**5. Brain mapping in neurosurgery: Criticisms and future perspectives**

Ideally, neurosurgeons could detect and locate the exact position of brain functions before performing tumor resection, allowing them to recommend surgery only in those patients with the prospect of radical or grossly subtotal resection. Moreover, technological support would serve as a guide during surgery in order to spare critical areas. Such complete and reliable technology is not yet available, but major advances have been made since the days when neurosurgeons performed brain surgery only via anatomical references.

to confirm reproducibility of the response. Once the proper current intensity is set, the entire surface of the tumor is thoroughly examined in order to exclude the presence of functional sites. When tumors are located in language areas, a neuropsychologist administers tests on a laptop screen (a series of slides with black and white pictures preceded by the words "this is a….") and describes the type of language disturbance observed (speech arrest, anarthria, anomia, or reading errors). These same tests are administered the day before surgery in order to detect baseline errors or hesitations that could be misinterpreted during intraoperative stimulation. Intraoperatively, the patient is unaware of the timing of stimulation, and the current is delivered just before presentation of the slide. After disruption of a language area, the patient rests for a while, then spontaneous speech and slide reading are tested, and stimulation starts again. Every time a positive response is encountered, a numbered tag is left in place and the function associated to the stimulation of that point is recorded. If the tumor is separated from a functional gyrus by a sulcus, maximal attention is paid in order to respect the arachnoid plane and the vasculature of the sulcus. If the tumor invades functional gyri or subcortical functional tracts, the resection must to be very careful since no anatomical limit is present between the infiltrated parenchyma and the normal functioning cortex. In these situations as well as for subcortical tumors, we test language or motor function throughout the resection even when no stimulation is applied, stopping whenever anomalies appear. Many authors have for a long time postulated a need to maintain a safe distance of at least 1 cm from a functional site (Haglund et al. 1994; Carrabba et al. 2007; Sanai & Berger 2008). More recently, this concept has been evolving because accumulated experiences have clearly demonstrated that continuous cortical and subcortical stimulations can enable the surgeon to identify and preserve eloquent cortex and the white matter bundles. Abandoning the idea of leaving a "safe margin" in favor of reaching functional boundaries yields an increase of the extent of resection, and thus, it is believed, has an increased impact on the natural history of the tumor. This more aggressive strategy is related to a higher percentage of transient postoperative neurological deficits, but it has also led to very satisfying long-term

In order to collect the largest amount of information about the unique functional organization of each individual patient, it is very important to record all the possible data from pre-, intra- and postoperative observations, including intraoperative photographs or films and, in cases of language area tumors, recordings of patients' voices. It also is important to register parameters such as current intensity, reproducibility of stimuli, and seizure occurrence, as well as the degree of pain control (at minimum a visual analog scale should be checked) and other anesthesiology concerns, such as nausea, vomiting, and need

**5. Brain mapping in neurosurgery: Criticisms and future perspectives** 

when neurosurgeons performed brain surgery only via anatomical references.

Ideally, neurosurgeons could detect and locate the exact position of brain functions before performing tumor resection, allowing them to recommend surgery only in those patients with the prospect of radical or grossly subtotal resection. Moreover, technological support would serve as a guide during surgery in order to spare critical areas. Such complete and reliable technology is not yet available, but major advances have been made since the days

neurological outcomes (Gil-Robles & Duffau 2010).

for respiratory support or for switching to general anesthesia.

Undoubtedly, CSES has gained a prominent role in neurosurgery above all because a large number of studies worldwide have shown a clear advantage in terms of usefulness, safety, and neurological and oncological outcomes (Berger 1994; Duffau et al. 2005; Duffau 2006; Kim et al. 2009; Sanai & Berger 2009; De Benedictis et al. 2010; Spena et al. 2010). The spatial accuracy and the ability to perform functional resection (that is, a resection in which limits are represented by spared functions) have met the approval of many neurosurgeons, who now use CSES routinely. However, there are some technical and methodological drawbacks of CSES that have yet to be addressed. First, the application of an electric current on the brain can have effects that are more complex than anticipated. For example, the excitation of the stimulated cortex can diffuse to near or far cortex by short or long-range white matter tracts. Consequently, the observed effect of the stimulation may not be related (or not only) to that portion of a gyrus. In this case the tumor resection might be prematurely arrested. At the same time, at which point is the surgeon sure that a functional area is essential and cannot be substituted by other epicenters? The concept of plasticity can explain recovery after various brain injuries, but the stimulation of a functional site intraoperatively cannot give information about the brain's potential to substitute that site. Another highly debated issue in CSES is the technique of negative stimulation, which means pursuing resection where no positive site is detected. Although results of such strategy have been encouraging (Sanai & Berger 2008; Kim et al. 2009), the question arises concerning the possibility of missing a positive site because of a false negative result during the intraoperative tests. This is especially true for cognitive functions, given that an awake patient has a limited time span for testing before fatigue arrives (normally no more than 90 minutes in our experience). Further, intraoperative cognitive tests (language, calculation, writing, visuo-spatial abilities) are limited to very simple tasks that cannot account for more complex functions. From this point of view, fMR allows a more comprehensive analysis of brain function because all the epicenters involved during a specific task are visualized and a real-time mapping is generated. If this represents a limitation of the spatial accuracy of fMR for surgical planning, at the same time it offers a means to non-invasively study a patient pre- and postoperatively, which is undoubtedly a unique opportunity to gain precious insights into functional organization and post-lesional adaptation at the individual level.

