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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 [email protected]
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 [email protected]
Jyrki Makelä, MD, PhD [email protected]
Vitikainen Anne-Mari, PhD [email protected]
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 [email protected]
Henri Hannula, MSc [email protected]
Petri Savolainen, MSc [email protected]
Nexstim Plc.
Elimäenkatu 9 B, 00510, Helsinki, Finland
Phone: +358 (9) 27271712, Fax: +358 (9) 27271717
Carolin Weiss Lucas, MD [email protected]
Center of Neurosurgery, University Hospital Cologne
Kerpener Str. 62, 50937 Cologne, Germany
Phone: +49 221 47882799. Fax: +49 221 4783189
Kathleen Seidel, MD [email protected]
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 [email protected]
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 [email protected]
Department of Clinical Neurophysiology (R2:01), Karolinska University Hospital
Solna, 17176 Stockholm, Sweden
Phone: +46 762238769
Juha Wilenius, MD [email protected]
Selja Vaalto, MD, PhD [email protected]
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 [email protected]
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 [email protected]
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 [email protected]
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.