax: +49 89 4140 4889

Complete contact information:Pantelis Lioumis, PhD plioumis@gmail.com

Jyrki Makelä, MD, PhD Jyrki.Makela@hus.fi

Vitikainen Anne-Mari, PhD Anne-Mari.Vitikainen@hus.fi

BioMag Laboratory, HUS Medical Imaging Center, University of Helsinki and

Helsinki University Hospital

P.O. Box 340, FI-00029 HUS, Helsinki, Finland

Phone: +358 9 47172096, Fax: +358 9 47175781

Jari Karhu, MD, PhD Jari.Karhu@nexstim.com

Henri Hannula, MSc Henri.Hannula@nexstim.com

Petri Savolainen, MSc Petri.Savolainen@nexstim.com

Nexstim Plc.

Elimäenkatu 9 B, 00510, Helsinki, Finland

Phone: +358 (9) 27271712, Fax: +358 (9) 27271717

Carolin Weiss Lucas, MD Carolin.Weiss@uk-koeln.de

Center of Neurosurgery, University Hospital Cologne

Kerpener Str. 62, 50937 Cologne, Germany

Phone: +49 221 47882799. Fax: +49 221 4783189

Kathleen Seidel, MD Kathleen.Seidel@insel.ch

Department of Neurosurgery Inselspital, Bern University Hospital

University of Berne

3010 Berne, Switzerland

Phone: +41 (0)31 632 24 09, Fax: +41 (0)31 632 69 60

Aki Laakso, MD, PhD Aki.Laakso@hus.fi

Department of Neurosurgery, Helsinki University Hospital

P.O.Box 266, Topeliuksenkatu 5, 00260 Helsinki, Finland

Phone: +358 9 4711, Fax: +358 9 471 87560

Mominul Islam, MD, PhD mominul.islam@karolinska.se

Department of Clinical Neurophysiology (R2:01), Karolinska University Hospital

Solna, 17176 Stockholm, Sweden

Phone: +46 762238769

Juha Wilenius, MD Juha.Wilenius@hus.fi

Selja Vaalto, MD, PhD Selja.Vaalto@hus.fi

Department of Clinical Neurophysiology, Helsinki University Central Hospital,

P.O.Box 340, FIN-00029 HUS, Finland

Phone: +358 947172492, Fax: +358 947180244

Henri Lehtinen, Lic. Psych, MSc Henri.Lehtinen@hus.fi

Epilepsy Unit, Department of Pediatric Neurology, Helsinki University Central

Hospital, Helsinki, Finland

Lastenlinnantie 2 PL 280, 00029 HUS

Phone: 358 50 427 2593

Phiroz E. Tarapore, MD TaraporeP@neurosurg.ucsf.edu

Department of Neurological Surgery, University of California at San Francisco,

505 Parnassus Ave, Moffitt, San Francisco, CA 94143, USA

Phone: +1 415 353 3933, Fax: +1 415 353 3910

Thomas Picht, MD Thomas.Picht@charite.de

Department of Neurosurgery, Charité–Universitätsmedizin Berlin,

Campus Benjamin Franklin

Augustenburger Platz 1, 13353 Berlin, Germany

Phone: +49 30 450 560 222, Fax: +49 30 450 560 900

Abstract

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 1,500 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 is used in the

framework of clinical studies to continue refinement of its protocol and increase

reliability.

Key words: brain tumor; epilepsy surgery; motor; language; preoperative

mapping; transcranial magnetic stimulation

1. INTRODUCTION

Navigated transcranial magnetic stimulation (nTMS) has gained increasing

acceptance for preoperative mapping of motor and language function in

neurosurgical centers across the world [8, 25, 37, 54, 74, 84].

Clinical evidence of its benefit for the patients is growing [24, 39, 54, 68]. Various

protocols for motor and language mapping have been published to enhance

specificity and sensitivity of nTMS, [28, 29, 43, 48, 55, 59, 83]. Protocols for

language mapping are particularly variable between centers [30, 43, 48, 75, 80].

This variability diminishes comparability of results and hampers its widespread

adoption in clinical practice.

This workshop report aims to recommend a common protocol for nTMS mapping

that addresses all aspects of its application, including the parameters used, data

analyses, and clinical integration. It is a part of a larger project to establish a

worldwide cooperation of researchers using nTMS for presurgical delineation of

motor and language function and to fully integrate nTMS in clinical standards of

care.

This report is not meant to replace existing guidelines on non-invasive stimulation

of the brain [63]. It represents an adjunct for previous guidelines focusing on the

presurgical use of nTMS in functional cortical mapping, particularly to benefit

neurosurgeons and affiliated researchers.

2. THE WORKSHOP MEETING

The nTMS workshop group, consisting of 11 experts with neurosurgical and

scientific experience in nTMS motor and language mapping of up to 14 years,

met in Helsinki, Finland on January 21-22 2016 and discussed current evidence

and individual experiences to forge a recommended protocol for preoperative

nTMS motor and language mappings.

To provide the best available evidence for the protocol, data from published

clinical nTMS studies was used as a basis of these recommendations. Therefore,

we reviewed the current literature via Medline search and identified and analyzed

all articles relevant for the use of nTMS in the neurosurgical field. The relevant

articles for each aspect of nTMS mapping are cited in the particular paragraph.