Direct mapping methods such as CSES are, at the moment, the safest procedures to achieve the most extensive resections with controllable risks. Preoperative brain mapping is useful when planning awake surgery to estimate the relationship between the tumor and functional brain regions. However, these techniques cannot directly lead the surgeon during resection. Intraoperative brain mapping is necessary to safely guide maximal resection and to guarantee a satisfying neurological outcome. It is unlikely that the study of functional connectivity and the longitudinal modification of brain maps will leave behind the integration of repeated fMR. This multimodal approach is more aggressive, leads to better outcomes, and should be used routinely for resection of lesions in eloquent brain regions.

It is probably no longer necessary to compare different methods of brain mapping because of their intrinsically different functioning; rather, we propose that now it would be most desirable to share preoperative (fMR, DTI, and neuropsychology) and postoperative protocols in order to accumulate a major cohort of patients in multicenter studies. At the same time, results of intraoperative stimulations should be well documented and standardized to create a common comprehensive database of intraoperative brain mapping results.

Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 355

Carrabba, G., Fava, E., Giussani, C., Acerbi, F., Portaluri, F., Songa, V., Stocchetti, N., Branca,

Catani, M., Howard, R.J., Pajevic, S. & Jones, D.K. (2002). Virtual in vivo interactive dissection of white matter fasciculi in the human brain. *Neuroimage* Vol. 17:77–94. Chang, E.F., Smith, J.S., Chang, S.M., Lamborn, K.R., Prados, M.D., Butowski, N., Barbaro,

D'Aubigné, R.M. (1980). Paul Broca and surgery of the motor system. *Chirurgie* Vol.

De Benedictis, A., Moritz-Gasser, S. & Duffau, H. (2010). Awake mapping optimizes the

Desmond, J.E., Sum, J.M., Wagner, A.D., Demb, J.B., Shear, P.K., Glover, G.H., Gabrieli, J.D.

Duffau, H., Lopes, M., Arthuis, F., Bitar, A., Sichez, J.P., Van Effenterre, R. & Capelle, L.

Duffau, H. (2005). Lessons from brain mapping in surgery for lowgrade glioma: insights into associations between tumour and brain plasticity. *Lancet Neurology* Vol. 4:476–486. Duffau, H. (2006). New concepts in surgery of WHO grade II gliomas: functional brain

Dymarkowski, S., Sunaert, S., Van Oostende, S., Van Hecke, P., Wilms, G., Demaerel, P.,

Egbert, L.D., Battit, G., Turndorf, H. & Beecher, H.K. (1963). The value of the preoperative visit by an anesthetist. *Journal of the American Medical Association* Vol.185:553–5. FitzGerald, D.B., Cosgrove, G.R., Ronner, S., Jiang, H., Buchbinder, B.R., Belliveau, J.W.,

Fox, P.T., Mintun, M.A., Raichle, M.E., Miezin, F.M., Allman, J.M. & Van Essen, D.C. (1986).

Wada-tested patients. *Brain* Vol. 118 (No. 6):1411–1419.

*Neurosurgery and Psychiatry* Vol. 76:845–851.

*Neuroradiology* Vol. 18(No. 8):1529–1539.

323(No. 6091):806–809.

Foerster, O. (1931). The cerebral cortex in man. *Lancet* Vol. 2:309–312.

classification system. *Journal of Neurosurgery* Vol. 94(No. 6):946-54.

extent of resection. *Journal of Neurosurgical Science* Vol. 51:45–51.

*Neurosurgery* Vol. 109:817–824.

106(10):791-3.

79:77–115.

1580.

66(No.6):1074-84.

activation in association with structural lesions in the rolandic region: a

V., Gaini, S.M. & Bello, L. (2007). Cortical and subcortical motor mapping in rolandic and perirolandic glioma surgery: impact on postoperative morbidity and

N.M., Parsa, A.T., Berger, M.S. & McDermott, M.M. (2008). Preoperative prognostic classification system for hemispheric low-grade gliomas in adults. *Journal of* 

extent of resection for low-grade gliomas in eloquent areas. *Neurosurgery*. Vol.

& Morrell, M.J. (1995). Functional MRI measurement of language lateralization in

(2005). 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. *Journal of Neurology,* 

mapping, connectionism and plasticity—a review. *Journal of Neurooncology* Vol.

Nuttin, B., Plets, C.& Marchal, G. (1998). Functional MRI of the brain: localisation of eloquent cortex in focal brain lesion therapy. *European Radiology* Vol. 8(No. 9):1573–

Rosen, B.R. & Benson, R.R. (1997). Location of language in the cortex: a comparison between functional MR imaging and electrocortical stimulation. *American Journal of* 

Mapping human visual cortex with positron emission tomography. *Nature* Vol.

