2010 NBSworkshop Abstracts 4

Abstracts from the 2nd International Workshop on Navigated Brain Stimulation in Neurosurgery
October 8-9th, 2010, Berlin, Germany Organized by Prof. Dr. P. Vajkoczy and Dr. Th. Picht
Department of Neurosurgery, Charit - Universittsmedizin Berlin, Berlin, Germany
Introduction to the 2nd International Workshop on Navigated Brain Stimulation in Neurosurgery

The treatment of brain pathologies in, or in close proximity to, the eloquent cortex on MR-imaging, benefits from 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 magnetic stimulation (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 Many of the presentations contained previously unpublished data and we are grateful to the authors for their permission to publish abstracts in this collective format.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. Picht Department of Neurosurgery, Charit - Universittsmedizin Berlin, Berlin, Germany
2nd International Workshop on Navigated Brain Stimulation in Neurosurgery (pub. May, 2011)
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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. Department of Neurosurgery, Charit - Universittsmedizin Berlin, Berlin, Germany 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 1 2 JULKUNEN P , JSKELINEN JE. 1 2 Department of Clinical Neurophysiology, Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland NBS-DCS AND FUNCTIONAL MAGNETIC RESONANCE IMAGING PREOPERATIVE MAPPING IN CENTRAL REGION TUMORS ...................................................................................................................................................................... 19 MT FORSTER, A SZELNYI Department of Neurosurgery, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany NEUROPHYSIOLOGIC MARKERS GENERATED BY MOTOR SPEECH-RELATED CORTICAL AREAS ..................................... 22 1,2 2 DELETIS VEDRAN, ROGID MAJA 1 2 St. Luke's - Roosevelt Hospital, New York, NY, USA School 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 noninvasive 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 a new 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 earlier technologies 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 new mapping technique needs to be demonstrated to be no less accurate than the gold standard direct 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 and 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 significant impedance. By Faradays law, a phasic magnetic pulse from a coil placed over the scalp will induce 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 designs 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 corresponding to each individual 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, or rapidly 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 selfreorganization should the brain be damaged or become diseased.
Figure 1: Electric field-targeted navigated TMS: motor evoked potential responses to a single TMS pulse using 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 single center

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 and other 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 indication and treatment plan. The neurosurgeon was requested to complete a questionnaire ranking the impact the additional 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 new functional 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. Permanent deterioration 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 indication and in an additional 25 % of the cases (ranking 4 and 5) NBS mapping information significantly improved the surgical approach.
4 %
NBS changed the surgical indication
55%
5 4 3 2 1 0
0%
NBS changed the planned extent of resection 9% NBS modified the operative access pathway 16% 26 NBS guided the DCS % NBS added knowledge about the functional 20% anatomy NBS confirmed the expected anatomy 25% no usable results from NBS
45%
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)
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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 surgical plan. 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 and electrophysiological 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 noninvasive 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 BrainLab navigation system. The NBS-mapped motor area (green dots) was used as the seeding region for DTI fiber tracking (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 the navigated 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-calculated motor 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 gold standard 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 decisionmaking. Excitability of the motor cortex can be indexed by measuring the resting motor threshold (MT) for a discrete 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, nTMS mapping 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 and intraoperative DCS, the distance between the DCS hotspot and CoG (not cluster-corrected) was 8.13 mm 5.60 mm. When cluster-corrected, the distance between the DCS hotspot and weighted
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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 target with 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 the weighted 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 equivalent perimeter of the representation before correction for multiple clusters, the red circle defines the perimeter of 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 distance between the DCS hotspot and the weighted centroid was reduced, in many cases significantly. When cluster-corrected, the calculated distance between the DCS hotspot and 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 through neuronavigator into optic field of operating microscope
Julkunen P1, Jskelinen JE.2
1 2
Department of Clinical Neurophysiology and Neurosurgery 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 threshold (MT) is determined 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 dense 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 the detailed image (right), responses from the hand muscle group are colored yellow and responses from the facial muscles, which partially overlap the lesion, are colored red (grey indicates no response at stimulation location). 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 MRI data set of the patients head, the tumor volume is drawn with purple. Right: View of optical field in the surgical microscope showing the motor area of the hand (visualized with green borders) relative to the tumor 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 postprocessing is still required to eliminate any artifacts. After analysis of the data file and confirmation of all successful 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 published indicating, 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 during surgery 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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C) DCS eliciting MEP (APB) A) fMRI hand area
B) nTMS eliciting MEP (APB)
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 preoperatively C) 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).
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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 speechrelated cortical areas