For questions not dealt with in published reports, expert opinions were distilled to

a common final statement. These recommendations, which cannot be proved to

date by any available literature and are therefore based on our group consensus,

do not possess any reference in their paragraph.

3. METHODOLOGICAL BACKGROUND ON NTMS

3.1.Motor mapping

Transcranial magnetic stimulation (TMS) is an electrophysiological technique for

the investigation of the human motor cortex and motor tracts [2]. Development of

TMS coils producing more focal cortical stimulation increased the spatial

resolution of TMS. TMS delivers a short (rise time 100 μs), strong (1-2.7 T)

magnetic field (pulse), which penetrates the skull and induces an electric field

within the cortex. When appropriate stimulus intensity is used, this electric field

activates cortical motoneurons of the corticospinal tract (CST). The descending

corticospinal volley then excites α-motoneurons of the anterior horn of spinal cord

generating a motor evoked potential (MEP) in the muscle. The amplitude of the

obtained MEP depends on stimulation intensity, coil shape and the quantity of

excited motoneurons [15]. The efficacy of TMS is evaluated by continuous

electromyography (EMG) monitoring to detect a MEP induced by stimulation of

each cortical site comparable to intraoperative direct cortical stimulation (DCS)

[36, 64, 65].

3.2.Language mapping

In contrast to motor mapping, which uses single TMS pulses to elicit a MEP,

language mapping protocols utilize repetitive TMS pulses (rTMS) [53]. As in DCS

mapping during awake surgery, patients perform language tasks and rTMS is

used to impair task performance by disrupting language-involved cortical regions

[14, 18, 78]. The exact mechanisms by which rTMS interferes with language

processing are not fully understood, but they likely involve a focal depolarization

and temporary inhibition of neuronal networks involved in language processing

[18].

3.3.Neuronavigation

When a TMS pulse is delivered, the affected cortical structure as well as the field

strength within the structure depend on individual brain anatomy. By integrating a

frameless stereotactic navigation system with the TMS coil and pulse generator,

precise, real-time navigation and quantification of the magnetic field becomes

possible. Current nTMS systems use a focal figure-of-eight TMS coil referenced

to coordinates of the patient’s head via an infrared tracking system. The induced

electric field is visualized on the surface of the 3D head model which is

reconstructed from the patient-specific MRI data. This technique, known as

“navigated TMS” (nTMS), thereby enables exact delivery of a specific electric

field to a given cortical structure, [36, 64, 65] and is a requirement for any pre-

surgical mapping application.

4. NTMS MOTOR MAPPING

4.1.Clinical evidence

Several studies have shown that motor cortical representations identified by

nTMS correlate well with findings from intraoperative DCS. Moreover, nTMS has

been shown to be useful in planning surgery of patients with brain tumors [22, 40,

56] and with medically intractable epilepsy [49, 79]. Importantly, preoperative

functional mapping of motor areas by nTMS also improves the outcome after

operation of supratentorial tumors located in presumed motor eloquent areas [24,

39, 41, 54]. Increasing evidence also suggests that motor cortical sites identified

by nTMS are closer to corresponding DCS sites than functional landmarks

obtained by magnetoencephalography (MEG) and functional magnetic

resonance imaging (fMRI) [22, 40, 77]. nTMS mapping may also provide signs of

post-operative plasticity after tumor [6, 9, 23, 72] or epilepsy surgery [81].

Moreover, a large distance between the nTMS landmarks and the operated

target and subcortical tracts may suggest that intraoperative neuromonitoring

(IOM) is not necessary [25]. nTMS may identify eloquent cortex in patients where

tumor or epilepsy-induced plastic changes have led to reorganization of

functional cortex, or tumor expansion has distorted anatomical cortical landmarks

[10]; IOM is recommended if eloquent cortex is located by nTMS in the proximity

of the operation target although anatomical features indicate non-eloquent tumor

location [57]. A more targeted and faster DCS mapping in some patients may

also be planned by nTMS landmarks [60]. We regard nTMS and IOM as

complementary methods, mutually increasing effectiveness and safety of

neurosurgery [38, 52].

4.2.Limitations of the method

The intraoperative use of nTMS data and integration of the anatomical MR

images into the neuronavigation system still has limitations. The results appear

highly accurate directly after opening the dura, but brain shift can impair the

precision as the resection proceeds [27, 73]. Moreover, the integrity of

subcortical pathways such as the CST is crucial for patient outcome; nTMS is not

able to detect or monitor these tracts, although nTMS results can be utilized to

delineate cortical seeding regions of interest (ROIs) for ROI-based MR diffusion

tensor tractography [8, 25, 37, 84]. Consequently, nTMS does not replace IOM or

DCS mapping.