#### **6. References**


Achten E., Jackson, G.D., Cameron, J.A., Abbott, D.F., Stella, D.L. & Fabinyi, G.C. (1999).

Agrawal, A., Kapfhammer, J.P., Kress, A., Wichers, H., Deep, A., Feindel, W., Sonntag, V.K.,

Annett, M. (1992). Parallels between asymmetries of planum temporale and of hand skill.

Baciu, M., Le Bas, J.F., Segebarth C. & Benabid A.L. (2003). Presurgical fMRI evaluation of

Ballmaier, M., Sowell, E.R., Thompson, P.M., Kumar, A., Narr, K.L. & Lavretsky H. (2004).

Bandettini, P.A., Wong, E.C., Hinks, R.S., Tikofsky, R.S. & Hyde J.S. (1992). Time course EPI

Bello L., Gambini, A., Castellano, A., Carrabba, G., Acerbi, F., Fava, E., Giussani, C., Cadioli,

Beppu, T., Inoue, T., Shibata, Y., Kurose, A., Arai, H., Ogasawara, K., Ogawa, A., Nakamura,

Berger, M.S. (1994). Lesions in functional ("eloquent") cortex and subcortical white matter.

Berger, M.S., Deliganis, A.V., Dobbins, J.D. & Keles, G.E. (1994): The effect of extent of

Boling, W., Parsons, M., Kraszpulski, M., Cantrell, C. & Puce A. (2008). Whole-hand

magnetic resonance imaging. *Journal of Neurosurgery* Vol. 108(No.3):491-500. Bookheimer, S. (2002). Functional MRI of language: new approaches to understanding the

Canales-Rodríguez, E.J., Iturria-Medina, Y., Alemán-Gómez, Y. & Melie-García, L. (2010). Deconvolution in diffusion spectrum imaging. *Neuroimage* Vol. 50(No.1):136-49. Carpentier, A.C., Constable, R.T., Schlosser, M.J., de Lotbinière, A., Piepmeier, J.M., Spencer,

malformations. *European Journal of Radiology*. Vol. 46(No. 2):139-46.

Procedures Techniques in Neurosurgery, Vol. 7, No. 1, March.

Presurgical evaluation of the motor hand area with functional MR imaging in patients with tumors and dysplastic lesions. *Radiology* Vol. 210(No.2):529–538. Aglio, L.S. & Gugino, L.D. (2001). Conscious sedation for Intraoperative Neurosurgical

Spetzler, R.F., & Preul, M.C. (2011). Josef Klingler's Models of White Matter Tracts: Influences on Neuroanatomy, Neurosurgery, and Neuroimaging. *Neurosurgery* Vol.

cerebral reorganization and motor deficit in patients with tumors and vascular

Mapping brain size and cortical gray matter changes in elderly depression.

of human brain function during task activation. *Magnetic Resonance in Medicine* Vol.

M., Blasi, V., Casarotti, A., Papagno, C., Gupta, A.K., Gaini, S., Scotti, G. & Falini A. (2008). Motor and language DTI Fiber Tracking combined with intraoperative subcortical mapping for surgical removal of gliomas. *Neuroimage* Vol. 39(1):369–

S. & Kabasawa, H. (2003). Measurement of fractional anisotropy using diffusion tensor MRI in supratentorial astrocytic tumors. *Journal of Neurooncology* Vol. 63: 109-

resection on recurrence in patients with low-grade cerebral hemisphere gliomas.

sensorimotor area: cortical stimulation localization and correlation with functional

cortical organization of semantic processing. *Annual Review of Neuroscience* Vol.

D.D. & Awad, I.A. (2001). Patterns of functional magnetic resonance imaging

**6. References** 

26 Epub ahead of print.

25(No. 2):390–397.

382.

16.

*Neuropsychologia* Vol. 30:951–962.

*Biological Psychiatry* Vol. 55:382–389.

*Clinical Neurosurgery*. Vol. 41:444-63.

*Cancer* Vol. 74: 1784-1791.

25:151–188.

activation in association with structural lesions in the rolandic region: a classification system. *Journal of Neurosurgery* Vol. 94(No. 6):946-54.


Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 357

Herholz, K., Thiel, A., Wienhard, K., Pietrzyk, U., von Stockhausen, H.M., Karbe, H.,

Holman, B.L. & Devous, M.D. (1992). Functional brain SPECT: the emergence of a powerful clinical method. *Journal of Nuclear Medicine* Vol. 33(No. 10):1888–1904. Holodny, A.I. & Ollenschleger, M. (2002). Diffusion imaging in brain tumors. *Neuroimaging* 

Holodny, A.I., Schulder, W.C., Liu, J.A., Maldjian, J.A. & Kalnin, A.J. (1999). Decreased

Jack, C.R., Thompson, P.M., Butts, R.K., Sharbrough, F.W., Kelly, P.J., Hanson, D.P.,

Josse, G., Mazoyer, B., Crivello, F. & Tzourio-Mazoyer, N. (2003). Left planum temporale: an

Keles, G.E., Lamborn, K.R. & Berger, M.S. (2001). Low-grade hemispheric gliomas in adults:

