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Abstracts from the2nd International Workshopon Navigated Brain Stimulation inNeurosurgery

October 8-9th, 2010, Berlin, Germany

Organized by Prof. Dr. P. Vajkoczy and Dr. Th. Picht

Department of Neurosurgery,

Charit - Universittsmedizin Berlin, Berlin, Germany


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2nd International Workshop on Navigated Brain Stimulation in Neurosurgery (pub. May, 2011) Page | 1

Introduction to the 2nd International Workshop onNavigated Brain Stimulation in Neurosurgery

The treatment of brain pathologies in, or in close proximity to, the eloquent cortex on MR-imaging, benefitsfrom reliable assessment of the functional significance of the cortical structures adjacent to the lesion. Direct

cortical and sub-cortical stimulation are well-established electrophysiological techniques for the examination

of cortical functions during surgery, but until recently we have lacked a reliable method for assessing cortical

function without first performing craniotomy. Functional MR-imaging (fMRI), which relies on measuring

hemodynamic changes in response to task paradigms, has shown unexpected shortcomings when tumor

growth alters the local vasculature. Imaging-based methods are also difficult, often impossible, to perform in

children and in patients with paresis.

The recently introduced NBS System (Nexstim Oy, Finland) is a navigated TMS device combining E-field

modelling with the well-understood technologies of 3D spatial navigation and transcranial magneticstimulation (TMS). Being noninvasive, information from the NBS System can be used prior to surgery to

select the appropriate treatment for the patient, as well as to help neurosurgeons fine-tune their approach

to resection, both before and during the surgery.

The goal of the 2nd International Workshop on Navigated Brain Stimulation (NBS) in Neurosurgery was to

share the experiences of experts in NBS, TMS, DCS and MEG. To further that goal, the presenters agreed to

make abstracts and images from their presentations available also to colleagues unable to attend the

workshop in person. Many of the presentations contained previously unpublished data and we are grateful

to the authors for their permission to publish abstracts in this collective format. The workshop program

covered:

Functional mapping in neurooncology Experiences and outcomes data from several large registries of NBS mapping in tumor Relative accuracy of NBS and FMRI compared to DCS Mapping of the speech areas with NBS Use of NBS mapping data directly in the OR microscope TMS, MCS and NBS in chronic pain therapy NBS mapping in epilepsy, with MEG, and in children The principles behind TMS

The Workshop also reminded the audience that it is important to put new methods, like NBS, onto a firm

scientific foundation by the publication of carefully planned clinical studies.

We also hope this publication will serve to spark your interest later this year: when we will have the pleasure

to invite you to the 3rd International Symposium on Navigated Brain Stimulation in Neurosurgery, here in

Berlin.

The organizers,

Prof. Dr. P. Vajkoczy and Dr. Th. PichtDepartment of Neurosurgery, Charit - Universittsmedizin Berlin, Berlin, Germany


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List of Abstracts

FUNCTIONAL ANALYSIS IN NEUROSURGERY: A CRITICAL APPRAISAL ............................................................................. 3

VAJKOCZY P.

Department of Neurosurgery, Charit - Universittsmedizin Berlin, Berlin, Germany

TMS PRINCIPLES ............................................................................................................................................................ 5

ROTHWELL J.

UCL Institute of Neurology, London, UK

NBS MAPPING - LESSONS FROM A 100-PATIENT SERIES AT A SINGLE CENTER ............................................................... 7

PICHT T.


NAVIGATED BRAIN STIMULATION CONNECTS NEURONAVIGATION AND ELECTROPHYSIOLOGICAL

NEUROMONITORING ................................................................................................................................................... 10

KRIEG S,BUCHMANN N,SHIBAN E,GEMP J,RINGEL F,MEYER B.

Department of Neurosurgery, Klinikum rechts der Isar, Technical University of Munich

NBS MOTOR MAPPING: MAPS, HOTSPOTS AND CENTERS OF GRAVITY ....................................................................... 13

BRANDT S,SCHMIDT S.

Clinic of Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany

TRANSFER OF NBS MOTOR MAPPING DATA THROUGH NEURONAVIGATOR INTO OPTIC FIELD OF OPERATING

MICROSCOPE ............................................................................................................................................................... 16

JULKUNEN P1,JSKELINEN JE.

21Department of Clinical Neurophysiology,

2Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland

NBS-DCS AND FUNCTIONAL MAGNETIC RESONANCE IMAGING

PREOPERATIVE MAPPING IN CENTRAL REGIONTUMORS ...................................................................................................................................................................... 19

MTFORSTER,ASZELNYI

Department of Neurosurgery, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany

NEUROPHYSIOLOGIC MARKERS GENERATED BY MOTOR SPEECH-RELATED CORTICAL AREAS ..................................... 221,2DELETIS VEDRAN,

2ROGID MAJA1St. Luke's - Roosevelt Hospital, New York, NY, USA

2School of Medicine University of Split, Croatia

FUNCTIONAL BRAIN MAPPING IN SURGICAL NEUROONCOLOGY ................................................................................. 25

DUFFAU H.

Department of Neurosurgery and INSERM U583), Hpital Gui de Chauliac, CHU Montpellier, France

COMBINING NBS AND MEG IN NEUROSURGERY ......................................................................................................... 29

MKEL JP.

BioMag Laboratory, HUSLAB, Helsinki University Central Hospital, Finland

NBS IN CHILDREN METHODOLOGICAL ASPECTS AND CASE STUDY ............................................................................ 31

THORDSTEIN,M.

Dep. of Clinical Neurophysiology, Sahlgrenska University Hospital, Gteborg, Sweden

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION AND IMPLANTED CORTICAL STIMULATION IN THE TREATMENT

OF NEUROPATHIC PAIN ............................................................................................................................................... 34

AHDAB R,LEFAUCHEUR JP.

Hpital Henri Mondor, Assistance Publique-Hpitaux de Paris, Universit Paris-Est, Crteil, France


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Functional analysis in neurosurgery: a critical appraisal

Vajkoczy P.


In general, patients with either low-, medium- or high-grade tumors benefit from surgical treatment, and

benefit most from maximum surgical resection. However, relying on anatomical information alone many

tumors would be deemed inoperable due to the risk that critical functions could not be preserved

postoperatively. Through practical experience we have come to learn that more patients benefit from total

resection when functional information on the eloquent areas and vital tracts are also available.

In addition to the established intra-operative techniques based on electrophysiology, a number of non-

invasive techniques have been developed for functional analysis and functional mapping of motor and

central areas of the cortex and subcortex. These techniques include functional magnetic resonance imaging

(fMRI), diffusion tensor imaging (DTI), and navigated TMS (nTMS). Navigated Brain Stimulation (NBS) is anew nTMS method based on MRI-guided TMS (NBS System, Nexstim Oy, Finland).

Retrospective studies have shown that intraoperative functional monitoring using either electrophysiology

or awake craniotomy, improved outcomes in tumor surgery compared to not using functional monitoring1.

When intraoperative monitoring is employed, more low-grade gliomas can be surgically treated, total

resection can be achieved more often and remaining deficits are less severe. A comparable level of proof of

clinical contribution also needs to be generated for these new non-invasive functional analysis techniques.

So far, there is limited experience of the optimum way to employ non-invasive functional techniques and

limited evidence on how the techniques influence clinical practice. History has shown that earliertechnologies for neurosurgery have been introduced without rigorous clinical evaluation. Most publications

on non-invasive mapping techniques have been small, single-center retrospective studies which do not

provide the level of scientific proof needed. It would therefore be valuable to conduct large, prospective

multi-site studies on how these new technologies impact clinical workflow and outcomes. Indeed,

widespread clinical use can reveal unexpected shortcomings in techniques which have worked well in a

limited number of cases. For example, correlating DCS and fMRI data have revealed significant discrepancies

and deviations in fMRI-generated information.

To achieve routine clinical acceptance, a new mapping technique has to be shown to offer reliable and

accurate information on the functionally essential cortical and subcortical areas. In practice, any newmapping technique nees to be emonstrate to be no less accurate than the gol stanar irect cortical

stimulation (DCS). A successful technique should be also readily available for all patients and at low cost. In

addition, a database registry encompassing how the new technique influences clinical workflow,

determination of surgical indication, approach to resection and therapy outcomes would offer the scientific

proof needed to speed clinical adoption on a wide scale.