4.3.Recommended protocol

4.3.1. Patient selection

Preoperative nTMS motor mapping is advisable for surgery of brain tumors in the

vicinity of the CS or the CST [52]. This motor map is used for identifying critical

structures and their relationship to the tumor. It may also be used to define seed

regions for diffusion tensor imaging fiber tracking (DTI-FT). Finally, this map can

provide useful preoperative information for surgery of tumors in pre- or

supplementary motor areas [6]. The assessment of the excitability of the motor

system by nTMS supports preoperative risk-benefit balancing [60]. Yet, electronic

or metallic implants made from magnetic materials in the head/neck region as

well as cardiac pacemakers are general contraindications for nTMS. However,

TMS has been carried out without adverse effects in patients having deep brain

stimulation electrodes [45], ventriculoperitoneal shunts [46, 47], and aneurysm

clips [33]. Pregnancy is not a contraindication for nTMS [19, 32]. Depending on

the protocol, TMS may induce seizures, particularly in patients with poorly

controlled epilepsy. Members of the workshop group have not reported any

manifest seizures induced by the single pulse or repetitive TMS protocols

recommended in this consensus [75, 76], and nTMS has been used successfully

and without inducing seizures in epilepsy surgery planning [49, 79, 80].

Nevertheless, patients with epilepsy should be counseled about the theoretical

risks of inducing seizures and the personnel involved in nTMS need to be aware

of the site-specific emergency procedures.

4.3.2. Preparation

An anatomical MRI with (not overlapping) thin slices (1 mm) is needed to create

an adequate 3D brain reconstruction and enable accurate navigated coil

positioning during nTMS mapping. In addition, a DWI dataset for white matter

tracking should be acquired to enable visualization of the cortico-subcortical

connectivity. Before the TMS examination, the patient should be informed about

the purpose of the procedure and the basics of the nTMS. A well-informed

patient is able to understand fully the procedure as a basis for his/her treatment.

This preparation significantly increases the patient compliance.

4.3.3. Selection of the monitored muscles

Selection of muscles for EMG recording is tailored according to the location of

the tumor and tissue at risk during surgery. Distal hand muscles provide the most

robust EMG signals and should always be included into definition of the resting

motor threshold (RMT). Abductor pollicis brevis (APB) and first dorsal

interosseus (FDI) muscles are recommended for use as they generally provide

least baseline EMG activity. The following muscles are recommended for EMG

recording depending on the tumor location:

Upper extremity:

- APB

- FDI

- abductor digiti minimi (ADM)

- flexor carpi radialis muscle (FCR)

- extensor carpi radialis muscle (ECR)

- biceps brachii muscle (BB)

Lower extremity:

- tibialis anterior muscle (TA)

- plantar toe flexor muscle (P)

- abductor hallucis muscle (AH)

Face [83]:

- mentalis muscle (M)*

- orbicularis oris muscle (OO)**

* inferior longitudinal muscle of the tongue is an excellent alternative (Weiss,

et al. 2013); the recording, however is technically more challenging due to

special requirements regarding the electrode and potential loss of contact

if the tongue is not properly dried or gets wet during the mapping. The use

of tongue recording is not recommended for users with limited experience.

**) M is a better choice than OO for face mapping as it usually enables robust

EMG recording (Weiss, et al. 2013)

For optimal EMG recordings, the skin is cleaned with an alcohol swab. Electrode

gel or disposable Ag/AgCl electrodes should be used in a belly-tendon montage

for EMG. The ground electrode should be placed at the ipsilateral elbow on the

olecranon process. Triggering of the EMG by the nTMS system is mandatory for

precise calculation of MEP latencies. Before the TMS onset, the EMG signal

strength and the maximum reduction of artifacts should be ensured for each

recorded muscle by a voluntary muscle contraction. During the TMS mapping,

the level of muscle contraction should be minimal (at rest), as indicated by the

continuous EMG. For prediction of motor outcome after the surgery, the

excitability (RMT and recruitment curve) should be assessed from both

hemispheres [60].

4.3.4. Mapping intensity

Intensities slightly above RMT limit the cortical volume of stimulation and produce

the most precise functional maps. As the excitability of the corticospinal motor

system varies from session to session the RMT needs to be determined before

each examination. Theoretically the RMT should be determined for each

recorded muscle, but for practical reasons the use of the RMT of a small hand

muscle (FDI) can be considered appropriate for the mapping of all upper

extremity muscle representations. For mapping of cortical representations of the

lower extremity and facial muscles, stimulation intensity usually needs to be

adapted (see below).

4.3.5. FDI hot spot

The search for the cortical sites producing maximum motor nTMS responses (the

“hotspots”) is started by identifying the anatomical landmarks of the motor cortex.

The functional hand motor area can approximately be identified by the omega-

shaped knob in the precentral gyrus [85]. The search for the hand (here: FDI)

hotspot is started from the anatomically identified hand motor area within the

precentral gyrus. FDI and ADM are equally useful for calculation of RMT [58] and

as the first focus of mapping. The stimulator output is adjusted to induce an

electrical field of 80-100 V/m on the cortex 20-25 mm below the coil

(approximately 35-40% of the maximum stimulator output, MSO). Thereafter

nTMS is delivered on the hand knob and the MEPs of the FDI are recorded. The

MEP latency should be about 15-30 ms; (usually 20-25 ms) the latency can be

longer in neurological disorders affecting e.g. the nerve conductivity. If very high

MEPs, exceeding 500 μV, are induced, the stimulation intensity is decreased by

1–2% steps; if no MEPs are seen, the intensity is increased stepwise. The

stimulation area is then extended along the central sulcus (CS) medially and

laterally using the same intensity. The orientation of the induced electric field is

kept perpendicular to the CS. The stimulated area is expanded until the MEPs

disappear (“rough mapping”). The site eliciting maximum FDI MEPs defines the

FDI hot spot.