1,2Deletis
1 2
Vedran, 2Rogi Maja
Department of Intraoperative Neurophysiology, St. Luke's - Roosevelt Hospital, New York, NY, USA Laboratory 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 production in 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 of serious 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 (Brodmanns 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 produces a long latency response (LLR) (1). Very identical stimulating points over the opercular part of Brocas area generate LLR when stimulated 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 and 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 performed 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 motor representations for the abductor pollicis brevis (APB) muscle, the cricothyroid (CRICO) muscle and the opercular part of Brocas are highlighted.
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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 motor areas 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 the vocalis 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 functional connection between inferior frontal gyrus and orofacial motor cortex in human. J Neurophysiol 2004; 92:1153-1164. 3. Deletis V, Fernandez-Conejero I, Ulkatan S, Costantino P. Methodology for intraoperatively eliciting motor evoked potentials in the vocal muscles by electrical stimulation of the corticobulbar tract. Clin Neurophysiol 2009; 120:336-341.
4. Deletis V, Fernndez-Conejero I, Ulkatan S, Rogid, M, Carb EL, Hiltzik D. Methodology for intraoperative recording 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 and 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, the EFNS-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 made 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 anatomofunctional 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, noninvasive 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 tumor invasion of the Brocas area. Because the tumor continued to grow, an awake surgery was proposed in our institution. (B) Intraoperative views before (left), and after (right) glioma resection, delineated by letter tags. IES shows a reshaping 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 an extensive resection of Brocas area was possible by preserving the subcortical connectivity in the depth of the cavity (49 and 50, corresponding to language pathways). (C) Postoperative axial FLAIR- and coronal T2-weighted MRI, demonstrating a near-complete resection of the glioma with removal of the corpus collosum, in a patient with neither neurological nor neurocognitive deficit, 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, intrasubject 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. Indeed, the plastic reshaping of the brains functions by resection can be utilized 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 dilemma over whether or not to recommend 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 of resection 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 anatomofunctionality 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 the need 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, HoangXuan 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. Metaanalyzing 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 devices. By mode 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 EEGbased methods. Like nTMS, MEG is co-registered with the anatomical MRI, and is therefore part of the navigated surgery paradigm. 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-D reconstruction of the patients brain seen from above. The epileptiform region near the motor cortex, as depicted by MEG, is colored yellow. The red dots indicate sites producing MEPs by nTMS. The green dot indicates the anatomic hand knob. Red circles mark the electrodes where stimulation elicited typical seizures, 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 the black lines. After the operation, the patient is seizure-free and has no motor deficits. Modified from Vitikainen 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 D, Blomstedt G, Valanne, L, Mkel JP, Gaily E: Combined use of non-invasive techniques for improved functional localization 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 corresponds to the gold-standard DCS paradigm, 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 latency jump, the difference between the latency of a TMS-evoked MEP measured at rest compared to the latency of the MEP evoked 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 and the 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 childs structural MR images were uploaded to the NBS System, an optimal visualized depth 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 childs head. The child was free 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 childs 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 colorcoded 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.