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Such a database registry should encompass, in particular:

- The impact of the technique on pre-surgical workup

- Whether use of the technique changes a prior decision to surgically operate, or not

- Whether the technique changes or modifies the previously planned surgical approach

- How the technique influences the strategy for intraoperative functional monitoring

Most of the progress in functional analysis of the cortex has been made with respect to the motor area. In

addition, the language areas, as well as the optic tracts, are applications of high interest in the clinic. For

tumors in the temporal lobe, often considered the most challenging surgeries due to the intimate

relationship of vascular and functional areas, many surgeons use individualized approaches - largely based

on anatomical considerations. Here, too, clinical neurosurgery could also benefit from the latest advances in

functional navigation and planning.

Conclusion

Navigated Brain Stimulation for cortical motor mapping is increasingly being used for presurgical workup in

tumor surgery. A significant body of data already demonstrates that NBS is more accurate than earlier

imaging-based techniques and initial reports suggest the data generated make a positive contribution to

clinical workflow and patient care. Now would appear to be the appropriate time to start building a database

registry of clinical experiences in order to put the routine use of NBS onto a firm scientific footing. A further

challenge will be to develop the appropriate tools to integrate all the information from new sources into the

clinics presurgical planning workflow.

References

1 Duffau H et. al. Contribution of intraoperative electrical stimulations in surgery of low grade

gliomas: a comparative study between two series without (1985-96) and with (1996-2003)functional mapping in the same institution. J Neurol Neurosurg Psychiatry. 2005 Jun;76(6):845-51.


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TMS principles

Rothwell J.

UCL Institute of Neurology, London, UK

The relatively new field of transcranial magnetic stimulation (TMS) builds on a longer history of electrical

stimulation, known to date back to an experiment in 1874 that demonstrated that electrically stimulating

one side of the human brain induces movement on the contralateral side of the body. Today, electrical

stimulation of the brain is an established technique in neurosurgery. Following craniotomy, there is no scalp

or skull bone to obstruct the precise placement of electrodes over the cortex and unlike in transcranial

electric stimulation, where pain receptors in the scalp are activated, direct cortical stimulation is painless

an permits awake brain surgery.

TMS is a non-invasive technique to achieve localized cortical stimulation. By generating a brief but strong

current in an electric coil, the resulting magnetic field can penetrate the skull without any significantimpeance. By Faraays law, a phasic magnetic pulse from a coil place over the scalp will inuce an electric

field in the brain tissues immediately below the coil. TMS is, therefore, essentially a tool to carry an electric

stimulus generated outside the head into the brain. Magnetic stimulation is also essentially painless, since a

brief magnetic pulse, despite being of the order of 2 Tesla, does not activate pain receptors in the scalp or

cause significant contraction of the underlying muscles.

Using a single coil, a TMS-induced stimulus is neither particularly focal, nor does the magnetic field

penetrate very far into the brain. The intrinsic limitation on the depth of the effect is not, however, an

obstacle to using TMS to probe or manipulate the cortex. Coils using figure-of-eight or butterfly esigns

allow the effective, overlapping area of the stimulus to be made significantly more focal. Therefore, although

TMS may appear in principle to be a method of limited scientific or clinical use, in practice a TMS device can

be constructed which is a highly useful tool for probing or modulating the brain. Perhaps the ideal

application for TMS is mapping the functions of the human cortex.

With rapidly rising and falling electric and magnetic fields, the electromagnetic properties of a single pulse of

TMS endure less than 1 ms. The brevity of the TMS pulse is deceptive in that a sufficiently powerful stimulus

causes a large amount of neural activation in the tissues below the coil. In fact, a single firing of a TMS coil

starts a complex physiological chain reaction in the brain typically lasting for 50 100 ms. The initial rapid

rise in electric field generates action potentials in the neurons at the immediate site of electrical stimulation

under the coil. Synchronized firing of these and adjacent neurons propagate along synapses to activate still

other adjacent neurons. Eventually, this artificially induced burst of neuron firing is terminated by an

inhibitory postsynaptic potential followed by a silent period. From a physiological perspective, a simple

input with a very short timeline results in a complex output with a timeline duration approximately one

hundred times as long.

When targeting the motor cortex with a TMS pulse strong enough to exceed the motor threshold, the

neuron firing is output down the corticospinal tract, causing a muscle twitch which can be measured by

placing EMG electrodes over the appropriate muscle. Probing the cortex with intracortical microstimulation

(ICMS) electrodes has enabled researchers to produce maps of the cortex showing that motor cortex output


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for distinct muscles is actually quite widely distributed over the motor cortex. It is therefore important to

consider that there may not be a single centre or hotspot corresponing to each iniviual muscle.

These research findings potentially have fundamental implications for our understanding of human

physiology. It has to be considered that divergent output and complex distribution, even redundancy, in the

motor cortex has been essential to human evolution: the brain can continue to control motor function, orrapidly re-learn, despite sudden injury. Indeed, movement has been shown to not necessarily always follow

anatomy. Monosynaptic connections can be anatomically traced to locations, not detectable by ICMS.

Potentially, these apparently dormant connections may, in fact, be a reserve substrate for cortical self-

reorganization should the brain be damaged or become diseased.

Figure 1: Electric field-targeted navigated TMS: motor evoked potential responses to a single TMS pulseusing a focal figure-of-eight coil. EMG recordings from the APB muscle (top, 1.26mV) and the ADM muscle(bottom, 67V).

Conclusion

Transcranial magnetic stimulation (TMS) is a valid non-invasive method for the electrical stimulation of

neural tissues. Single TMS stimuli can focally depolarise neurons intra-cortically and evoke measurable

physiological effects. TMS would appear to be ideally suited to mapping the cerebral motor cortex, however

clinicians need to be aware that individual muscle representations may be distributed over large areas of the

cortex and individual muscles cannot be solely associated with precise cortical locations. Conversely, a

distributed motor cortical somatotopy may be a fundamental evolutionary factor behind the re-organization

of the cortex as a response to progressive disease or cortical re-organization following surgery, trauma or

stroke.


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NBS mapping - lessons from a 100-patient series at a singlecenter

Picht T.


Introduction

Navigated TMS (nTMS), a new method for presurgical evaluation of neurosurgery candidates, has recently

become available for use in a clinical setting. Presurgical mapping using nTMS was integrated into the clinical

workflow of a busy neurosurgical department of a large university teaching hospital two years ago. With a

series of 100 patients now systematically evaluated by nTMS, a preliminary, quantitative assessment of the

impact of this novel technique on treatment strategies and clinical outcome can be made.

Methods

All patients undergoing presurgical workup for brain tumors presumed to be in, or in close proximity to,

eloquent motor cortex based on anatomical MRI, were mapped with nTMS (NBS System, Nexstim Oy,

Helsinki, Finland). Immediately following the NBS mapping sessions, the functional and anatomical images

were used as an aid to explain and recommend therapy options to the patients. For patients deemed to

benefit from surgical resection, the NBS mapping images were exported to a surgical navigation system for

intraoperative reference.

Of the 100 patients, 63% were male and 37% female. More than half (54%) had had seizures. 39% of the

patients were diagnosed with gliomas, 41% with metastasis and the remaining 10% with meningeomas andother histologies. By departmental protocol, intraoperative direct electrical stimulation (DES) was performed

only on patients with tumors in direct contact with either the primary motor cortex or the pyramidal tract. In

27 cases, NBS mapping results indicated that the tumors were not in eloquent areas, and as a consequence

these patients had surgery without the use of intraoperative DES.

In order to critically assess the clinical impact of navigated TMS on treatment strategies, the neurosurgeon

was requested to initially determine the surgical indication and approach for each of the 100 patients based

on anatomical MR-images and clinical assessment. Subsequently the NBS cortical mapping results were

made available to the neurosurgeon for review and re-assessment of each patients surgical inication an

treatment plan. The neurosurgeon was requested to complete a questionnaire ranking the impact theadditional NBS cortical mapping data made on the actual treatment received by each patient.

Evaluation of the impact of NBS mapping results on the treatment strategies was assessed using a

questionnaire employing a descriptive ranking scale 0 - 6, where: 0 = NBS mapping did not provide usable

data, 1 = NBS mapping confirmed expected anatomy and functionality, 2 = NBS mapping added knowledge

about the functional anatomy, 3 = NBS mapping added awareness of high-risk areas and guided DCS, 4 = NBS

mapping led to the modification of the operative access pathway, 5 = NBS mapping led to a change in the

planned extent of resection, 6 = NBS mapping led to a change in the surgical indication.