Trouble shooting:

“bad EMG quality”: Ask patient to relax, try to increase comfort; check

electrode impedance, check the ground electrode; arrange EMG

cables so that noise is cancelled out; check for interference from other

electronic devices.

“hand knob not visible”: Use alternative landmarks, e.g., i) the “pli de

passage fronto-pariétal moyen” (PPFM), manifesting as an elevation in

the floor of the central sulcus at its midpoint, which can usually be seen

as a “passage” through the sulcus when searching systematically for

the depth from the cortical surface [5]; ii) continuation of the central sul-

cus on the mesial surface, just anterior to the well identifiable posterior

ramus of the cingulated sulcus (Berger et al. 1990); iii) broader precen-

tral motor than postcentral somatosensory gyrus at the vertex (Mäkelä

et al. 2001). If still in doubt, start from the most likely cortical area and

increase area of rough mapping according to EMG responses.

4.3.6. Resting motor threshold measurement

The RMT is defined as the lowest TMS intensity capable of eliciting a 50 μV MEP

in a relaxed small hand muscle in 5 out of 10 stimulations [62]. The target muscle

should be at rest and monitoring of muscle activity is critical during the

determination of the RMT. The FDI hot spot is stimulated at the rough mapping

stimulation intensity by turning the coil in 20° steps to identify the optimal coil

rotation evoking the largest MEPs. Thereafter, the position is fixed to determine

the motor threshold. Ten stimulations, separated by 5-10 seconds, are delivered.

The peak-to-peak amplitude of the FDI MEP is classified (no response <50 μV /

response >50 μV). The spontaneous EMG must be observed throughout the

procedure to exclude responses elicited during target muscle activation (baseline

EMG activity >50 μV).

4.3.7. Mapping of hand motor area

To optimize accuracy, the mapping should be carried out at the lowest possible

intensity. The coil should be oriented so that the induced electric field is

perpendicular to the CS.

1. The stimulator output is set to 105% of the RMT of FDI.

2. The stimulation is done along the precentral gyrus with 2-3 mm spacing of

the target sites. The induced electric field is oriented perpendicular to the

CS. There should be at least a 2-s interval between stimulations.

3. After mapping the precentral gyrus along the CS, the gyri posterior and

anterior to it should be mapped as well. Each stimulation site should be

separated from neighboring sites by 2–5 mm. In critical areas, for example

those close to the brain lesion, the density of mapping should increase

and different stimulation orientations at the same cortical site should be

tested, particularly if the anatomy is distorted. Premotor areas are

stimulated as far frontally as visible MEPs are elicited.

4. When MEPs are induced far away from the presumed primary motor

cortex or close to the lesion (e.g. tumor), the electric field orientation

needs to be changed between +45 and -45 degrees to test the

consistency of the MEPs.

An investigation of motor mapping approaches was performed by Raffin and

colleagues; their paper describes in greater detail the theoretical background of

the recommendation above [58].

4.3.8. Mapping of lower extremity motor area

The cortical representations of most leg and foot muscles are located deep

within the interhemispheric fissure. Consequently, higher nTMS intensities

are needed to elicit MEPs from the foot than from the hand muscles

(Figure 2) [40, 56].

1. The stimulation intensity is set to 110% RMT of the FDI and the coil

orientation is kept perpendicular to interhemispheric fissure towards the

hemisphere of interest at the junction of the CS and interhemispheric

fissure.

2. If no MEPs are detected, increase stimulation intensity in steps of 10% of

the FDI RMT.

3. If MEPs are detected, sites anterior and posterior along the central fissure

are stimulated until no MEPs are elicited. Sites along the CS, up to 3 cm

from the central fissure, are stimulated as far as MEPs are induced.

Troubleshooting:

“no MEPs”: i) increase stimulation intensities up to 100% MSO, if

tolerated by the patient; ii) to facilitate MEPs, ask patient to activate

and relax the target muscle and then deliver nTMS pulse; iii) test

alternative leg/foot target muscle(s); iv) deliver nTMS during tonic

muscle contraction and look for the cortical silent period.

4.3.9. Mapping of facial motor area

The cortical face representation has several particular features. First, it is usually

not restricted to the precentral gyrus but extends more anteriorly and posteriorly

than the arm and the leg representations [83]. Second, the face representation is

bilateral as a considerable percentage of uncrossed cortico-muscular projections

contribute to MEPs [21]. Third, nTMS mapping of the face representation is made

difficult by frequent co-stimulation of cranial nerve fibers; this interference can

cause ipsilateral clenching and a brief neuralgiform pain. It should also be noted

that the direct nerve fiber stimulation induces MEPs with latencies shorter than

11 ± 4 ms seen with stimulation of face motor cortex [83]. As the direct nerve

stimulation depends on the strength of the electric field, lowering the stimulation

intensity may help to reduce the problem. Only limited evidence is available

about the clinical impact of resections affecting the face area. Partial resection of

the unilateral face representation seems to lead only to transient muscular

deficits in most cases.

