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Objective Intraoperative language mapping is traditionally performed with low-frequency bipolar stimulation (LFBS). High-frequency train-of-five stimulation delivered by a monopolar probe (HFMS) is an alternative technique for motor mapping, with a lower reported seizure incidence. The application of HFMS in language mapping is still limited. Authors of this study assessed the efficacy and safety of HFMS for language mapping during awake surgery, exploring its clinical impact compared with that of LFBS. Methods Fifty-nine patients underwent awake surgery with neuropsychological testing, and LFBS and HFMS were compared. Frequency, type, and site of evoked interference were recorded. Language was scored preoperatively and 1 week and 3 months after surgery. Extent of resection was calculated as well. Results High-frequency monopolar stimulation induced a language disturbance when the repetition rate was set at 3 Hz. Interference with counting (p = 0.17) and naming (p = 0.228) did not vary between HFMS and LFBS. These results held true when preoperative tumor volume, lesion site, histology, and recurrent surgery were considered. Intraoperative responses (1603) in all patients were compared. The error rate for both modalities differed from baseline values (p < 0.001) but not with one another (p = 0.06). Low-frequency bipolar stimulation sensitivity (0.458) and precision (0.665) were slightly higher than the HFMS counterparts (0.367 and 0.582, respectively). The error rate across the 3 types of language errors (articulatory, anomia, paraphasia) did not differ between the 2 stimulation methods (p = 0.279). Conclusions With proper setting adjustments, HFMS is a safe and effective technique for language mapping.

We describe how a neuropsychological evaluation in patients with brain tumors should be performed, specifically in the case of low-grade gliomas. Neuropsychological examination is crucial before starting any treatment as well as during the follow-up, since it can improve neurosurgery techniques and reveal potential cognitive effects of chemotherapy and radiotherapy, besides planning rehabilitation. We underline that sensitive and wide-ranging tests are required; specific tasks based on the lesion site should be added. Moreover, some tests can provide additional information about the evolution of the tumor. A careful, thorough examination improves quality of life. © Springer Science+Business Media, LLC. 2012.

Low-grade gliomas ([LGGs] WHO Grade II) are slow-growing intrinsic cerebral lesions that diffusely infiltrate the brain parenchyma along white matter tracts and almost invariably show a progression toward malignancy. The treatment of these tumors forces the neurosurgeon to face uncommon difficulties and is still a subject of debate. At the authors' institution, resection is the first option in the treatment of LGGs. It requires the combined efforts of a multidisciplinary team of neurosurgeons, neuroradiologists, neuropsychologists, and neurophysiologists, who together contribute to the definition of the location, extension, and extent of functional involvement that a specific lesion has caused in a particular patient. In fact, each tumor induces specific modifications of the brain functional network, with high interindividual variability. This requires that each treatment plan is tailored to the characteristics of the tumor and of the patient. Consequently, surgery is performed according to functional and anatomical boundaries to achieve the maximal resection with maximal functional preservation. The identification of eloquent cerebral areas, which are involved in motor, language, memory, and visuospatial functions and have to be preserved during surgery, is performed through the intraoperative use of brain mapping techniques. The use of these techniques extends surgical indications and improves the extent of resection, while minimizing the postoperative morbidity and safeguarding the patient's quality of life. In this paper the authors present their paradigm for the surgical treatment of LGGs, focusing on the intraoperative neurophysiological monitoring protocol as well as on the brain mapping technique. They briefly discuss the results that have been obtained at their institution since 2005 as well as the main critical points they have encountered when using this approach.