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Results

NBS mapping was successful in all 100 patients. No seizures were observed during mapping with the NBS

System. 16 patients experienced some discomfort (usually minor) and 2 patients reported transient

headaches following the procedure. In the 27 patients in whom analysis of NBS mapping results had shown

that the tumor was not near an eloquent area, and intraoperative DES therefore not performed, no newfunctional deficits were observed postoperatively. In the 73 patients mapped by intraoperative DES,

agreement between the results for NBS mapping and phase reversal DES for location of the precentral gyrus

was 100%. In 21 of the 73 patients, subcortical DES monitoring was performed. Intraoperative DES

monitoring resulted in termination of tumor resection in a total of 12 cases (16%), of which subcortical DES

monitoring accounted for 7 of the terminations (10%).

Gross total surgical resection, based on 48-hour postoperative MRI analysis, was achieved in 62% (n =18),

63% (n= 6) and 70% (n= 10) of patients with grade IV, grade III and grade II gliomas, respectively. At 48-hour

follow-up, 28% of patients experienced new motor deficits. Motor deficits resolved in three-quarters of

these patients at 3 months postoperatively. 7 patients had permanent new deficits at 3 months. Permanentdeterioration in post-operative motor status was significantly correlated (p < 0.05) with tumor location

involving the precentral gyrus, pre-operative motor impairment and glioma IV- histology status, as well as

with NBS mapping sessions requiring a high number of stimulations.

Overall, NBS mapping was assessed to have had a concrete benefit in 55% of the cases (ranking 3-6).

In 4% of the cases (ranking 6) the additional information provided by NBS mapping changed the

neurosurgeons initial treatment inication an in an aitional 25 % of the cases (ranking 4 an 5) NBS

mapping information significantly improved the surgical approach.

Figure 1: Clinical impact of the results of presurgical NBS mapping on the final surgical indication and the

treatment plan for tumors in or near eloquent cortex (series of 100 patients)

6 4%

NBS changed the surgical indication

59%

NBS changed the planned extent of resection

416%

NBS modified the operative access pathway

3 26%

NBS guided the DCS

220%

NBS added knowledge about the functional

anatomy

125%

NBS conf irmed the expected anatomy

0 no usable results from NBS0%

55%

45%


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Conclusion

This large, 100-patient study confirms that NBS mapping is a safe and useful addition to preoperative

neurosurgical workflow. NBS mapping results can determine preoperatively the need for intraoperative DES

mapping with no negative impact on outcomes and a consequent saving of resources. In more than half of

cases (55%), NBS mapping results had a concrete positive impact on the surgical indication or the surgicalplan. In the 25% of the cases where NBS mapping improved the surgical approach either by changing the

extent of resection or changing the access pathway to the tumor, it can be presumed that NBS mapping

helped optimize the extent of resection while minimizing the incidence of permanent new motor deficits. In

the remainder of the cases, confirmatory results from the NBS System were subjectively considered to

increase the confidence level of the neurosurgical team.


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Navigated Brain Stimulation connects neuronavigation andelectrophysiological neuromonitoring

Krieg S, Buchmann N, Shiban E, Gemp J, Ringel F, Meyer B.

Department of Neurosurgery, Klinikum rechts der Isar, Technical University of Munich

Introduction

Navigated brain stimulation (NBS), using MRI-navigated TMS, is a new, rapidly evolving technique for non-

invasive neurodiagnostics. Although NBS mapping has recently been adopted clinically for the preoperative

mapping of the central region of the cortex, there is little data published on the accuracy of NBS compared

to the more commonly used modalities of direct cortical stimulation (DCS) and functional MRI (fMRI).

Methods

Using a recently installed eXimia NBS System (Nexstim Oy, Helsinki, Finland), we examined a first series of 22

patients with tumors either in, or close to, the precentral gyrus or in the subcortical white matter motor

tract. In 12 patients the lesions were located either within or adjacent to the precentral gyrus and in 10

patients the lesions were located in the subcortical white matter motor tract. In the 22 patient series, 5

cases were for recurrent tumor after earlier surgery. After NBS mapping was performed for motor cortex

characterization, the patient data was sent to a BrainLab neuronavigation system (Brainlab AG, Feldkirchen,

Germany). When possible, fMRI was also performed on patients prior to surgery. During surgery, all patients

were mapped and monitored with navigated DCS.

Results

NBS mapping of the motor area was successful in all patients, including the five patients having had previous

surgery, despite the presence of significant edema in conjunction with the lesions. Stimulation of the lower

extremity using the NBS System was successful in more than half of the cases (54.5%), which was a better

response than that achieved during intraoperative DCS mapping.

In the 12 patients with lesions in, or near to, the precentral gyrus, the results of preoperative motor cortex

characterization with the NBS System were compared to the results obtained both from preoperative fMRI

and from invasive intraoperative DCS. Compared to DCS, the calculated deviation of the NBS mapping results

was 4.5 3.5 mm. When comparing the NBS mapping results with the fMRI results, however; the deviation

was greater, with a deviation of 9.6 7.9 mm measured for the upper extremities and a deviation of 15.0

12.8 mm measured for the lower extremities. In 11 out of the 12 cases, the neurosurgeon considered that

identification of the central region was facilitated by the use of preoperative NBS mapping data. In 9 cases,

the neurosurgeon considered that the availability of the NBS mapping data increased their confidence. In 5

out of the 12 cases, the surgeon recognized that the information provided by the NBS System positively

influenced the operative result, and in 2 cases the information from the NBS System information actually

caused the neurosurgeon to change the previously planned surgical strategy.


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In the 10 patients with subcortical lesions, Diffusion tensor imaging (DTI)-based fiber tracking was performed

using the NBS mapping results to determine the seed region. Compared to conventional fiber tracking, using

the NBS mapping-derived seed region resulted in a subjectively more specific presentation of the

corticospinal tract. The fiber tracking information in combination with the navigated direct subcortical

stimulation mapping data allowed for mutual confirmation of the location of the white matter tracts during

subcortical resection.

Out of the 22 patients, none considered mapping by the NBS System to be painful, although one patient

considered the experience to be unpleasant. None of the patients experienced seizures during NBS mapping,

although 13 patients had a history of seizures.

Figure 1: Presurgical planning in a patient with recurrent subcortical tumor as displayed in the BrainLabnavigation system. The NBS-mapped motor area (green dots) was used as the seeding region for DTI fibertracking (the tumor is marked in blue, the fiber tracts are marked in yellow).


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Figure 2: Left: Overlay of the NBS-mapped motor area on MRI as displayed on an intraoperative BrainLab

neuronavigation system screen. The cortical regions eliciting motor responses are marked in green, with thenavigated direct stimulation electrode location shown by the rod (the fiber tracts are marked in yellow).Right: For calculation of correlations, the NBS-mapped stimulation points are overlaid on the fMRI-calculatedmotor area.

Conclusion

Despite the many factors that could be supposed to contribute to inaccuracy, we found that the results of

NBS mapping of the motor area prior to surgery correlated well with the results of gol stanar

intraoperative DCS mapping. Preoperative delineation of the functional motor area using NBS mapping

results seemed to be a superior technique compared to delineation using fMRI data. NBS mapping was less

susceptible to edema compared to either fMRI or DCS. Moreover, NBS mapping was shown to be accepted

by the neurosurgeon as an additional and helpful modality, not only during resection of tumors within motor

eloquent areas, but also during preoperative planning.


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NBS motor mapping: maps, hotspots and centers of gravity

Brandt S, Schmidt S.

Clinic of Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany

The ability to determine corticospinal excitability in the primary motor cortex is fundamental to the study of

neuroplasticity the mechanism understood to be behind many neurological phenomena. Of particular

clinical interest, neuroplasticity is considered the mechanism which best explains non-spontaneous motor

recovery in stroke rehabilitation.