Due to the technical difficulties and unproven clinical benefit, mapping the face

region is not strongly recommended in routine clinical practice. However, it is of

interest for clinical studies. The examination protocol is as follows:

1. nTMS is started at 100% of the (FDI) RMT roughly half-way between

the hand knob and the Sylvian fissure; the induced electric field is

oriented perpendicular to the CS.

2. Rough mapping is done to find typically configured MEPs with a

latency of 11 ± 4 ms [83]. Importantly, the area for the rough mapping

should not be too small.

3. Once a potential hot spot is identified, RMT should be re-adjusted (e.g.

using the 5-out-of-10 rule; MEPs outside the expected latency window

should be ignored, manual adjustment of latencies may be necessary.

The mapping is then continued with an intensity matching 105% of the

face RMT.

4. If no MEPs can be obtained, the stimulation intensity is increased in

2% steps.

5. The mapping area should be extended within the area of interest until

at least two consecutive TMS pulses have not elicited a motor

response (>50 μV).

6. Separate hot spots for the same muscle can be present and the

resulting representational map is usually not restricted to the precentral

gyrus.

7. The configuration and latencies of MEPs need to be checked carefully.

It is reasonable to discard responses with latencies lower than 2

standard deviations of the mean (of each muscle) as the latency range

of 11 ± 4 ms provides only a rough time window for face MEPs [83].

Troubleshooting:

“no (reliable) MEPs”: If only motor responses with short latencies (<8

ms) are obtained or if pain/discomfort/clenching is encountered, the

simulation intensity is reduced in 2% steps and the patient is asked to

purse his/her lips (as constantly as possible; follow-up via free-running

EMG and remind the patient whenever necessary). Once reliable

MEPs are obtained the mapping is continued with the same intensity

and setting.

4.3.10. Utilization of mapping data for surgical planning

Export of the functional cortical sites to surgical planning software should be

tailored on the basis of individual features of each patient. In principle, the tissue

at risk during surgery should be outlined by the nTMS responses. The planned

cortical entry site and the peritumoral tissue should be taken into account. If fiber

tracking (e.g. of the CST) is planned using a ROI-based approach, the exported

data should be used to define the cortical ROI for optimized (somatotopic)

tractography.

1. All positive stimulation sites in the vicinity of the planned corticotomy

and/or the cortical aspect of the tumor are exported.

2. All negative stimulation sites overlying the tumor or the planned

corticotomy are exported as well. Alternatively, to minimize the amount of

image overlay, institutions can agree not to export the negative stimulation

sites based on the agreement that all critical areas not indicated by

markers have been nTMS-negative.

3. TMS-positive cortical sites can be used as starting points for white matter

tracking via nTMS-based fiber tracking (FT) [8, 25, 37, 84].

4. In addition to the TMS-derived topographical information, patient

counseling and risk-benefit balancing can be supported by the RMT ratio

of the hemisphere ipsilateral to the tumor divided by that of the

contralateral hemisphere. The ratios above 110% or below 90% indicate

an increased risk for postoperative motor deterioration [60].

5. During surgery the TMS maps can be used to identify the motor cortex

and, if applicable, guide cortical and subcortical electrical mapping thus

making intraoperative DCS mapping faster and more safe [38].

5. NTMS LANGUAGE MAPPING

5.1.Clinical evidence

Repetitive nTMS (rTMS) is used for mapping of the cortical language functions.

Clinical studies indicate that cortical sites where repeated rTMS did not disrupt

language processing during a picture-naming task corresponded very rarely to

language-eloquent sites in intraoperative DCS, suggesting a high correlation of

“rTMS-language-negative” brain regions with DCS (Krieg, et al. 2014b, Picht, et

al. 2013[74]). Moreover, rTMS language mapping was associated with smaller

craniotomies in awake surgery. In preoperative language mapping of brain tumor

patients, rTMS may be superior to functional magnetic resonance imaging

(fMRI), particularly in regions close to brain lesions, which can induce alterations

in vascular dynamics and tissue oxygenation that disrupt fMRI [26, 35].

Moreover, rTMS language mapping may help to identify seed regions for DTI of

subcortical language tracts (Figure 3) [51, 70]. It may also aid in preoperative risk

stratification by characterizing interhemispheric connectivity as measured by

transcallosal nTMS-based tractography of language fibers [34, 71]. So far, rTMS

language mapping has mainly been used for preoperative planning of tumor

surgery. A recent report compares rTMS language mapping with DCS results in

epilepsy surgery [1]; the results (as well as our unpublished experience; H.

Lehtinen, personal communication) are in line with those obtained in tumor

surgery, suggesting a high correlation of language eloquent areas between both

modalities.