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Repetitive transcranial magnetic stimulation and implanted cortical 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 provided by navigated procedures (nTMS) based on individual patients brain MRimaging. 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 when the coil has an anteroposterior orientation, reflecting the preferential activation of horizontal fibers within the precentral gyrus. A similar observation was made concerning the origin of the analgesic effect produced by epidural MCS. Thus, epidural MCS or motor cortex rTMS relieve pain by activating various neural structures distant from the site of stimulation through the recruitment of corticocortical, corticosubcortical, or even corticospinal connections. Some brainstem and spinal structures could be involved in rTMS-induced analgesia in the context of topdown modulation, because patients with brainstem or spinal cord lesion appeared to be less good responders than patients with neuropathic pain of cortical or peripheral origin. Motor cortex rTMS, as well as epidural MCS, can modulate sensory perception thresholds in the painful zone, thereby affecting the sensory discriminative aspect of pain. However, the analgesic effects produced by motor cortex rTMS also likely result from a functional impact on the emotional and affective aspects of pain, due to the influence of rTMS on limbic structures, blunting the patients distressful reaction to pain. Although the mechanisms by which noninvasive motor cortex rTMS and implanted epidural MCS modulate pain are very similar, they are not identical, especially regarding the precise targeting of the stimulation within the precentral gyrus. The target strictly corresponds to the representation of the painful region of the body in the motor cortex for epidural MCS, but to an adjacent cortical region for rTMS. This may reflect differences in the geometry of the induced currents in the brain between these two techniques of cortical stimulation. Epidural MCS is an effective method to treat drug-resistant neuropathic pain. However, reliable preoperative criteria are lacking to predict the outcome of such an invasive procedure. A positive response to rTMS tests could serve to identify responders to subsequent MCS therapy, but a negative response to rTMS tests cannot exclude patients from implantation. Preoperative rTMS tests can also be used to identify placebo responders as well as the patients with severe psychiatric and personality disorders who must be discarded from surgery. As aforementioned, the repetition of rTMS sessions every day for several weeks is required to obtain the prolonged pain relief necessary for therapeutic purpose. Therefore, rTMS appears to be an unsuitable method to treat chronic pain syndrome in the long term, apart perhaps from non-neuropathic pain conditions, such as fibromyalgia, since invasive electrode implantation cannot be proposed in this clinical condition. In conclusion, high-frequency rTMS is able to produce analgesic effects, at least when the stimulation is targeted over the precentral gyrus (primary motor cortex). The potential of other targets and other parameters of stimulation are being evaluated. Stimulation has clearly benefited from the development of navigated procedures (nTMS). Thus, the use of rTMS therapy in pain domain is promising, and deserves further research.
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Figure 1: The use of the individual patients brain MR-image is essential to optimize cortical stimulation targeting for pain relief. The target usually corresponds to the anatomical representation of the painful region of the body on the precentral gyrus (primary motor cortex). This can be defined by the hot spot of cortical stimulation providing motor evoked potentials of maximal amplitude in the muscles of the painful zone. When the painful limb is completely paralyzed, this motor hot spot cannot be determined by this procedure. In such cases, it is necessary to use functional imaging to delineate the motor cortical representation of the painful region. In the case example illustrated above, the motor hot spot could not be determined in the painful limb because of a complete brachial plexus avulsion. We performed functional magnetic resonance imaging (fMRI) with a mental motor task (the patient had to think about moving his paralyzed fingers) to determine the functional motor cortical representation of the painful hand. Repetitive transcranial magnetic stimulation (rTMS) precisely delivered over the fMRI region of activation, using an eXimia NBS System (Nexstim Oy, Helsinki, Finland) led to significant pain relief that lasted several days beyond the time of stimulation. Thereafter, a quadripolar Resume electrode (Medtronic Inc., Minneapolis, USA) was implanted over the same target. Epidural motor cortex stimulation (EMCS) also resulted in significant pain relief that was prolonged in the long term. Such a case illustrates the value of navigated rTMS in the preoperative assessment of patients who are candidates for cortical neuromodulation therapy of chronic refractory pain.
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Workshop supported by:
Nexstim Oy, Elimenkatu 9 B, FI-00510 Helsinki, Finland Phone +358-9-2727-1710. Fax +358-9-2727-1717 www.nexstim.com
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2010 NBSworkshop Abstracts 4

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Abstracts from the 2nd International Workshop on Navigated Brain Stimulation in Neurosurgery

Introduction to the 2nd International Workshop on Navigated Brain Stimulation in Neurosurgery

Functional analysis in neurosurgery: a critical appraisal

NBS mapping - lessons from a 100-patient series at a single center

NBS changed the surgical indication

Navigated Brain Stimulation connects neuronavigation and electrophysiological neuromonitoring

NBS motor mapping: maps, hotspots and centers of gravity

C) DCS eliciting MEP (APB) A) fMRI hand area

B) nTMS eliciting MEP (APB)

Neurophysiologic markers generated by motor speechrelated cortical areas

Vedran, 2Rogi Maja

Functional brain mapping in surgical neurooncology

Combining NBS and MEG in neurosurgery

NBS in children methodological aspects and case study

Case study: 3-year-old patient

Workshop supported by:

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