There are a large number of factors influencing cortical excitability (CE). Over approximately the past 20

years, various authors have shown that that CE is dependent at least on the optimal location of the stimulus,

the optimal orientation and strength of the stimulus as well as subject handedness, attention, motor

imagery, ovarian hormone level, deception, affective disorders, emotions, representations and decision-

making. Excitability of the motor cortex can be indexed by measuring the resting motor threshold (MT) for adiscrete muscle using navigated TMS (nTMS). Repeated measurements of MT at the same precise location in

the cortex can overcome influences on the initial transient state of a muscle, with experimental data

showing that a series of 20 consecutive stimuli allow for a reliable estimate of CE. However, it has been

shown that there is a high level of variability in the measurement of CE using a single location generating the

strongest MEP response in a muscle representation area. Calculating a center of gravity (CoG) for the area of

all responses is hypothesized to lower variability in the estimation of MT, thereby improving replication of

measurements of CE.

Non-invasive mapping of somatotopic organization has shown that a response area of multiple clusters may

best correspond to the representation of a discrete muscle. The response areas for discrete muscles, e.g.

finger muscles, can be differentiated but they also substantially overlap one another within the motor area

for the hand. Further, task-related activities can be shown to affect corticospinal outputs, presumably

reflecting intrinsic plasticity in the motor cortex.In order to test for the existence multiple clusters, 47

patients with brain tumors participated in a study of their individual somatotopy using nTMS (NBS System,

Nexstim Oy, Helsinki, Finland). 20 of the patients were also mapped intraoperatively with direct cortical

stimulation (DCS) in addition to nTMS mapping.

Results

nTMS cortical mapping was successful in 45 out of 47 patients (96%). In two patients with plegia, nTMSmapping was not successful. Total duration of an nTMS mapping session (comprising rough mapping, resting

motor threshold finding and fine mapping) averaged 30 min. On average, 100 stimuli per patient were

administered. There were no major adverse events (seizures) either during, or subsequent to, nTMS

mapping sessions.

In 9 out of 47 patients, more than one cluster could be identified. In the other 38 patients there was only

one cluster and no significant difference between the center of gravity and the weighted centroid (center of

gravity of the cluster). Overall, nTMS and DCS showed good concordance. In the 20 patients mapped with

both nTMS an intraoperative CS, the istance between the CS hotspot an CoG (not cluster-corrected)

was 8.13 mm 5.60 mm. When cluster-corrected, the distance between the CS hotspot an weighte


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Figure: Top left - The cartography of the TA muscle representation (blue) and the APB muscle representation(red) from a typical preoperative motor mapping session. The targets depict the DCS-hotspot (orange targetwith dark head) and the TMS-weighted centroid (orange target with orange head).

Top right - A scatter plot, color-coded blue through red, of the raw data from a subject with one cluster of

responses.

Bottom left - Plots of smoothed data maps are on the adjacent axes. The maximum point of the plots is theweighted centroid (WCntrd); the red points to the corresponding CoG.

Bottom right - Exemplary case with five clusters, depicted in the contour map and plots from smoothed data.Note the dislocation of the CoG (indicated by the red ). The magenta circle defines the equivalentperimeter of the representation before correction for multiple clusters, the red circle defines the perimeterof the representation after correction for multiple clusters.


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centroid was 7.23 mm 3.34 mm. In the 6 patients with multiple clusters, who also underwent direct cortical

stimulation, the istance between the CS hotspot an the weighte centroi was reuce, in many cases

significantly. When cluster-correcte, the calculate istance between the CS hotspot an the nTMS

centroid was reduced in 4 out of the 6 patients (in one patient the hotspot-centroid distance increased after

cluster correction).

Conclusion

nTMS can be employed to map the cortical representation area for a discrete muscle in detail. A detailed

analysis of the data provides evidence for the existence of multiple sub-clusters of muscle representation,

rather than a single cluster and this finding should be considered when interpreting the results of motor

mapping. In addition, the study provided evidence that the response area of the sub-clusters contributing to

the measurement of CE is related to the degree of clinical deficit, with patients with light to moderate

paresis having a larger response area, compared to patients without paresis.


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Transfer of NBS motor mapping data throughneuronavigator into optic field of operating microscope

Julkunen P1, Jskelinen JE.2

1Department of Clinical Neurophysiology and 2Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland

In our neurosurgical practice, we have found fMRI to be an unsatisfactory preoperative mapping method

when lesions reside close to the primary motor areas (M1) of the cortex. Navigated TMS (NBS System,

Nexstim Oy, Helsinki, Finland) is a new method for the direct mapping of the M1 cortex, and, in our hands,

the NBS System has been more reliable and robust than fMRI. We use direct intraoperative stimulation of

the M1 cortex and motor white matter tracts under general anesthesia without neuromuscular blockade.

The correlation to preoperative NBS mapping data is straightforward, as the NBS mapping technique is

analogous to direct cortical stimulation.

Mapping with the NBS System can be readily integrated into the existing neurosurgical workflow because

the NBS System utilizes the same MR image stack as required for the neurosurgical navigator, the

intraoperative neurophysiology systems and the navigated operating microscope (for example, the Zeiss

OPMI Pentero surgical microscope). We report on the procedures our department has developed to

generate reliable pre-operative functional M1 mapping data using the NBS System, the workflow needed to

make the data available intraoperatively, and our practical experiences.

Motor mapping with the NBS System

By department protocol, only the M1 areas in the immediate vicinity of the lesion, based on the anatomical

MRI, are mapped using the NBS System. Therefore, the hand, face and leg M1 areas are mapped as required.Up to six muscles, corresponding to the six available EMG channels are mapped per muscle group. For each

muscle group, the resting motor threshol (MT) is etermine at the hotspot representation of one

particular muscle in that group. The thenar muscle, with its normally large representation area, is usually

chosen for the hand. The mentalis muscle, being easy for the patient to relax, is typically chosen for the

facial muscle group. The tibialis muscle is commonly chosen as the representative muscle of the leg muscle

group. For higher quality results, and also patient comfort and ease of co-operation, MT measurements are

made only on fully relaxed muscles. Stimulation intensity at resting MT has been found to vary considerably

between the different muscle group areas, and not only the leg compared to the hand groups. In the case

example shown in Figure 1, the MT was found at 61% of maximum stimulator intensity for the thenar muscle

(hand), but at 76% for the mentalis muscle (face). Therefore, by simply mapping at a rule of thumb 110%

of thenar muscle resting MT it would have been easy to overlook representations of the facial muscle group

due to poor technique.

Patients are focally mapped at 105% and 110% of resting MT with muscle group-specific MT, on the principle

that optimal results are obtained from fine responses out of ense stimuli. With the TMS coil optimally

orientated to the cortical anatomy perpendicular to the sulcal anatomy the boundaries of the lesion area

are mapped and mapping is extended distally until no further responses to stimuli can be detected. The total

duration of patient mapping is commonly between 30 and 60 min, including mapping of the corresponding

areas of the unaffected hemisphere for comparison data.


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Figure 1. Motor mapping of five facial and six hand muscles, as displayed on the NBS System screen. In thedetailed image (right), responses from the hand muscle group are colored yellow and responses from thefacial muscles, which partially overlap the lesion, are colored red (grey indicates no response at stimulationlocation). The muscle area boundaries (dashed lines) are manually drawn.

Figure 2. Left: Neuronavigator planning screen display of the NBS mapping data (green) fused into the MRIata set of the patients hea, the tumor volume is drawn with purple. Right: View of optical field in thesurgical microscope showing the motor area of the hand (visualized with green borders) relative to thetumor region (delineated with purple border).


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Preparation and transfer of functional mapping data

The patients level of muscle relaxation is monitored during the session allowing the NBS System user to

reject clearly spurious responses in real-time. Responses of greater than 50 V can usually be assumed to

originate from functionally active cortical locations, however manual review of the data during post-

processing is still required to eliminate any artifacts. After analysis of the data file and confirmation of allsuccessful responses, the mapping results are projected to an optimal depth below the scalp in the NBS

System software, usually either 15 or 20 mm below the cortical surface. Response locations are fused with

the structural MR-image (the same image to be used in the surgical navigator and by the surgical

microscope) and DICOM-exported (grey-scale images) from the NBS System. The mapping results image is

transferred from the NBS System to the surgical navigation system via the hospital PACS. The NBS mapping

results and the structural MR images are co-registered in the neurosurgical navigation systems planning

workstation. Throughout all these processes the patient data retain the same coordinate system as used in

the original anatomical MRI. Finally, in order to allow the functional maps to be projected onto the exposed

brain tissue in the visual field of the surgical microscope, the mapped response clusters transferred from the

NBS System are manually outlined and color-visualized in each MRI slice (Figure 2).