Objective: To assess the role of the superior longitudinal fascicle, the inferior fronto-occipital fascicle, and the posterior parietal lobe in visuospatial attention in humans during awake brain surgery. Experimental design: Seven patients with hemispheric gliomas (six in the right hemisphere) entered the study. During surgery in asleep/awake anesthesia, guided by Diffusion Tensor Imaging Fiber Tractography, visuospatial neglect was assessed during direct electrical stimulation by computerized line bisection. Principal observations: A rightward deviation, indicating left visuospatial neglect, was induced in six of seven patients by stimulation of the parietofrontal connections, in a location consistent with the trajectory of the second branch of the superior longitudinal fascicle. Stimulation of the medial and dorsal white matter of the superior parietal lobule (corresponding to the first branch of the superior longitudinal fascicle), of the ventral and lateral white matter of the supramarginal gyrus (corresponding to the third branch of the superior longitudinal fascicle), and of the inferior occipitofrontal fasciculus, was largely ineffective. Stimulation of the superior parietal lobule (Brodmann's area 7) caused a marked rightward deviation in all of the six assessed patients, while stimulation of Brodmann's areas 5 and 19 was ineffective. Conclusions: The parietofrontal connections of the dorso-lateral fibers of the superior longitudinal fascicle (i.e., the second branch of the fascicle), and the posterior superior parietal lobe (Brodmann's area 7) are involved in the orientation of spatial attention. Spatial neglect should be assessed systematically during awake brain surgery, particularly when the right parietal lobe may be involved by the neurosurgical procedure

The brain's plasticity in response to sensory deprivation and other perturbations is well established. While the functional properties of the reorganized areas are under vigorous investigation, the factors that constrain cortical reorganization remain poorly understood. One factor constraining such reorganization may be long-distance subcortical connectivity between relevant cortical regions-reorganization attempts to preserve the functionality of subcortical connections. Here we provide human neurophysiological evidence for the role of the subcortical connections in shaping cortical reorganization of the networks involved in object naming following perturbation of normal function. We used direct electrical stimulation (DES) during surgical removal of gliomas to identify the sites that are involved in naming different categories of objects. The sites that were selectively inhibited in naming either living or non-living objects were displaced relative to those observed with other subject populations, possibly reflecting cortical reorganization due to slowly evolving brain damage. Subcortical DES applied to the white matter underlying these regions also led to category-specific naming deficits. The existence of these subcortical fiber pathways was confirmed using diffusion tensor tractography. These results constitute the first neurophysiological evidence for the critical role of subcortical pathways as part of the neural circuits that are involved in object naming; they also highlight the importance of subcortical connectivity in shaping cortical reorganization following perturbations of normal function

OBJECT: It has been hypothesized that specific brain regions involved in face naming may exist in the brain. To spare these areas and to gain a better understanding of their organization, the authors studied patients who underwent surgery by using direct electrical stimulation mapping for brain tumors, and they compared an object-naming task to a famous face-naming task. METHODS: Fifty-six patients with brain tumors (39 and 17 in the left and right hemispheres, respectively) and with no significant preoperative overall language deficit were prospectively studied over a 2-year period. Four patients who had a partially selective famous face anomia and 2 with prosopagnosia were not included in the final analysis. RESULTS: Face-naming interferences were exclusively localized in small cortical areas (< 1 cm2). Among 35 patients whose dominant left hemisphere was studied, 26 face-naming specific areas (that is, sites of interference in face naming only and not in object naming) were found. These face naming-specific sites were significantly detected in 2 regions: in the left frontal areas of the superior, middle, and inferior frontal gyri (p < 0.001) and in the anterior part of the superior and middle temporal gyri (p < 0.01). Variable patterns of interference were observed (speech arrest, anomia, phonemic, or semantic paraphasia) probably related to the different stages in famous face processing. Only 4 famous face-naming interferences were found in the right hemisphere. CONCLUSIONS: Relative anatomical segregation of naming categories within language areas was detected. This study showed that famous face naming was preferentially processed in the left frontal and anterior temporal gyri. The authors think it is necessary to adapt naming tasks in neurosurgical patients to the brain region studied.

Objective: We report, for the first time, the occurrence of interference between a Cavitron ultrasonic surgical aspirator (CUSA) and intraoperative brain mapping performed by direct electrical stimulation (DES). METHODS: Intraoperative polygraphic recordings (electrocorticogram and electromyogram) were gathered from a 44-year-old patient harboring a recurrent Grade II oligoastrocytoma operated on with the aid of a CUSA and DES. RESULTS: Simultaneous use of CUSA and DES at the subcortical level in proximity to the corticospinal tract brought about the abolition of previously evident motor responses. This abolition was fully reversible after the CUSA was turned off. An analogous pattern of motor response inhibition was evident when the DES was applied cortically and the CUSA was used subcortically close to motor pathways. Interestingly, the authors had already observed a similar phenomenon in many patients when the CUSA was used for resection of lesions located within or in proximity to subcortical language pathways. In this setting, the CUSA induced transient speech disturbances that were confirmed afterwards by the DES. This interference with language and motor mapping might be interpreted as a transitory inhibition of axonal conduction. CONCLUSION: The clinical significance of this interference is relevant when the CUSA and DES are used simultaneously for motor mapping because the CUSA can decrease the sensitivity of the brain mapping technique. Further studies will be required to determine the neurophysiological mechanism underlying this interference.

Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation

OBJECTIVE: Subcortical stimulation can be used to identify functional language tracts during resection of gliomas located close to or within language areas or pathways. The objective of the present study was to investigate the feasibility of the routine use of subcortical stimulation for identification of language tracts in a large series of patients with gliomas and to determine the influence that subcortical language tract identification exerted on the extent of surgery and on the appearance of immediate and definitive postoperative deficits. METHODS: Subcortical stimulation for language tract identification was systematically used during surgical removal of 88 gliomas (44 high-grade and 44 low-grade gliomas) involving language pathways. Procedures were performed during asleep/awake craniotomy. Subcortical stimulation was continuously alternated with surgical resection in a back-and-forth fashion. Language performances were tested by neuropsychological language evaluation preoperatively and at 3, 30, and 90 days after surgery. RESULTS: Language tracts were identified in 59% of patients, with differences according to tumor location but not according to histological grade. Language tract identification influenced the ability to reach a complete tumor removal in low-grade gliomas, in which tracts were documented inside the peripheral mass of the tumor. Identification of language tracts was associated with a higher occurrence of transient postoperative deficits (67.3% of cases), but a low occurrence of definitive morbidity (2.3% of cases). A pattern of typical language disturbances related to the phonological and semantic system can be identified according to tumor location, with preservation being important for the maintenance of language integrity. CONCLUSION: Our study supports the routine use of subcortical stimulation for language tract identification as a reliable tool for guiding surgical removal of gliomas in or in close proximity to language areas or pathways

OBJECTIVE: Intraoperative localization of speech is problematic in patients who are fluent in different languages. Previous studies have generated various results depending on the series of patients studied, the type of language, and the sensitivity of the tasks applied. It is not clear whether languages are mediated by multiple and separate cortical areas or shared by common areas. Globally considered, previous studies recommended performing a multiple intraoperative mapping for all the languages in which the patient is fluent. The aim of this work was to study the feasibility of performing an intraoperative multiple language mapping in a group of multilingual patients with a glioma undergoing awake craniotomy for tumor removal and to describe the intraoperative cortical and subcortical findings in the area of craniotomy, with the final goal to maximally preserve patients' functional language. METHODS: Seven late, highly proficient multilingual patients with a left frontal glioma were submitted preoperatively to a battery of tests to evaluate oral language production, comprehension, and repetition. Each language was tested serially starting from the first acquired language. Items that were correctly named during these tests were used to build personalized blocks to be used intraoperatively. Language mapping was undertaken during awake craniotomies by the use of an Ojemann cortical stimulator during counting and oral naming tasks. Subcortical stimulation by using the same current threshold was applied during tumor resection, in a back and forth fashion, and the same tests. RESULTS: Cortical sites essential for oral naming were found in 87.5% of patients, those for the first acquired language in one to four sites, those for the other languages in one to three sites. Sites for each language were distinct and separate. Number and location of sites were not predictable, being randomly and widely distributed in the cortex around or less frequently over the tumor area. Su

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo

Angiogenesis, tumor cell proliferation, and migration are the hallmarks of solid tumors, such as gliomas. This study demonstrates that a fragment derived from the autocatalytic digestion of matrix metalloproteinase (MMP)-2, called PEX, acts simultaneously as an inhibitor of glioma angiogenesis, cell proliferation, and migration. PEX is detected in the cultured medium of various human glioma, endothelial, breast, and prostate carcinoma cell lines. PEX is purified from the medium of glioma cell lines by chromatography, where PEX is constitutively expressed as a free and a TIMP-2-bound form. In human glioma tissue, PEX expression correlates with histological subtype and grade and with alpha v beta 3 integrin expression to which it is bound. Systemic administration of PEX to s.c. and intracranial human glioma xenografts results in a 99% suppression of tumor growth with no signs of toxicity. Thus, PEX is a very promising candidate for the treatment of human malignant gliomas