Kim, S.S., McCutcheon, I.E., Suki, D., Weinberg, J.S., Sawaya, R., Lang, F.F., Ferson, D.,

Kinoshita, M., Yamada, K., Hashimoto, N., Kato, A., Izumoto, S. & Baba T. (2005). Fiber-

Kombos, T., Suess, O., Ciklatekerlio, O. & Brock, M. (2001). Monitoring of intraoperative

Krings ,T., Reinges, M.H., Thiex, R., Gilsbach, J.M. & Thron, A. (2001). Functional and

Krishnan, R., Raabe, A., Hattingen, E., Szelényi, A., Yahya, H., Hermann, E., Zimmermann,

Kuo, L.W., Chen, J.H., Wedeen, V.J. & Tseng, W.Y. (2008). Optimization of diffusion

Leclercq, D., Duffau, H., Delmaire, C., Capelle, L,, Gatignol, P., Ducros, M., Chiras, J. &

anatomy of verb generation. *Neuroimage* Vol. 3:185–194.

invasive cortical mapping. *Radiology* Vol. 190(No.1): 85–92.

*Clinic of North America* Vol. 12: 107-24.

*Journal of Neuroradiology* Vol. 20:609–612.

*Cognitive Brain Research* Vol. 18:1–14.

matter stimulation. *Neuroimage* Vol. 25:424–429.

cortex. *Journal of Neurosurgery* Vol. 95(No.4):608– 614

*Neurosurgery* Vol. 95: 735-745.

*Neurosurgery* Vol. 95: 816-24.

41(No.1):7-18.

*Neurosurgery* Vol. 55 (No.4):904–914.

845.

Kessler, J., Bruckbauer, T., Halber, M. & Heiss, W.D. (1996). Individual functional

BOLD functional MR activation of the motor and sensory cortices adjacent to a glioblastoma multiforme: implications for image-guided neurosurgery. *American* 

Riederer, S.J., Ehman, R.L., Hangiandreou, N.J. & Cascino, G.D. (1994). Sensory motor cortex: correlation of presurgical mapping with functional MR imaging and

anatomical marker of left hemispheric specialization for language comprehension.

a critical review of extent of resection as a factor influencing outcome. *Journal of* 

Heimberger, A.B., DeMonte, F. & Prabhu. S.S. (2009). Awake craniotomy for brain tumors near eloquent cortex: correlation of intraoperative cortical mapping with neurological outcomes in 309 consecutive patients. *Neurosurgery* Vol. 64(No.5):836–

tracking does not accurately estimate size of fiber bundle in pathological condition: initial neurosurgical experience using neuronavigation and subcortical white

motor evoked potentials to increase the safety of surgery in and around the motor

diffusion-weighted magnetic resonance images of space-occupying lesions affecting the motor system: imaging the motor cortex and pyramidal tracts. *Journal of* 

M. & Seifert V. (2004). Functional magnetic resonance imaging-integrated neuronavigation: correlation between lesion-to-motor cortex distance and outcome.

spectrum imaging and q-ball imaging on clinical MRI system. *Neuroimage*. Vol.

Lehéricy, S. (2010). Comparison of diffusion tensor imaging tractography of


Frahm, J., Merboldt, K.D., Hänicke, W., Kleinschmidt, A. & Boecker, H. (1994). Brain or vein

Fujiki, M., Furukawa, Y., Kamida, T., Anan, M., Inoue, R., Abe, T. & Kobayashi, H. (2006).

Gabrieli, J.D., Poldrack, R.A. & Desmond, J.E. (1998). The role of left prefrontal cortex in language and memory. *Proceedings of Natural Academic Science* Vol. 95(3):906–913. Gaillard, W.D. (2004). Functional MR imaging of language, memory, and sensorimotor

Geschwind, N. (1971). Current concepts: aphasia. *New England Journal of Medicine* Vol.

Gevins, A., Leong, H., Smith, M.E., Le, J. & Du, R. (1995). Mapping cognitive brain function

Gil-Robles, S. & Duffau, H. (2010). Surgical management of World Health Organization

Gossl, C., Fahrmeir, L., Putz, B., Auer, L.M. & Auer, D.P. (2002). Fiber tracking from DTI

Grabowski, T.J. (2000). Investigating language with functional neuroimaging, *in* MJ Toga

Haglund, M., Berger, M., Shamseldin, M., Lettich, E. & Ojemann, G. (1994). Cortical

Hämäläinen, M., Ilmoniemi, R.J., Knuutila, J. & Lounasmaa, O.V. (1993).

Hall, W.A., Liu, H. & Truwit, C.L. (2005). Functional magnetic resonance imaging-guided resection of low-grade gliomas. *Surgical Neurology* Vol. 64(No.1):20–27. Heeger, D.J. & Ress, D. (2002). What does fMRI tell us about neuronal activity? *Nature* 

Hendler, T., Pianka, P., Sigal, M., Kafri, M., Ben-Bashat, D., Constantini, S., Graif, M., Fried,

Henry, R.G., Berman, J.I., Nagarajan, S., Mukherjee, P. & Berger, M.S. (2004). Subcortical

diffusion-tensor imaging. *Journal of Neurosurgery* Vol. 99: 1018-27.

with modern high-resolution electroencephalography. *Trends in Neuroscience* Vol.