Conclusion

Integration of the preoperative functional M1 mapping data from the Nexstim NBS System into the visual

field of an operating microscope is a practical addition to current concepts in neurosurgical workflow and

supports safer gross resection of lesions located near to the M1 cortex. So far, the mapping results from the

NBS System have shown good concordance with the results from intraoperative DCS, but brain shift

following craniotomy needs to be taken into account. Clinical experience with the NBS System has so far

been limited to mapping of the primary (M1) motor areas. Mapping the speech areas is a promising research

area although it may be challenging to differentiate the M1 cortex from the Brocas area. Furthermore,unlike in motor mapping, speech mapping will require full co-operation from the patient.


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NBS-DCS and functional magnetic resonance imaging preoperative mapping in central region tumors

MT Forster, A Szelnyi

Department of Neurosurgery, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany

In order to reduce permanent deficit postoperatively, as well as to enable a higher degree of resection, most

neurosurgeons employ electrophysiological techniques such as direct cortical stimulation (DCS) to assess the

functional cortex during resection. However, when brain tumors are diagnosed to be located within, or

adjacent to the motor cortex, neurosurgeons face a difficult initial decision on whether to recommend

resection to the patient with the sole aid of anatomical images.

By visualizing hemodynamic responses to movement tasks, functional magnetic resonance imaging (fMRI)

has been available as a preoperative planning tool for almost 20 years. However, because fMRI provides

images of all cortical areas involved in the planning and execution of a performed task, large cortical areas

functionally related to the action are often visualized. All the more because moving only one muscle during a

given task is difficult to perform, and the inadvertent use of other muscles sometimes occurs. Additional

difficulties influencing the reliability of fMRI arise from examiner-dependent analysis thresholding, resulting

in user-dependent variability of fMRI data.

It is now approximately 25 years since TMS was introduced (Barker et al, 1985) and approximately ten years

since a paper on the concordance of fMRI and TMS was publishedindicating, for the first time, the

potential of navigated TMS to contribute to preoperative planning (Krings et al 2001). However, this study

neither compared fMRI, nor TMS, to the gold standard of intraoperative DCS.

Recent studies comparing nTMS to DCS also spared comparison of nTMS to fMRI. Therefore we aimed to

compare the spatial accuracy of both fMRI and nTMS in relation to DCS. Over a period of two years, 18 out of

58 brain tumor patients met the inclusion criteria (tumors in or very close to the eloquent motor cortex. 15

of the patients were male, 3 were female, and the average age of the cohort was 43 years.

The preoperatively acquired 3D MRI anatomical data set and co-registrated fMRI activations were loaded in

the NBS System. FMRI maps were obtained for 12 patients. In 5 patients, fMRI was not available; in one

patient fMRI tasks could not be performed by the patient due to hemiparesis. Using an NBS System (eXimia

NBS System, Nexstim Oy, Helsinki, Finland), nTMS cortical mapping was performed successfully in all 18

patients. In total, 38 muscles were mapped by nTMS, with no adverse events. DCS was performed duringsurgery in all patients.

The coordinates of preoperative nTMS mapping were not shown during surgery in order to exclude the

possibility of bias. All cortical points where DCS elicited MEPs were co-registered in a surgical navigation

system and transferred to the NBS System for post-hoc comparison. For each specific muscle MEP, pairwise

Euclidian distances between the DCS coordinates and the corresponding nTMS coordinates were calculated

in the NBS System. Likewise, the pairwise Euclidian distances between the same DCS coordinates and the

corresponding coordinates of the centroid of fMRI activation were calculated in the NBS System.


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Figure 1. Location results for a single patient as displayed on the NBS System.A) Representation area of the hand as determined by fMRI

B) Representation area of the abductor pollicis brevis (APB) muscle by nTMS mapping preoperativelyC) Location of the same APB muscle representation area by DCS immediately after opening the dura

Results

The comparison of localization results yielded mean distances of 10.8 5.7 mm and 14.5 7.6 mm for nTMS

and fMRI centroid, respectively, from the corresponding DCS electrode location (p=0,0002). In order to

appreciate the significance of the results in the clinical context, it has to be considered that there are

inherent inaccuracies in replicating muscle representation area measurements by DCS, both related to the

electrode placement as well as to the errors introduced by stereotactic navigation systems. Since the mean

distance between two replicated DCS localizations would be expected to be 7.8 mm, a mean distance of 10.8

mm between nTMS localization and DCS localization can be considered comparable in the clinical context.

In terms of surgical outcome in the 18 patients undergoing resection, 6 patients (33%) experienced transient

paresis which resolved in the postoperative period. One patient (6%) with histology of diffuse reactive

astrogliosis had a new permanent deficit (distal leg paresis MRC 4).

C) DCS eliciting MEP (APB)

B) nTMS eliciting MEP (APB)

A) fMRI hand


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Conclusion

The results of this study show that in patients with the distorted anatomy associated with cerebral tumors,

nTMS enables location of the eloquent cortex with an accuracy which is quite comparable to that of gold

standard intraoperative DCS. When comparing the accuracy of nTMS to the accuracy of fMRI, both

independently correlated to DCS.

This study shows that nTMS is more precise than fMRI. nTMS has also proven to be a more robust and

patient-friendly technique compared to fMRI: motor tasks for fMRI are not feasible in patients requiring

sedation for claustrophobia and, in addition, some patients are not able to adequately perform fMRI-related

motor tasks due to paresis. In both of these aforementioned situations, mapping by nTMS is unaffected.

As a non-invasive method, nTMS mapping is an excellent new tool for preoperative evaluation to

complement preoperative clinical decision making and may contribute to decisions on recommending

resection. Nevertheless, verification of the nTMS-determined location of eloquent cortex by direct cortical

and subcortical electrical stimulation needs to be performed intraoperatively.


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Neurophysiologic markers generated by motor speech-related cortical areas

1,2Deletis Vedran, 2Rogi Maja

1Department of Intraoperative Neurophysiology, St. Luke's - Roosevelt Hospital, New York, NY, USA2Laboratory for Human and Experimental Neurophysiology, School of Medicine University of Split, Croatia

When operating near the eloquent areas of the brain, it is a neurosurgical priority to preserve the patients

ability to speak. During surgery, a standard neurophysiologic method to avoid speech and language deficits is

to locate the presumed motor speech-related cortical areas by producing speech arrest while electrically

stimulating those areas. To elicit speech arrest, and therefore locate motor speech related cortical areas of

the brain, one of the requirements is the awake patient actively participating in a specific speech task.

However, as awake surgery is not always an option, especially in young children and uncooperative

patients, it would be valuable to locate (map) and monitor the cortical areas essential for speech productionin patients under general anesthesia.

Unlike the other oropharyngeal muscles, it is believed that the laryngeal muscles have evolved relatively

recently in humans and have become specialized in speech production. Furthermore, it has been proposed

that the principal areas of the motor cortex required for controlling vocalization are closely and uniquely

associated with the laryngeal muscles. If this is indeed the case, we believe it may be possible to define

neurophysiologic markers for the identification of the specific motor speech related cortical areas via the

linking of evoked responses in the laryngeal muscles with the stimulation of those areas in the cortex. As

with the more common clinical biochemical markers, such a neurophysiologic marker for the individual

patient would share the following clinical attributes: central nervous system specificity, predictability ofserious injury and reproducibility, as well as being relatively inexpensive.

Three different cortical areas in the frontal cortices have been found to be involved in speech arrest, all of

which having very similar clinical appearance. Speech arrest has been achieved after stimulation of the

primary negative motor areas (NMA), after stimulation of the opercular part of Brocas area (Bromanns

area 44) and after the stimulation of the primary motor cortex (M1) area for the laryngeal muscle, as well as

other muscles involved in speech production. The responses in the laryngeal muscles (cricothyroid and vocal)

associated with stimulation of the M1 can be clearly recognized due to their significantly different latencies:

stimulation of the M1 produces a short latency response (SLR), whereas stimulation of the opercular part of

Brocas area prouces a long latency response (LLR) (1). Very identical stimulating points over the opercularpart of Brocas area generate LLR when stimulate with a 50 Hz train of stimulation pulses, producing speech

arrest. Studies indicate that areas of the M1 are responsible for controlling the muscle movements needed

for vocalization, whereas the opercular part of Brocas area is responsible for phonological processing.