5.2.Limitations of the method

We have been able to induce some language errors in all patients with the rTMS

parameters recommended here and applied in previous studies. The safety

profile has been excellent [75, 76]. However, nTMS is not able to stimulate deep

frontal or temporomesial structures. Additionally, the fusion of nTMS data with

the intraoperative neuronavigation system has the same limitations as described

for the motor cortex data.

Depending on the subject and on the stimulation parameters, rTMS-induced pain

often limits the spatial extent of rTMS language mapping, particularly when

stimulating the orbital and polar inferior frontal gyrus and temporal lobe [42]. A

median visual analogue scale (VAS) score of 4.5 for the maximum experienced

pain has been reported but the discomfort of rTMS was not considered

distressing by most patients [75]. Assessing and minimizing the discomfort and

pain experienced during mapping is critical to obtaining a reliable language map.

Tests of rTMS with higher frequency trains/bursts may provide further insight of

the mechanisms inducing language disturbances [59]. However, induction of pain

and muscle tetanization might limit the use of higher stimulation intensities and

frequencies, at least when rTMS is delivered in long trains [14].

Preserving subcortical language fibers during the operation is essential for

patient outcome. rTMS is not able to detect these fibers although the rTMS-

based maps may be used to improve tractography results. The rTMS data can

help to define the location and extent of the craniotomy and may enable more

targeted and faster intraoperative DCS mapping [68]. rTMS data can assist in

predefining the best site for thresholding the DCS stimulation by enabling the

surgeon to find positive DCS points quickly [52, 68]. rTMS language mapping

cannot replace awake craniotomy and IOM, but can improve patient selection for

awake surgery and facilitate intraoperative language testing.

5.3.Recommended protocol

5.3.1. Patient selection

The main indication for preoperative rTMS language mapping is the presence of

a lesion in ”classical“ language areas, i.e. in the left perisylvian cortex, the frontal

operculum and temporo-parietal region, or planned corticotomy in these areas

[31]. Nevertheless, evidence for language function residing outside these areas,

including in the non-dominant hemisphere, is accumulating [12, 13, 72]. These

reports have led to the recent paradigm shift from the traditional “localizationist”

view of language function in specific cortical regions towards a hodotopical view

of parallel, highly dynamic cortico-cortical and cortico-subcortical networks

supporting speech and language [7, 16, 17]. This shift emphasizes the role of

long association fibers in language processing. The preservation of the functional

integrity of the main language tracts seems to be at least as important as

preservation of the cortical functions. White matter tracking for connectivity of

different language-related functions is therefore highly advisable.

The workshop participants recommend a liberal use of rTMS language mapping

in patients with left perisylvian tumors, tumors in the vicinity of the main language

tracts and with tumors in atypical locations if there is any doubt about the surgical

risk to the patient’s language network. This approach may be particularly useful

in left-handed patients with right-sided tumors or in patients with tumors outside

the classical language areas who present with previous / transient clinical signs

of aphasia / language disruption.

Exclusion criteria for preoperative rTMS language mapping are identical to those

for motor mapping. Additionally, the naming performance needs to be normal or

impaired only slightly. Language mapping can be feasible even in young children

(ages 8 and above).

5.3.2. Preparation

Preparation for rTMS language mapping is identical to that required for motor

mapping. In addition, it is mandatory to describe the language task and

emphasize the necessity of focused attention and good motivation throughout the

procedure to provide the best possible results.

5.3.3. Language task

The content and complexity of the task during language mapping affects the

incidence, location and type of observed errors [20]. For intraoperative language

mapping during awake surgery, the most frequently used task is confrontational

object-naming with or without a written lead-in phrase. The task is usually well

tolerated by the patients and it fits within the time and space requirements of the

intraoperative procedures. It also interrogates multiple aspects of language and

speech. No other task has been proven superior for “general“ mapping of

language-eloquent brain areas [29-31]. For these reasons, the workshop

participants recommend confrontational object naming for rTMS language

mapping as well. Tailored language tasks based on individual requirements e.g.,

lesion location, language capacity and psychosocial status need to be developed

but they are not part of this recommendation.

5.3.4. Baseline and rTMS object-naming

For stimuli, black and white drawings of common objects are recommended. The

image set should contain only objects without synonyms to prevent erroneous

interpretation of subject performance. The image set needs to be presented in

full to the patient at least two times before actual rTMS mapping (“baseline

naming”) to guarantee that language and speech disturbances are caused by

rTMS and not by other confounding effects. All images misnamed or named with

delay should be discarded. During the actual naming task, the remaining images

should be presented time-locked to trains of TMS pulses. The stimulation coil

should be moved randomly between the presentations of the images in roughly

10 mm steps over the perisylvian cortex. The induced current should be oriented

perpendicular to the sulcus close to the stimulated point to induce a maximum

effect. The mapped cortical area should include the perisylvian cortex and all

areas of surgical relevance. Altogether, 40-80 cortical sites of the frontal,

temporal, and parietal cortex should be stimulated at least 3 times each. The

same sites should not be targeted consecutively to prevent summation effects or

focal seizure-type phenomena. Areas of particular importance for resection, e.g.

the lesion and its proximity, should be examined in more detail, i.e. with a denser

raster (3-5 mm spacing). Mapping of both hemispheres is advisable to elucidate

their involvement in language processing. During the examination it is of utmost

importance that the patient is comfortable and maintains a consistent level of

attention. If the rTMS stimulation is too distracting or uncomfortable, it may be

possible to improve tolerability by reducing the stimulation intensity, adapting the

coil orientation (perpendicular to the temporal muscle fibers) or having breaks

during the mapping. Video material demonstrating the language mapping

procedure is available in supplementary material of publications by group

members [30, 48].