Grade II gliomas in eloquent areas: the necessity of preserving a margin around

using linear state space models: detectability of the pyramidal tract. *Neuroimage*

AW, *Brain mapping: the systems*, Academic Press, San Diego, San Francisco, New

localization of temporal lobe language sites in patients with gliomas. *Neurosurgery*

Magnetoencephalography -theory, instrumentatation and applications to noninvasive studies of the working human brain. *Review of modern physics* Vol.

I. & Assaf, Y. (2003). Delineating gray and white matter involvement in brain lesions: three-dimensional alignment of functional magnetic resonance and

pathways serving cortical language sites: initial experience with diffusion tensor imaging fiber tracking combined with intraoperative language mapping.

cortex. *Neuroimaging Clinics of North America* Vol. 14 (No. 3):471-85.

activation. *NMR in Biomedicine* Vol. 7(No.1-2):45–53.

functional structures. *Neurosurgical Focus* Vol. 28(2):E8

York, Boston, London, Sydney, Tokio, 425–461.

*Reviews Neuroscience* Vol. 3: 142-51.

*Neuroimage* Vol. 21:616–622.

Vol. 104(No.1):85–92.

284(No. 12):654–656.

18(No. 10):429–436.

Vol. 16: 378-88.

Vol. 34: 567–576

65:413–487.

– oxygenation or flow? On signal physiology in functional MRI of human brain

Intraoperative corticomuscular motor evoked potentials for evaluation of motor function: a comparison with corticospinal D and I waves. *Journal of Neurosurgery*


Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 359

Narr, K.L., Bilder, R.M., Luders, E., Thompson, P.M., Woods, R.P., Robinson, D., Szeszko,

Nucifora, P.G., Verma, R., Lee, S.K. & Melhem, E.R. (2007). Diffusion-Tensor MR Imaging

Ogawa, S., Menon, R.S., Tank, D.W., Kim, S.G., Merkle, H., Ellermann, J.M. & Ugurbil, K.

Ogawa, S., Tank, D.W., Menon, R., Ellermann, J.M., Kim, S.G., Merkle, H. & Ugurbil, K.

Ojemann, G., Ojemann, J., Lettich, E. & Berger, M. (1989). Cortical language localization in

Ozawa, N., Muragaki, Y., Nakamura, R. & Iseki, H. (2009). Identification of the pyramidal

Penfield, W. & Boldrey, E. (1937). Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. *Brain* Vol. 60:389–443 Penfield,W. & Erickson, T.C. (1941). Epilepsy and Cerebral Localization. A Study of the

Penfield, W. & Rasmussen, T. (1950). Secondary Sensory and Motor Representation. New

Petrovich, N., Holodny, A.I., Tabar, V., Correa, D.D., Hirsch, J., Gutin, P.H. & Brennan. C.W.

Price, S.J., Burnet, N.G., Donovan, T., Green, H.A., Peña, A., Antoun, N.M,, Pickard, J.D.,

Raichle, M.E. (1983). Positron emission tomography. *Annual Review of Neuroscience* Vol.

Rijntjes, M. & Weiller, C. (2002). Recovery of motor and language abilities after stroke: the contribution of functional imaging *Progress in Neurobiology* Vol. 66:109–22. Rossini, P.M., Calautti, C., Pauri, F. & Baron, J.C. (2003). Post-stroke plastic reorganisation in

tracking in glioma surgery. *Neurosurgery* Vol. 61(1 Suppl):178-85.

biophysical model. *Biophysical Journal* Vol. 64(No.3):803–812.

245(No.2): 367-384.

87(1):18–24.

Charles C Thomas.

York, Macmillan.

274

58: 455-62.

6:249–267.

*Science* Vol. 89(No.13):5951–5955.

patients. *Journal of Neurosurgery* Vol. 71:316–326.

Penfield, W. (1950). The cerebral cortex of man. New York, MacMillan.

the adult brain. *Lancet Neurology* Vol. 2: 493–502.

P.R., Dimtcheva, T., Gurbani, M. & Toga, A.W. (2007). Asymmetries of cortical shape: effects of handedness, sex and schizophrenia. *Neuroimage* Vol. 34:939–948. Nimsky, C., Ganslandt, O., Hastreiter, P., Wang, R., Benner, T., Sorensen, A.G. & Fahlbusch,

R. (2007). Preoperative and intraoperative diffusion tensor imaging-based fiber

and Tractography: Exploring Brain Microstructure and Connectivity. *Radiology* Vol.

(1993). Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a

(1992). Intrinsic signal changes accompanying sensory stimulation:functional brain mapping with magnetic resonance imaging. *Proceedings of the National Academy of* 

left, dominant hemisphere. An electrical stimulation mapping investigation in 117

tract by neuronavigation based on intraoperative diffusion-weighted imaging combined with subcortical stimulation. *Stereotactic Functional Neurosurgery* Vol.

