**2. The evolution of the concept of eloquent brain regions**

When dealing with brain functions it is quite strange to consider a part of the brain "eloquent" and some other part not, since the brain as a whole is considered the most eloquent organ of the body. Actually, in the routine practice of a neurosurgeon this riddle very often arises, particularly when a tumor is located in an area usually considered "eloquent" (i.e. central region, Broca's area, Wernicke's area). The concept of brain function organization into well defined and localized areas is the legacy of pioneering studies of the 19th and 20th centuries (D'Aubigné 1980; Mohr 2004). The basic method of these revolutionary inquiries rested on the connection between neurological deficits and postmortem anatomical observations. Consequently, every area of the brain cortex was associated with a specific neurological function and a lesion in that region would have led to a well-defined neurological impairment. This anatomo-functional correlation gave rise to the assertion that some cortical gyri were "eloquent," for example, the triangular gyrus of the frontal operculum (Broca's area), the supramarginal gyrus (Wernicke's area), the angular gyrus, the precentral gyrus (motor area), and so on, while others were not. This tight coupling between anatomy and function has deeply influenced the practice of neurosurgery, making some patients with brain tumors in specific areas aprioristically not suitable for surgery. Even today in clinical practice, neurosurgeons very often rely mainly on standard anatomical cortical references as the initial basis for which resection of a tumor is considered potentially critical or at high risk of causing neurological damage. The excellent anatomical definition produced by MR imaging has made the process of investigation of the cerebral gyri even easier. The Rolandic region, for example, has been extensively portrayed as a model of cerebral landmarks for specific functions (sensory-motor area), but there has also been evidence that reliability is not always absolute. Intrinsic neuroanatomical variability accounts for a distinct challenge to strict anatomo-functional coupling. There are multiple factors that affect neuroanatomical variability, including sex, handedness, aging, and

latest MR imaging advancement, allows reconstruction of the anatomy of the main white matter tracts. Using this imaging modality, further information can be gathered on the

It is crucial that contemporary neurosurgeons understand how to properly use these technological advancements to improve postoperative neurological results. It is also vital that critical analysis and discussion of the limits and appropriate use of these devices is part

In this chapter, we will focus on some fundamental aspects of brain mapping, particularly regarding the surgical resection of gliomas. First, we will review the concept of eloquent brain regions and the evolution of the concept of critical areas. Then, we will deal with stateof-the-art functional imaging and diffusion tensor imaging, underlining their conceptual and technical limitations and explaining how to use them in surgical planning. Direct brain mapping by CSES will also be examined from a practical point of view, focusing on basic technique, anesthesia, equipment, patient selection, limitations, and future directions. Finally, we will discuss how to integrate these different mapping modalities while

We hope that this chapter will help those who are approaching brain mapping in a clinical and neurosurgical setting not only by showing mechanisms and usefulness but also in

When dealing with brain functions it is quite strange to consider a part of the brain "eloquent" and some other part not, since the brain as a whole is considered the most eloquent organ of the body. Actually, in the routine practice of a neurosurgeon this riddle very often arises, particularly when a tumor is located in an area usually considered "eloquent" (i.e. central region, Broca's area, Wernicke's area). The concept of brain function organization into well defined and localized areas is the legacy of pioneering studies of the 19th and 20th centuries (D'Aubigné 1980; Mohr 2004). The basic method of these revolutionary inquiries rested on the connection between neurological deficits and postmortem anatomical observations. Consequently, every area of the brain cortex was associated with a specific neurological function and a lesion in that region would have led to a well-defined neurological impairment. This anatomo-functional correlation gave rise to the assertion that some cortical gyri were "eloquent," for example, the triangular gyrus of the frontal operculum (Broca's area), the supramarginal gyrus (Wernicke's area), the angular gyrus, the precentral gyrus (motor area), and so on, while others were not. This tight coupling between anatomy and function has deeply influenced the practice of neurosurgery, making some patients with brain tumors in specific areas aprioristically not suitable for surgery. Even today in clinical practice, neurosurgeons very often rely mainly on standard anatomical cortical references as the initial basis for which resection of a tumor is considered potentially critical or at high risk of causing neurological damage. The excellent anatomical definition produced by MR imaging has made the process of investigation of the cerebral gyri even easier. The Rolandic region, for example, has been extensively portrayed as a model of cerebral landmarks for specific functions (sensory-motor area), but there has also been evidence that reliability is not always absolute. Intrinsic neuroanatomical variability accounts for a distinct challenge to strict anatomo-functional coupling. There are multiple factors that affect neuroanatomical variability, including sex, handedness, aging, and

status of these tracts (e.g., infiltration, displacement, interruption).

highlighting clinical evidence from our experience and that of other authors.