Evidence of functional connections between M1 for laryngeal muscles and the opercular part of Brocas area

using cortical-cortical evoked potential recording has been found (2). These findings have been recently

confirmed by fiber tractography showing functional connectivity between the supplementary motor area

and Brocas areas (J. Espadaler, personal communication) and connectivity between Brocas area an M1 (J.

C. Fernandez-Miranda, personal communication).


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In patients without muscle relaxants, mapping of the M1 for the laryngeal muscles and the opercular part of

Brocas area was performe by inserting a hook wire electrode in the vocal muscle (3) in anesthetized

patients or in the cricothyroid muscle in awake patients (4). Using short trains of stimuli, applied either

extracranially or to the exposed motor cortex, it was possible to obtain SLR when stimulating the M1, and

LLR while stimulating the opercular part of Brocas area. This technique is easily mastered and the procedure

is painless when performed in awake patients or volunteers, using navigated transcranial magnetic

stimulation (nTMS).

There has also been progress in the techniques available for use for non-invasive stimulation. The recent

introduction of nTMS, which uses MRI-based stereotactic navigation, is likely to spur research into speech

mapping as a noninvasive technique but without the shortcomings of transcranial electrical stimulation

methodology. Using an nTMS device, the NBS System (Nexstim Oy, Helsinki, Finland), it has been shown that

it is possible to accurately locate the representation area of the cricothyroid muscle in the M1 by eliciting a

SLR and to locate the speech-related opercular part of Brocas area by eliciting a LLR in the laryngeal muscles

(Figure 1).

Figure 1. The motor speech related cortical areas for a single subject, elicited by nTMS. The primary motorrepresentations for the abductor pollicis brevis (APB) muscle, the cricothyroid (CRICO) muscle and theopercular part of Brocas are highlighte.


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Discussion

Research indicates that the stimulation of motor speech-related cortical areas in the M1 and the

phonological part of Brocas area generate distinguished and replicable responses in the intrinsic laryngeal

muscles. Further research is needed to determine the methodologies to locate the negative motor areas for

speech within the supplementary motor cortex and, even more importantly, in the primary negative motorareas for speech within the premotor cortex. Once we have validated the localization/mapping methods we

will have robust neurophysiological markers for expressive speech detection.

Defining reliable neurophysiologic markers of the motor speech-related cortical areas would significantly

contribute to surgical care of lesions in the frontal lobe. Such markers would not only help in the selection of

patients for surgery and planning of safe access to lesions, but also in preserving motor speech-related

cortical areas in patients undergoing surgery under general anesthesia.

References

1. Deletis V, Ulkatan S, Cioni B, Meglio M, Colicchio G, Amassian V, Shrivastava R. Responses elicited in thevocalis muscles after electrical stimulation of motor speech areas.Rivista Medica 2008; 14:159-165.

2. Greenlee JD, Oya H, Kawasaki H, Volkov IO, Kaufman OP, Kovach C, Howard MA, Brugge JF. A functionalconnection between inferior frontal gyrus and orofacial motor cortex in human.JNeurophysiol2004;92:1153-1164.

3. Deletis V, Fernandez-Conejero I, Ulkatan S, Costantino P. Methodology for intraoperatively elicitingmotor evoked potentials in the vocal muscles by electrical stimulation of the corticobulbar tract. Clin

Neurophysiol2009; 120:336-341.

4. Deletis V, Fernndez-Conejero I, Ulkatan S, Rogid, M, Carb EL, Hiltzik D. Methodology for intraoperativerecording of the corticobulbar motor evoked potentials from cricothyroid muscles. Clin Neurophysiol

2011, In Press


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Functional brain mapping in surgical neurooncology

Duffau H.

Department of Neurosurgery and INSERM U583 (Institute for Neuroscience), Hpital Gui de Chauliac, CHU Montpellier, France

Although relatively rare, low-grade gliomas (LGG), WHO classified Grade II gliomas, mainly affect young

people (median age at diagnosis 35 years) at the peak of their active lives. Until recently, the clinical course

was usually wait an see - assuming that, unlike high-grade gliomas, low grade tumors were "benign

tumors". However, since LGGs have been found to become aggressive neoplasms which infiltrate the brain

along white matter tracts, theEFNS-EANO Task Force guidelines (Soffietti et. al.) now recommend resection

as the first treatment option also for LGGs, with the goal to maximally resect the tumor mass while at the

same time minimizing postoperative morbidity1. Furthermore, it has been shown that the extent of resection

positively correlates with overall survival and the time to malignant transformation.

Patients with LGGs present predominantly with seizures, since the tumors tend to occur in eloquent areas.The rationale for surgical treatment is therefore based on the ability of resection to control seizures as well

as to delay anaplastic transformation. Since the patients are relatively young, and the natural history of LGGs

relatively long, it is paramount to conserve the patients simple and complex neurological functions at the

same time as maximizing the extent of resection. This dual, antagonistic challenge makes the role of

functional brain mapping crucial, both in presurgical planning and resection.

The presumed reason for seizures in LGG patients is that the tumors are frequently located in the eloquent

areas, especially in language regions. When considering surgical treatment, we need to be concerned about

the preservation of speech, not only the ability to produce vocalization and articulation, but also with the

preservation of the crucial abilities of understanding, thinking, comprehension and cognition. The

neurooncologists goal of achieve the maximum extent of resection versus preserving function is mae

especially difficult by individual variability in functional limits. It is only partially true that the human brain is

functionally organized in a classically similar manner. Cortical functional organization and anatomo-

functional connectivity are, in fact, all individual. Indeed, plasticity, which depends on reorganization of the

cortex, is likely to be even more individual. Therefore, it has to be assumed that the mechanisms by which

the brain is processing information are also highly individual.

The challenge of intra-subject variability has been illustrated in a study by Vigneau et al., examining

variability of language cluster activation based on analysis of 130 scientific reports2. The diverse and

overlapping localizations of phonology, semantics and syntax suggest large scale networks and broad

individual variation in language localization. In fact, it appears that the language network is not confined to

the Brocas area. The clinical reality is therefore complex. For example, language function cannot always be

directly associated with handedness, and the right hemisphere may be crucial for language in right-handed

patients. Consequently, it is critical to use awake mapping for language during surgery. Navigated rTMS,

which allows accurate focal activation and inhibition of neurons, now gives the possibility of a reliable, non-

invasive diagnostic tool to determine dominant hemisphere prior to surgery by inducing transient deficits in

one hemisphere. In certain patients, this information would determine the need for awake mapping during

resection.


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Figures: (A) Axial FLAIR-weighted MRI in a right-handed young woman who experienced inaugural seizures.

The patient met several neurosurgeons, who claimed that it was impossible to operate due to tumorinvasion of the Brocas area. Because the tumor continued to grow, an awake surgery was proposed in ourinstitution.(B) Intraoperative views before (left), and after (right) glioma resection, delineated by letter tags. IES shows areshaping of the eloquent maps, with a recruitment of perilesional language sites located behind the glioma,within the precentral gyrus (1, 2, 3). There was no crucial site within the left inferior frontal gyrus, thus anextensive resection of Brocas area was possible by preserving the subcortical connectivity in the depth ofthe cavity (49 and 50, corresponding to language pathways).(C) Postoperative axial FLAIR- and coronal T2-weighted MRI, demonstrating a near-complete resection of theglioma with removal of the corpus collosum, in a patient with neither neurological nor neurocognitivedeficit, leading a normal socioprofessional life.It is worth noting that there is a FLAIR-hyperintensity visible

deep in the cavity, i.e. located within the still functional deep gray nuclei and white matter tracts.


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A localizationist view of one specific cortex area being responsible for one specific function is an

oversimplification of the human brain; cortical mapping is the first step in functional analysis, but alone it is

not sufficient. Rather, we need to take a connectionist view, adding subcortical mapping while performing

resection. Under local anesthesia, stimulation can be used to elicit involuntary movement for mapping of the

motor areas, sensory areas can be mapped by induction of paresthesias and the cognitive functions

(language, calculation, comprehension, memory and writing) can be tested by transient disturbances. With

awake cortical and subcortical mapping, the neurooncologist can be careful to preserve the specific skills

individual patients themselves desire for quality of life (QoL).