Mechanism, Treatment, and Prevention of Epileptic Seizures. Springfield, IL:

(2005). Discordance between functional magnetic resonance imaging during silent speech tasks and intraoperative speech arrest. *Journal of Neurosurgery* Vol. 103:267–

Carpenter, T.A. & Gillard. J.H. (2003).Diffusion tensor imaging of brain tumors at 3 T : a potential tool for assessing white matter tract invasion? *Clinical Radiology* Vol.

language tracts and intraoperative subcortical stimulations. *Journal of Neurosurgery* Vol. 112(No.3):503-11.


Lehéricy, S., Duffau, H., Cornu, P., Capelle, L., Pidoux, B., Carpentier, A., Auliac, S.,

Logothetis, N.K. (2003) The underpinnings of the BOLD functional magnetic resonance

Logothetis, N.K. & Pfeuffer, J. (2004). On the nature of the BOLD fMRI contrast mechanism.

Logothetis, N.K. & Wandell, B.A. (2004). Interpreting the BOLD signal. *Annual Review of* 

Lu, S., Ann, D., Johnson, G. & Cha, S. (2003). Peritumoral diffusion tensor imaging of high-

Luders, E., Narr, K.L., Thompson, P.M., Woods, R.P., Rex, D.E., Jancke, L., Steinmetz, H. &

Majos, A., Tybor, K., Stefańczyk, L. & Góraj, B. (2005). Cortical mapping by functional

Mascalchi, M., Filippi, M., Floris, R., Fonda, C., Gasparotti, R. & Villari, N. (2005). Diffusion-

Mattay, V.S. & Weinberger, D.R. (1999). Organization of the human motor system as studied

Mazziotta, J.C., Phelps, M.E. & Carson, R.E. (1982). Tomographic mapping of human cerebral metabolism: auditory stimulation. *Neurology* Vol. 32(No. 9):921–937. Menon, R.S., Ogawa, S., Hu, X., Strupp, J.P., Anderson, P. & Uğurbil, K. (1995). BOLD based

Mohr, J.P. (2004). Historical observations on functional reorganization. *Cerebrovascular* 

Moritz, C. & Haughton, V. (2003). Functional MR imaging: paradigms for clinical

Mueller, W.M., Yetkin, F.Z., Hammeke, T.A., Morris, G.L. 3rd, Swanson, S.J., Reichert, K., Cox, R. & Haughton, V.M. (1996). *Neurosurgery* Vol. 39(No.3):515-20

grade gliomas and metastatic brain tumors. *American Journal of Neuroradiology* Vol.

Toga, A.W. (2005). Mapping cortical gray matter in the young adult brain: effects of

magnetic resonance imaging in patients with brain tumors. European Radiology

weighted MR of the brain: methodology and clinical application. *Radiologia Medica*

by functional magnetic resonance imaging. *European Journal of Radiology* Vol.

functional MRI at 4 Tesla includes a capillary bed contribution: echoplanar imaging correlates with previous optical imaging using intrinsic signals. *Magnetic Resonance* 

preoperative mapping. Magnetic Resonance Imaging *Clinics of North America* Vol.

imaging signal. *Journal of Neuroscience* Vol. 23(10):3963–3971.

*Magnetic Resonance Imaging* Vol. 22(10):1517–1531.

Vol. 112(No.3):503-11.

Lichtheim, L. (1885). On aphasia. *Brain* Vol. 7:433–484.

gender. *Neuroimage* Vol. 26:493–501.

*in Medicine* Vol. 33(No.3):453–459

*Disease* Vol. 18(No.3):258-9

*Physiology* Vol. 66:735–769.

Vol. 15(No. 6):1148-58.

Vol. 109(3):155-97.

30(No.2):105-14.

11(No. 4):529-42.

598.

24: 937-41.

language tracts and intraoperative subcortical stimulations. *Journal of Neurosurgery*

Clemenceau, S., Sichez, J.P., Bitar, A., Valery, C.A., Van Effenterre, R., Faillot, T., Srour, A., Fohanno, D., Philippon, J., Le Bihan, D. & Marsault, C. (2000). Correspondence between functional magnetic resonance imaging somatotopy and individual brain anatomy of the central region: comparison with intraoperative stimulation in patients with brain tumors. *Journal of Neurosurgery* Vol. 92(4):589–


Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 361

Stippich, C., Mohammed, J., Kress, B., Hähnel, S., Günther, J., Konrad, F. & Sartor, K. (2003).

Thompson, P.M., Moussai, J., Zohoori, S., Goldkorn, A., Khan, A.A., Mega, M.S., Small,

Toh, C.H., Castillo, M., Wong, A.M., Wei, K.C., Wong, H.F., Ng, S.H. & Wan, Y.L. (2008).

Toronov, V., Walker, S., Gupta, R., Choi, J.H., Gratton, E., Hueber, D. & Webb, A. (2003). The

Tummala, R.P., Chu, R.M., Liu, H. & Hall, W.A. (2003). Application of duffusion tensor

Tzourio-Mazoyer, N., Josse, G., Crivello, F. & Mazoyer, B. (2004). Interindividual variability in the hemispheric organization for speech. *Neuroimage* Vol. 21(No.1):422-35. Ulmer, J.L., Hacein-Bey, L., Mathews, V.P., Mueller, W.M., DeYoe, E.A., Prost, R.W., Meyer,

Ward NS. (2004). Functional reorganization of the cerebral motor system after stroke.