**2. The evolution of the concept of eloquent brain regions** 

of the neurosurgical routine.

posing questions and criticisms.

neurological diseases (Annet 1992; Thompson et al. 1998; Toga et al. 2001; Ballmaier et al. 2004; Luders et al. 2005; Narr et al. 2007). In the complex relationship between neuroanatomy and function, the significance of neuroanatomical variability is evidenced by its association with and probable contribution to distinct patterns of functional organization. For example, interhemispheric anatomical asymmetries (especially with respect to the planum temporale) have repeatedly been shown to be related to language lateralization (Josse et al. 2003; Steinmets et al. 1991). A trustworthy functional representation of a defined anatomical landmark is typically feasible for the hand motor area, showing as a correlate a characteristic dorsally oriented convexity in the precentral gyrus (the so-called "handknob") (Yousry et al. 1997; Boling et al. 2008). However, motor activity can also be detected outside of the typical landmarks, and the pattern of motor cortex activation is modulated by different physiological factors (Yousry et al. 2001; Mattay & Weinberger 1999). The discrepancy between anatomical references and functions becomes even more complex when dealing with higher cognitive functions, such as language, which have multiple and extensively distributed epicenters. It is nowadays accepted that the classical language model (Lichtheim 1885; Geschwind 1971) is not sufficient to reflect the complexity of cortical language representations (Gabrieli et al. 1998; Grabowski 2000; Bookheimer 2002). The view that there are no well-defined language areas is strongly supported by many fMR studies, as well as cortical and subcortical electrical stimulation (CSES) studies, that have identified widespread and overlapping networks for phonological, semantic, orthographic, and syntactic processing (Ojeman et al. 1989; Herolz et al. 1996; Tzourio-Mazoyer et al. 2004). In an extensive analysis performed on more than 200 patients operated on for intrinsic brain tumor through an awake craniotomy and CSES, Berger et al. (Sanai et al. 2008) showed that sites associated with speech function are variably located along the cortex and can go well beyond the classic anatomical boundaries.

In the neurosurgical population, additional inter-patient anatomical variability arises from the presence of intracranial pathology. Brain tumors can alter the understanding of neuroanatomy and function localization through two mechanisms. The first is related to the deformity created by the space-occupying lesion on adjacent sulci such that normal anatomical and imaging landmarks are more difficult or impossible to identify. The second is related to the reorganization and redistribution that occur in the cortical functional maps as a consequence of the presence of the brain tumor. Post-lesional recovery and the pattern of brain reorganization involved in functional compensations have been well documented in stroke patients (Rijntes & Weiller 2002; Rossini et al. 2003; Ward 2004). These studies have elucidated the concept of cerebral plasticity: the natural capacity of the brain to remodel itself as a consequence of learning and developmental strategy. Cerebral plasticity defines a continuous process that allows reshaping of the neuronosynaptic maps to optimize the functioning of brain networks. It is also the way to recover from lesions of different origin. Gliomas, especially low-grade gliomas, have in the very recent years increasingly attracted researchers because of their tendency to reach large volumes in eloquent areas, frequently without causing neurological symptoms. Functional MR studies have shown how these slow growing tumors can induce functional reshaping by displacing critical epicenters either around the tumor or even to the contralateral hemisphere (Mueller et al., 1996; Carpentier et al. 2001; Baciu et al. 2003). Moreover, several authors have reported series of patients who have undergone awake craniotomy and CSES in whom tumors in critical areas were safely and efficiently removed without permanent morbidity. In these series authors have documented different types and mechanisms of tumor-induced functional

Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 343

resonance imaging (fMRI) is the most widely used method of functional neuroimaging in both the clinical and research environments. For the latter purpose, and unlike more invasive mapping methods, fMR allows for the study of subjects who are free from neurological illness and enables the modeling of brain processes and of individual differences in brain organization. These are the principal factors that account for the enormous advancements brought by fMR to the understanding brain functional

The two predominant diagnostic aims of presurgical fMR are the localization of eloquent brain areas and their relationships with the tumor, and the determination of the dominant hemisphere for language. As a clinical research tool, fMR can be performed longitudinally