5.3.5. Result analysis and interpretation

The enormous complexity of the cortico-subcortical network involved in

perception, processing and production of language makes it a difficult target for

single trial mapping. Intraoperatively, cortical areas involved in speech production

can be identified by DCS using the mono- or bipolar montage, predominantly by

inducing speech arrests. Subtler disruption of language subtasks can be more

difficult to repeat reliably in the single trial setting. Although stimulation of white

matter tracts can lead to distinct behavioral responses, identification of the

relevant tracts can be challenging, especially in the vicinity of brain tumors.

The stimulation frequencies and the delivered electrical charge used in rTMS

speech mapping differ significantly from DCS and a single rTMS train does not

give conclusive information about language involvement of any particular cortical

site. Successful rTMS language mapping is based on application of several

stimulation trains within the same cortical area and meticulous observation and

documentation of the rTMS-induced behavioral changes. This analysis is only

possible by video-based off-line review [48]. Clusters of sites inducing language

disturbances within the same cortical area suggest that this area is relevant for

speech processing. Isolated single deviations from the baseline performance

indicate need for further DCS examination of the area. Interpretation of the rTMS

language mapping results requires experience and careful consideration of each

individual case.

5.3.6. Stepwise description of the procedure

5.3.6.1. Baseline

1. Patients are seated comfortably and informed about each step of the

examination

2. Patients are instructed to name the objects in their mother tongue as quickly

and precisely as possible; no written lead-in sentence is used

3. The baseline is repeated 2 to 3 times and all imprecise or slowly named

images are discarded; error rates above 25% indicate unreliable TMS and

DCS language mapping

5.3.6.2. Stimulation and task parameters

Table 1 shows an overview on the currently used rTMS setting of language

mappings in the involved centers of the authors. The recommended parameters

are:

o Interpicture interval (IPI): 2500 ms as default setting; to be adapted

according to patient capabilities within a 2000 – 5000 ms time-window

o Picture presentation time (PPT): 700 ms as default setting; to be adapted

according to patient capabilities within a 300 – 1000 ms time-window

o Stimulation intensity corresponds to or is less than the ipsilateral RMT to

ensure patient comfort; yet, a minimum electric field of 50 V/m at cortical

surface of the target area should be maintained whenever possible

o Duration and frequency of the stimulation: 5 Hz/ 5 pulses as default

setting; if ineffective or intolerable, 7 Hz/7 pulses or 10 Hz/10 pulses

o Picture to rTMS trigger interval (PTI): 0 ms delay as default setting; if

ineffective, within a 0 – 400 ms window [43, 69]

o Mapping should start from parietal or frontal areas distant from trigeminal

nerve branches and temporal muscle to avoid early discomfort

o Number of stimulation trains is on average 200-250 / hemisphere

o The stimulation of the same cortical patch is repeated non- consecutively

at least three times per mapping; the induced e-field is directed

perpendicular to underlying sulci when possible

5.3.6.3. If no language/speech disruptions observed:

1. Shorten IPI in 200-300 ms steps

2. Shorten PPT in 100-200 ms steps

3. Increase rTMS frequency

4. Vary PTI delay

5. Increase stimulation intensity

5.3.7. Result analysis

Detection of subtle disturbances is achieved by comparing the baseline response

to the response during rTMS stimulation [11, 55]:

o No-response errors: stimulation leads to a complete lack of naming

(speech arrest and aphasic anomia can be usually distinguished by the

absence of effort to overcome the motor blockade in speech arrest and

the “blank face” in anomia).

o Performance errors: form-based distortions, words are slurred, stuttered or

imprecisely articulated. This category contains both dysarthria and oral

motor speech disorder such as apraxia of speech.

o Hesitation: the response is significantly slower than during baseline;

ideally the response delay is measured [80].

o Neologisms: form-based errors, which are possible but nonexistent words.

For example, the target word “horse” is replaced with the word “herp”.

o Semantic paraphasias: errors in which the patient substitutes a

semantically related or associated work for the target word. For example,

the target word “cow” is replaced by the word “horse”.

o Phonological paraphasias: characterized by unintended phonemic

modification of the target word. The spoken word resembles the target

word, but is phonetically different. For example, the target word “pants” is

replaced with “plants”.

o Circumlocution errors: errors in which the subject talks about or “around”

the target instead of naming it. For example, the target word “chair” is

replaced with “sit down”, explaining the use of the target word.