As stated earlier, it is only partially correct that the human brain is similarly organized, anatomo-functional

differences exist not only between individuals, but there is also clear evidence of time-dependent, intra-

subject variability during tumor growth and following resection. Recognizing the dynamism of plasticity

allows the neurooncologist to take advantage of individual cortical functional reorganization following

resection as the basis for not only preserving function, but also improving function, and thereby restoring

the patients real QoL. Reorganization can be intralesional, perilesional or contralesional. Inee, the plastic

reshaping of the brains functions by resection can be utilize to treat lesions lying within eloquent areas. In

a series of 39 patients, Martino et. al. reported that a second repeat or third repeat operation improved the

extent of resection in 80% of cases, despite anaplastic transformation in 50% of cases3. The functional

outcomes for the patients were good with no severe deficits and no deaths, either post-operatively or in the

6-year median follow-up after surgery. Here, as a direct stimulating device, nTMS could have an important

role in confirming, prior to repeat surgery, plastic re-organization of the cortex and significantly ease the

neurooncologists ilemma over whether or not to recommen repeat surgeries to patients.

With the understanding that a significant cause of post-operative morbidity is major cerebrovascular

incident (1.5% of risks of stroke), and no more the removal of tissue, tumors in difficult to access locations

can be more safely approached via incisions in eloquent areas with the knowledge that post-operative

plasticity in the functional network will compensate for lost eloquent tissue. To minimize vascular damage,

tumors in the insular area can be preferentially resected by access through the frontal operculum, even in

the left dominant hemisphere, for example.

Conclusion

Low grade gliomas should be surgically treated without hesitation, balancing oncological considerations with

the preservation of QoL. In LGGs, tumor growth negatively impacts neurocognition, whereas surgery has

been shown to not only control epilepsy and preserve functions, but also to improve brain function. The

introduction of functional brain mapping of eloquent areas has widened indications, increased the extent ofresection and improved functional outcomes. However, in order to further widen the indications for

resection therapy, we need new functional mapping tools to better understand individual anatomo-

functionality and connectivity.

Due to the time-constraints of resection, the application of this new understanding needs to happen prior to

the surgery. FMRI has been a useful tool for over 10 yrs but, fMRI alone is of limited use in decision-making

since it is not able to differentiate between essential and compensable areas. Similarly, diffusion tensor

imaging (DTI) provides anatomical sub-cortical white matter tracking, but, again, is of limited use as DTI tells

nothing about the function of the white matter. However, recent advances have brought nTMS into the

clinical domain. nTMS can be used to validate fMRI findings and differentiate the essential eloquent areas.nTMS promises to link neurooncology with the basic cognitive neurosciences, giving nTMS a key role in


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presurgical planning, particularly with regard to language and cognition. Being noninvasive, nTMS could be

used for post-operative follow up of cortical reorganization and provide conclusive proof of the validity of

intraoperative mapping and results. In the future, there exists the novel concept of using navigated rTMS to

push cortical plasticity and proactively prepare the brain for reoperations.

Ultimately, the limit to plasticity, whether spontaneous, assisted or surgically-induced, is likely to be theneed for the brain itself to retain, and the neurooncologist to preserve, the critical subcortical functional

pathways.

References

Soffietti R, Baumert BG, Bello L, von Deimling A, Duffau H, Frnay M, Grisold W, Grant R, Graus F, Hoang-

Xuan K, Klein M, Melin B, Rees J, Siegal T, Smits A, Stupp R, Wick W; European Federation of Neurological

Societies. Guidelines on management of low-grade gliomas: report of an EFNS-EANO* Task Force. Eur J

Neurol. 2010 Sep;17(9):1124-33.

Vigneau M, Beaucousin V, Herv PY, Duffau H, Crivello F, Houd O, Mazoyer B, Tzourio-Mazoyer N. Meta-

analyzing left hemisphere language areas: phonology, semantics, and sentence processing. Neuroimage.

2006 May 1;30(4):1414-32. Epub 2006 Jan 18.

Martino J, Taillandier L, Moritz-Gasser S, Gatignol P, Duffau H. Re-operation is a safe and effective

therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas. Acta Neurochir (Wien). 2009

May;151(5):427-36; discussion 436. Epub 2009 Apr 1.


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Combining NBS and MEG in neurosurgery

Mkel JP.

BioMag Laboratory, HUSLAB, Helsinki University Central Hospital, Finland

Patients with focal epilepsy that cannot be controlled by antiepileptic drugs are potential candidates for

surgical treatment. However, it is crucial to establish that the proposed resection removes the source of the

epilepsy without an intolerable risk of permanent post-operative morbidity. Preoperative diagnostics also

has a role in helping the patient and their families balance the acceptable risks with the benefits that

successful surgery would have on their lives. Combining the non-invasive techniques of

magnetoencephalography (MEG) and navigated TMS (nTMS) holds promise for improving presurgical

planning in epilepsy. MEG can be used to determine the sources of interictal and sometimes also ictal

epileptiform activity, and the primary somatosensory cortex , while nTMS can be used to map the extent of

the motor cortex, obtain fine detail, and confirm the MEG findings.

Intracellular electrical activity in active neurons induces magnetic fields. Although the magnetic fields

produced in the cortex are very weak, they can be detected outside the skull using superconducting

quantum interference evices. By moe of action, MEG can be thought of as inverse TMS. Like TMS, MEG

is essentially unaffected by overlying tissue and bone, and therefore has greater spatial resolution than EEG-

based methods. Like nTMS, MEG is co-registered with the anatomical MRI, and is therefore part of the

navigate surgery paraigm.

We report on the feasibility and outcomes using an nTMS device, the NBS System (Nexstim Oy, Helsinki,

Finland), and MEG in planning for epilepsy surgery. In 19 out of a series of 20 patients, motor mapping with

the NBS System were successful (95%); one patient (age 7 years) could not be convinced to voluntarily

participate in the examination. There were no seizures during the stimulation sessions, although one patient

suffered one seizure between stimulations. In 17 cases surgical resection was performed. In 15 patients

subdural grid electrodes (SGE) were implanted after craniotomy for invasive preoperative

electrocorticography (EcOG) and direct cortical stimulation.

Results and discussion

In the 15 patients in which SGE mapping was performed, there was a general match between SGE and

preoperative non-invasive NBS mapping in 14 out of 15 patients (93%). Of the 16 patients followed long

enough for post-operative evaluation, the outcome of 10 patients (63%), was classified as Engel 1 (EI ,seizure free or auras only), 4 patients were EII ( =infrequent seizures) and there was one patient in each of

the EIII and EIV categories.

Premotor cortex activation can confound mapping of primary motor cortex using nTMS. However, since the

resting motor threshold (MT) is approximately 20% higher in the premotor cortex than M1, careful finding of

muscle group MT and adjustment of the stimulator output can control for this possibility. As cortex drives

movements, not individual muscles, several muscles may be represented at the same cortical location. It

needs to be kept in mind that the motor responses shown on the NBS System screen are limited to those

predetermined muscles recorded by the EMG electrodes.


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Figure: Comparison of preoperative mapping and ECoG in a patient with epilepsy, depicted on a 3-Dreconstruction of the patients brain seen from above. The epileptiform region near the motor cortex, asdepicted by MEG, is colored yellow. The red dots indicate sites producing MEPs by nTMS. The green dotindicates the anatomic hand knob. Red circles mark the electrodes where stimulation elicited typicalseizures, the dark blue circle indicates a site producing hand movements and a seizure, and light blue circles

indicate sites producing hand and arm movements. The surgeon removed the cortical area delineated by theblack lines. After the operation, the patient is seizure-free and has no motor deficits. Modified fromVitikainen et al., 2009.

Conclusion

In presurgical planning for epilepsy, data from NBS mapping and MEG offer information which may be

decisive in difficult cases and not available from other methods. NBS mapping results are useful to confirm

the MEG results and add additional information on the extent of the eloquent motor areas, thus helping to

define the volume of tissue, which can be safely resected. NBS mapping results aid in the positioning of the

grid when EcOG is required and assists in interpretation of the results when ECS results are confounded by

after-discharges or seizure induction. In patients with seizures frequent enough for ictal MEG and

epileptogenic zone near the sensorimotor cortex, the combination of NBS mapping and MEG may be precise

enough to replace invasive ECS.