Wedeen, V.J., Wang, R.P., Schmahmann, J.D., Benner, T., Tseng, W.Y., Dai, G., Pandya, D.N.,

Wieshmann, U.C., Clark, C.A., Symms, M.R., Franconi, F., Barker, G.J. & Shorvon, S.D.

Wieshmann UC, Symms MR, Parker, G.J., Clark, C.A., Lemieux, L., Barker, G.J. & Shorvon,

Witwer, B.P., Moftakhar, R., Hasan, K.M., Deshmukh, P., Haughton, V., Field, A., Arfanakis,

Yoshikawa, K., Kajiwara, K., Morioka, J., Fujii, M., Tanaka, N., Fujisawa, H., Kato, S.,

volume in the fMRI BOLD signal. *Neuroimage* Vol. 19: 1521-31.

normal aging and Alzheimer's disease. *Cerebral Cortex* Vol. 8:492–509. Toga, A.W., Thompson, P.M., Mega, M.S., Narr, K.L. & Blanton, R.E. (2001). Probabilistic

31;346(No. 1-2):109-13

*Embryology* Vol. 204:267–282.

*Neurosurgery* Vol. 39: 39-43.

*Journal of Neuroradiology* Vol. 29: 471-75.

assessments. *Neurosurgery* Vol. 55:569–579.

*Neuroimage* Vol. 41(No. 4):1267-77.

*Neurosurgery and Psychiatry* Vol. 68: 501-3.

cerebral neoplasm. *Journal of Neurosurgery* Vol. 97: 568-75.

1269-74.

*Current Opinion in Neurology* Vol. 17(No.6):725-30.

Robust localization and lateralization of human language function: an optimized clinical functional magnetic resonance imaging protocol. *Neuroscience Letters* Vol.

G.W., Cummings, J.L. & Toga, A.W. (1998). Cortical variability and asymmetry in

approaches for atlasing normal and disease-specific brain variability. *Anatomy and* 

Primary Cerebral Lymphoma and Glioblastoma Multiforme: Differences in Diffusion Characteristics Evaluated with Diffusion Tensor Imaging. *American* 

roles of changes in deoxy-hemoglobin concentration and regional cerebral blood

imaging to magnetic-resonance-guided brain tumor resection. *Paediatric* 

G.A., Krouwer, H.G. & Schmainda, K.M. (2004). Lesion-induced pseudodominance at functional magnetic resonance imaging: implications for preoperative

Hagmann, P., D'Arceuil, H., de Crespigny, A.J. (2008). Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers. *American Journal of* 

(1999). Reduced anisotropy of water diffusion in structural cerebral abnormalities demonstrated with diffusion tensor imaging. *Magnetic Resonance Imaging* Vol. 17:

S.D. (2000). Diffusion tensor imaging demonstrates deviation of fibres in normal appearing white matter adjacent to a brain tumour. *Journal of Neurology,* 

K., Noyes, J., Moritz, C.H., Meyerand, M.E., Rowley, H.A., Alexander, A.L. & Badie, B. (2002). Diffusion-tensor imaging of white matter tracts in patients with

Nomura, S. & Suzuki, M. (2006). Improvement of functional outcome after radical


*Acta Neurochirurgica(Wien)* Vol. 152(No.11):1835-46.


Roux, F.E., Boulanouar, K., Ranjeva, J.P., Manelfe, C., Tremoulet, M., Sabatier, J. & Berry, I.

Rutten, G.J., Ramsey, N.F., van Rijen, P.C., Noordmans, H.J. & van Veelen, C.W. (2002).

Rutten, G.J. & Ramsey, N.F. (2010). The role of functional magnetic resonance imaging in

Sanai, N. & Berger, M.S. (2008). Mapping the horizon: techniques to optimize tumor resection before and during surgery. *Clinical Neurosurgery* Vol. 55:14–19. Sanai, N., Mirzadeh, Z. & Berger, M.S. (2008). Functional outcome after language mapping for glioma resection. *New England Journal of Medicine* Vol. 358:18–27. Sanai, N. & Berger, M.S. (2009). Operative techniques for gliomas and the value of extent of

Sanai, N. & Berger, M.S. (2010). Intraoperative stimulation techniques for functional pathway preservation and glioma resection.. *Neurosurgical Focus* Vol. 28(No.2): E1 Schonberg, T., Pianka, P., Hendler, T., Pasternak, O. & Assaf, Y. (2006). Characterization of

Sinha, S., Bastin, M.E., Whittle, I.R. & Wardlaw, J.M. (2002). Diffusion tensor MR Imaging of high-grade cerebral gliomas. *American Journal of Neuroradiology* Vol. 23: 520-7. Smits, M., Vernooij, M.W., Wielopolski, P.A., Vincent, A.J., Houston, G.C. &van der Lugt, A.