5.3.8. Result interpretation

o rTMS does not provide the same powerful blocking stimulus as DCS.

o Ideally, a language specialist / neuropsychologist is involved in analysis of

the language tasks and is also present in the operating room (OR) during

awake surgery to confirm similar interpretation of both nTMS and DCS

results.

o During evaluation of the rTMS responses, the examiner should be blinded

to the cortical stimulation sites to avoid bias based on the anatomical

information.

o Exclude errors associated with/caused by:

Pain, discomfort, fading attention/lack of co-operation,

Perseveration-type errors (same word is repeated over and over or

the same image is producing frequent errors)

Errors occurring in consecutive stimulations (at different sites)

5.3.9. Utilization of mapping data for surgical planning

The current experience and evidence suggests that cortical areas repeatedly

targeted with no language disturbances induced by rTMS are most likely not

carrying essential language function [43]. Clustering of rTMS-induced language

disturbances within a distinct cortical area suggests relevant involvement in

language processing and DCS confirmation is recommended. Isolated cortical

spots of a single rTMS-induced language disturbance have a questionable

significance and DCS testing is recommended. Moreover, the combination of

rTMS-positive cortical spots with white matter tracking via DTI-FT can aid in

interpretation of the results and add important information pertaining to the

location of relevant cortical structures and subcortical pathways. Protocols for

rTMS-based DTI-FT have been described and compared to existing protocols

[51, 70].

6. USE OF NTMS DATA IN THE OPERATING ROOM

nTMS-positive sites for language and motor functions should be imported into the

neuronavigation and hospital picture archiving system [50]. The DICOM standard

supports this procedure. It is useful to export nTMS-positive stimulation points on

various cortical and subcortical levels (i.e., peeling depths) to inform the surgeon.

A standard color-coding of the implemented rTMS data should be established at

to aid interpretation of the depicted functional anatomy and intraoperative use of

the rTMS data (Figure 3). The combination of rTMS results with rTMS-based FT

to visualize language-related subcortical fibers and the CST is recommended.

For language and motor eloquent lesions, however, final surgical decisions

regarding the functional relevance of both cortical tissue and subcortical fiber

tracts are made based on the intraoperative mapping and monitoring results [3,

4, 66, 67].

7. SAFETY ISSUES

The protocols described here have been used for many years at the institutions

of the authors. A safety analysis of these protocols revealed no major adverse

events in 733 patients and 258 healthy subjects [75, 76]. Local pain was maximal

when applying rTMS over the temporal muscle with a median VAS score of 4.5

out of 10. This large multicenter dataset showed that none of the investigated

subjects or patients reported persistent discomfort for more than 1 hour after the

procedure. No TMS induced epileptic seizures were observed and rates of

seizures in patients suffering from epilepsy were not increased with the

recommended protocols. TMS mapping of motor and language functions [1, 80]

has also been used in patients with medically intractable seizures before epilepsy

surgery without complications. The stimulation parameters need to remain within

the established guidelines for safe application of single pulse and repetitive

nTMS [44, 61, 63, 82].

8. CONCLUSION AND OUTLOOK

nTMS motor mapping displays excellent accuracy in comparison with DCS and

the level of evidence is sufficient to recommend it for routine neurosurgical work-

up. nTMS can be a valuable adjunct for established IOM workflows when

planning and performing surgery in presumed motor eloquent areas.

The workshop group recommends nTMS language mapping in the frame of

clinical studies but not to replace awake surgery for eloquent lesions. Moreover,

development of experimental protocols should be a priority for clinicians

interested in the management of lesions in eloquent brain regions. The group

members involved in these recommendations will use the common protocols as

they have been described and will compare the results in upcoming meetings.

9. FUNDING

Nexstim Plc. (Helsinki, Finland) provided financial support in the form of travel

funding to the venue site at BioMag Laboratory, HUS Medical Imaging Center,

University of Helsinki and Helsinki University Hospital, Helsinki, Finland. The

sponsor had no role in the design or conduct of this report.

10.CONFLICTS OF INTEREST

SK and TP are consultants for Brainlab AG (Munich, Germany) and for Nexstim

Plc. (Helsinki, Finland). PL is consultant for Nexstim Plc. HH, PS, and JK are

employed by Nexstim Plc. Yet, all authors report no conflict of interest concerning

the materials or methods used in this study or the findings specified in this paper.

11.ETHICAL APPROVAL

Since this is a report from an expert panel, no ethics approval was obtained. This

article does not contain any studies with human participants performed by any of

the authors.

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13.FIGURE LEGENDS

Figure 1: Electric field

Visualization of the induced electric field including quantification of the induced

electric field strength in V/m.

Figure 2: Motor mapping of the leg area

This graph shows a guide to obtain optimal results for motor mapping of cortical

leg areas.

Figure 3: Example of standardized color coding

The screenshot shows a case of a left-sided oligodendroglioma WHO grade III

located in the triangular part of the inferior frontal gyrus which was primarily

judged by another neurosurgical department to be not resectable. This case

gives an example how nTMS can falsify presumed eloquence. Moreover, these

screenshots show how to standardize different colors for cortical motor areas

(green), corticospinal tract (yellow), cortical language areas (purple) and

subcortical language-related fiber tracts (purple). This allows an optimal

preoperative preparation (A) and intraoperative clarification of the functional

anatomy (B).

Table 1: Language mapping parameters

This table shows the variability of stimulation parameters as recommended by

the different groups. n.r. = no recommendation.