References

Vitikainen A-M, Lioumis P, Paetau R, Salli E, Komssi S. Metshonkala L, Paetau A, Kiid , Blomstet G,

Valanne, L, Mkel JP, Gaily E:Combined use of non-invasive techniques for improved functionallocalization for a selected group of epilepsy surgery candidates. NeuroImage 45, 342-348, 2009


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NBS in children methodological aspects and case study

Thordstein, M.

Dep. of Clinical Neurophysiology, Sahlgrenska University Hospital, Gteborg, Sweden

Background

As part of a presurgical evaluation, the delineation of the motor areas is as essential in children as it is in

adults. Use of the most common technique, functional magnetic resonance imaging (fMRI), is often difficult

in children, and in the very young and/or cognitively affected, impossible. This is because the fMRI technique

requires that the child is able to lie still in the bore of the magnet for long periods of time and also actively

participate in the required tasks. An alternative, more child-friendly method would therefore be welcome.

We have previously used navigated transcranial magnetic stimulation (nTMS) for the precise demarcation of

primary motor areas in adults with brain lesions. The system used (Navigated Brain Stimulation, NBS System,Nexstim Oy, Helsinki, Finland), utilizes the patients structural MR-image for guidance. So far, the clinical

utility of nTMS has not been studied to the same extent in children as in adults.

Our comparisons of fMRI and nTMS suggest that the two techniques can give discordant results and thus

may not be mapping the same physiological phenomenon. Examinations by others of the spatial distances

between independently measured centers of activity for nTMS and intra-operative direct cortical stimulation

(DCS), suggest that nTMS results closely approximate DCS results. If the nTMS technique more closely

correspons to the gol-stanar CS paraigm, the better accuracy of nTMS would be an additional

beneficial feature when mapping motor areas in children.

In motor mapping, nTMS has advantages over fMRI in children since specific task co-operation is not

required. The child does not have to be in a confined environment, may move, and may even sit or lie in the

lap of one of the parents during mapping. In children taking multiple anti-epileptic drugs, the threshold to

elicit motor evoked potentials (MEPs) is very high and pre-activation of the muscles is often necessary in

order to obtain measurable responses. Here, the presence of the parents and their ability to activate and

play with the child during the mapping session can be crucial to obtaining a successful result.

TMS-EMG studies in children differ in several respects compared to those in adults. The stimulator output

needed to evoke MEPs is usually higher than in adults. Another difference is the latencyjump, the

difference between the latency of a TMS-evoked MEP measured at rest compared to the latency of the MEPevoked with muscle pre-activation. In children, the latency jump is greater than in adults. As the degree of

pre-activation often varies over time, the interpretation of the MEPs may be difficult.


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Case study: 3-year-old patient

Here we describe an nTMS study on a 3-year-old girl, to our knowledge the youngest patient that has been

studied using the NBS System. The child had been diagnosed with therapy-resistant epilepsy resulting in

focal seizures visibly starting proximally in the right arm and presumed to be originating close to the left

central sulcus. At the age of three, continuous spike-wave disturbances could be seen in EEG recordings andthe child began to lose her language functions. There was therefore a need for a full epilepsy surgery

evaluation prior to making any treatment decision.

Mapping procedure

The child was positioned in the lap of one of the parents, who, in turn, sat in a comfortable chair. After the

chils structural MR images were uploae to the NBS System, an optimal visualize epth was chosen to

help the search for stimulation points. A tracking system with infrared light was used to inform the system of

the location of fixed points on the head, also defined in the MR image. The tracker eyeframe with reflecting

spheres was kept tightly in place by fixating it with a net helmet pulled over the chils hea. The child wasfree to move in the lap and to play with her parents (Figure 1). The muscles chosen for investigation, all

right-sided, were the abductor pollicis brevis (APB), the abductor digiti minimi (ADM), extensor carpi radialis

muscle (ECR), the musculus deltoideus (Delt) and the musculus trapezius (Trap).

Figure 1. A view of the investigational situation. Note the participation of the mother (far left), aiding in

accomplishing pre-activation of the chils muscles.


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Results

The left hemisphere was extensively stimulated. Motor mapping was successful and the results showed a

normal somatotopy (Figure 2). An electroencephalographic examination pointed to an origin of ictal spike

activity in the posterior part of the precentral gyrus. The results of the electroencephalographic examination

were manually fused with the motor map from the NBS System for further surgical evaluation (Figure 2).

Figure 2. The results from motor mapping along the left precentral gyrus in a 3-year-old patient. The color-

coded symbols indicate the locations from which responses were achieved in different muscles: green = APB,

orange = ADM, yellow = ECR, blue = Delt and purple = Trap. The grey symbols indicate locations from which

no MEP responses could be elicited in the muscles. The red X marks the probable origin of the spikes, as

indicated by electroencephalography.

Conclusion

This case illustrates the capability of the high precision NBS System to perform non-invasive investigation

and mapping of motor function in young children, as has been previously shown in older children and adults.

nTMS can be used in individuals where fMRI is difficult or even impossible to perform, which is often the

case with children. In the neurosurgical context, the ability to fuse the three-dimensional mapping results

with those from other presurgical examinations and to export images to navigation systems may make the

results of this method useful also during surgery.

X


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Repetitive transcranial magnetic stimulation and implantedcortical stimulation in the treatment of neuropathic pain

Ahdab R, Lefaucheur JP.

A 4391, Service de Physiologie, Explorations Fonctionnelles, Hpital Henri Mondor, Assistance Publique-Hpitaux de Paris,

Universit Paris-Est, Crteil, France

Motor cortex stimulation (MCS) using surgically implanted epidural electrodes, was first introduced twenty

years ago for the treatment of chronic neuropathic pain. Since then, this technique has proven to be safe

and effective to treat refractory neuropathic pain. However, the mechanisms of action of MCS are still not

yet fully understood and no preoperative criteria have been validated to predict which patients would

benefit from this invasive procedure.

A decade ago it was shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered

to the motor cortex could also produce analgesic effects in patients with drug-resistant neuropathic pain.

Because rTMS is noninvasive, the technique is particularly suited to study the mechanisms involved in the

modulation of pain perception by cortical stimulation. In addition, the reliability, precision, and repeatability

of rTMS targeting is now provie by navigate proceures (nTMS) base on iniviual patients brain MR-

imaging.

The frequency of stimulation is critical for the analgesic effects of rTMS. Motor cortex rTMS was shown to

relieve pain when applied over the hemisphere contralateral to the pain side at high frequency (5Hz or

more) but not at low frequency (1Hz or less). High frequencies were thought to potentiate synaptic

transmission beyond the time of stimulation, whereas low frequencies were thought to be inhibitory. Unlike

frequency, increased intensity does not enhance the analgesic efficacy of the stimulation. That is because

increased intensity only leads to the recruitment of fibers deeper in the cortex, whereas pain relief is

obtained by activating neural circuits in the most superficial layers of the cortex. Due to induced processes of

synaptic plasticity, the peak of the analgesic effect of rTMS is delayed about 2 to 3 days and can extend for

up to one week after a single rTMS session. The use of daily rTMS sessions for several weeks could increase

the degree and the duration of pain reduction beyond the time of stimulation. Long-term relief, however,

can only be provided by implanted epidural MCS, to date.

The analgesic effect of rTMS was also shown to depend on the precise location of the stimulation site on the

precentral gyrus, contralateral to pain side. For this purpose, one may rely exclusively on sulcal anatomy for

image-guided nTMS. For the hand motor area, the target is located at the level of the median genu of the

motor knob, which is easily identifiable in 90% of cases, in the anterior bank of the central sulcus. When the

motor knob cannot be reliably identified, the target was determined at the level of the apparent interruption

of the central sulcus. This apparent interruption is due to the presence of an outgrowth in the posterior wall

of the central sulcus at a level corresponding to the motor representation of hand muscles. In rare cases,

where neither the motor knob nor the apparent interruption of the central sulcus can be identified (3% of

cases), the target can be determined on the anterior bank of the central sulcus at the level of the superior

frontal sulcus in the mediolateral axis.


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Finally, rTMS efficacy also depends on the spatial orientation of the coil. Analgesia is usually obtained when

the coil has an anteroposterior orientation and not when the coil has a lateromedial orientation, even at the

optimal site of stimulation in the precentral gyrus. Indirect corticospinal descending volleys are produced by

stimulation of the motor cortex

2010 nbsworkshop abstracts 4

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