Spena, G., Nava, A., Cassini, F., Pepoli, A., Bruno, M., D'Agata, F., Cauda, F., Sacco, K.,

Staempfli, P., Reischauer, C., Jaermann, T., Valavanis, A., Kollias, S. & Boesiger, P. (2007).

Steinmetz, H., Volkmann, J., Jäncke, L. & Freund, H.J. (1991). Anatomical left-right

Stendel R. (2009). Extent of resection and survival in glioblastoma multiforme: identification

Stippich, C., Rapps, N., Dreyhaupt, J., Durst, A., Kress, B., Nennig, E., Tronnier, V.M. &

of and adjustment for bias. *Neurosurgery* Vol. 64(No. 6) E1206.

methodology, correlation, and usefulness based on clinical outcomes.

*American Journal of Neuroradiology* Vol. 28(No.7):1354–1361.

displaced white matter by brain tumors using combined DTI and fMRI. *Neuroimage*

(2007). Incorporating functional MR imaging into diffusion tensor tractography in the preoperative assessment of the corticospinal tract in patients with brain tumors.

Duca, S., Barletta, L. & Versari P. (2010). Preoperative and intraoperative brain mapping for the resection of eloquent-area tumors. A prospective analysis of

Combining fMRI and DTI: a framework for exploring the limits of fMRI-guided DTI fiber tracking and for verifying DTI-based fiber tractography results.

asymmetry of language-related temporal cortex is different in left- and right-

Sartor, K. (2007). Localizing and lateralizing language in patients with brain tumors: feasibility of routine preoperative functional MR imaging in 81 consecutive

229.

*Neurology* Vol. 51:350–360.

Vol. 30(No.4):1100–1111.

*Acta Neurochirurgica(Wien)* Vol. 152(No.11):1835-46.

*Neuroimage* Vol. 39 (No. 1):119–126.

patients. *Radiology* Vol. 243(3):828-36.

handers. *Annals of Neurology* Vol. 29:315–319

surgery. *Neurosurgical Focus* Vol. 28(No.2):E4.

resection. *Neurotherapeutics* Vol. 6(3):478-86.

(1999). Cortical intraoperative stimulation in brain tumors as a tool to evaluate spatial data from motor functional MRI. *Investigative Radiology* Vol. 34(No.3):225–

Development of a functional magnetic resonance imaging protocol for intraoperative localization of critical temporo-parietal language areas. *Annals of* 


**18** 

*Sweden* 

**Radiation Immune Modulation** 

Since Roentgens discovery of the X-rays 1895, radiation therapy (RT) has been one of the most successful modalities used to treat cancer (Rontgen 1995). The experimental radiation treatment of glioma, however, took place first in 1938 (Bailey & Brunschwig 1938). Since then advances in radiation technology have expanded the role and value of using ionizing radiation in diagnosis, imaging and therapy of glioma. But despite substantial technical improvements in the current treatment modalities the survival rate for glioma patients is still very low (Barnholtz-Sloan, et al. 2007 ). Although the recently addition of temozolomide to conventional fractionated radiotherapy for newly diagnosed glioblastoma has resulted in

Immunotherapy utilizes the fact that the immune system has a potential to react against tumour antigens and that this can result in immunological control of the tumour. There is an increasing body of evidence that the activation of cytotoxic T-lymphocytes (CTL) has a positive effect on the long-term survival of cancer patients receiving traditional therapies such as surgery, chemo- or radiation-therapy (Nakano 2001; Prall 2004; L. Zhang, et al. 2003). It has been clearly demonstrated that tumour immune reactivity is of importance in treatment of several types of tumours (Shankar & Salgaller 2000). The immune response to glioma is primarily a result of the cell-killing function by the activated cytotoxic T cells (CTL). The aim of vaccination regimes is to enhance the effectors functions of CTL and the number of lymphoid cells within the glioma. But even if immune therapy cause large populations of lymphocytes to enter CNS tumours, total eradication of the glioma do not occur. This is partly due to the immunosuppressive factors produced by the glioma, which

Traditional fractionated radiation therapy decrease the number of radiation sensitive T cells and damping the immune response of immunotherapy. Thus the interest in combining radiation therapy and immunotherapy has so far been very sparse. The use of sterotactic techniques with single radiation exposure or hypo-fractionated radiation therapy, however, does modulate the immune response and increases the therapeutic outcome (Lee, et al. 2009; Wersäll, et al. 2006). This radioimmuno modulatory effect of radiation opens for a new

Currently, there is a growing interest in combining radiation with other kinds of therapy, of which some are immunotherapy, to treat a broad range of malignancies (Chakraborty, et al.

approach in glioma therapy by the combination of radiation- and immune-therapy.

**1. Introduction** 

an increased time of survival (Stupp, et al. 2005).

result in non-functioning CTL (Roszman, et al. 1991).

**Therapy of Glioma** 

Bertil R.R. Persson *Lund University* 

surgery in glioblastoma patients: the efficacy of a navigation-guided fence-post procedure and neurophysiological monitoring. *Journal of Neurooncology* Vol. 78(No.1):91–97.