Any clinical application of fMRI involves a "paradigm," a defined functional measurement including stimulation, and a task that is presumed to activate the cortical area to be studied. For motor function, the patient is scanned while performing an active blocked motor task. The task consists of 12 seconds of foot plantarflexion/dorsiflexion, hand opening/closing, or tongue movement, with a frequency of 0.5 Hz, followed by 12 seconds of rest for a total acquisition time of 5 minutes. The sensory cortex test is similar, with an active condition of 0.5-Hz brushing of the foot or hand. Language is investigated as follows: in the active condition, the patient listens to a list of nouns and generates associated verbs for 21 seconds; in the rest condition, the patient counts from 1 to 10 for 15 seconds. These paradigms are those usually performed in our routine. For further technical details refer to the

Due to its good spatial resolution and direct correlation to surface anatomy BOLD-fMRI has been used since shortly after its first description (Bandettini et al. 1992) (Kwong et al. 1992; Ogawa et al. 1992) for presurgical localization of the primary sensorimotor cortex in patients with rolandic brain tumors (Jack et al. 1994), for determination of the language dominant hemisphere in patients with left frontal or temporo-parietal tumors (Desmond 1995), and for the localization of Broca and Wernicke language areas (FitzGerald et al. 1997; Stippich et al.

The most relevant concern in presurgical visualization of eloquent areas is the reliability of the spatial position and the extent of the spot of activation as depicted on the fMR. It is important to clarify that the spots of activation are strictly related to the statistical threshold chosen for data evaluation. Even with the use of one or more fixed statistical thresholds, BOLD signal intensities and cluster sizes differ significantly from one patient to another and between different paradigms (e.g. foot movement, hand movement), even when examinations are carried out in a standardized way. This has a direct impact on the planning of the neurosurgeons, who may, based on an fMR map, consider a determined eloquent area to be wider or narrower than it actually is. To address this matter, comparisons of presurgical fMRI data with a reference procedure such as CSES have been performed. In patients with lesions around the central sulcus (Dymarkowski et al. 1998; Achten et al. 1999; Roux et al. 1999), many studies have reported highly concordant data of presurgical fMRI and CSES, with correlation ranging from 83% to 92% (Majos et al. 2005; Lehericy et al. 2000; Spena et al. 2010). However, for language areas, the utility of fMRI to predict the presence of language epicenters in or around the tumor surface is diminished. This is seen in our results (42.8%) as well as in previous works that have indicated variable sensitivities and specificities ranging from 59% to 100% and from 0% to 97%, respectively

pre- and postoperatively to identify neuroplastic changes in brain activity.

bibliography (Moritz & Haughton 2003; Gaillard 2004).

2003; Stippich et al. 2007).

organization.

reorganization (Duffau 2005; Duffau 2006). In addition, in some cases functional tissue is located within the tumor nidus, and it is now understood that the standard surgical principle of debulking tumor from within to avoid neurological deficits is not always safe (Duffau et al. 2005; Berger et al. 2010; Spena et al. 2010).

The concept of the eloquent area is not limited to cortical functional maps. It is also applied to the bundles of axons connecting a cortical area to secondary neurons and to other areas of a specific cortical network. Hence, the most thorough examination of a tumor requires a careful consideration of its relationship with subcortical white matter. In particular, gliomas are well known to invade white matter tracts through which they can reach the contralateral hemisphere. Accumulating evidence has demonstrated that postsurgical or post-stroke damage to subcortical critical pathways can result in irreversible deficits. There is no documented plasticity in the white matter, and recovery after interruption of a subcortical functional bundle is difficult. Hence, presurgical planning should determine whether tumor invades or simply displaces subcortical pathways. In the very recent years a new application of MR diffusion sequences imaging called Diffusion Tensor Imaging (DTI) has created the opportunity to reconstruct the anatomy of the main white matter tracts. A virtual in vivo dissection of white matter, very similar to those coming from cadaver studies, has been produced, adding new insights into the relationship between tumors and white matter bundles (Catani 2002, Ozawa 2009, Nimsky 2007). The availability of this new tool marks a period in which neuroscientists have given great resonance to connectionism to explain brain functions and neurosurgeons have focused their efforts on gaining preoperative information about subcortical pathways.

This brief overview of advances in understanding of the brain function has given us the opportunity to point out that the modern-era neurosurgeon should be able to preoperatively collect a large amount of information on the distinctive functional and anatomical organization of each patient's brain in order to individualize surgical strategy.
