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Cortical stimulation in the definition of eloquent cortical areas
Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging Handbook of Clinical Neurophysiology, Vol. 3 Felix Rosenow and Hans O. Lüders (Eds.) © 2004 Elsevier B.V. All rights reserved
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CHAPTER 2.19
Cortical stimulation in the definition of eloquent cortical areas Deepak K. Lachhwania,∗ and Dudley S. Dinnerb Department of Neurology, a Division of Pediatric Epilepsy and b Section of Epilepsy and Sleep Disorders, S-90 Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
1. Introduction Ideally, epilepsy surgery should render a patient with medically refractory epilepsy seizure-free with no consequent neurological deficits. Functional mapping of the different areas of the brain therefore forms an integral step towards realization of this goal (Risinger and Gumnit, 1995). It provides a road map of crucial information for the surgeon, which helps to avoid inadvertent resection of areas serving important functions while planning a surgical strategy. Since the dawn of epilepsy surgery, many pioneers in this field have pursued the study of cortical function with relentless zeal, implementing newer modalities as they have become available. The turn of the 20th century saw the evolution of systematic electrical stimulation as a method to perform functional mapping of the cortex. The intervening century has witnessed the invention of several other methods of charting cortical function. Some of these methods are fMRI (Latchaw and Hu, 1995; Puce et al., 1995; Dymarkowski et al., 1998; Pujol et al., 1998; McDonald et al., 1999), functional connectivity MRI (Cordes et al., 2000), magnetic resonance spectroscopy (MRS), positron emission tomography (PET; Duncan et al., 1997; Vinas et al., 1997; Bittar et al., 1999), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG; Maestu et al., 1999; Minassian et al., 1999; Otsubo et al., 2001). Although these different modalities have been instrumental in contributing to the body of evidence in support of incriminating a candidate epileptogenic area in any given patient, they have only been able to provide supplementary information in ascribing function to any given cortical area. In this regard, electrical stim∗
Correspondence to: Deepak K. Lachhwani MBBS, MD. E-mail address: [email protected] Tel.: +1-216-445-9818.
ulation of the brain continues to be the gold standard and hence the preferred method to map eloquent cortical areas. 2. Eloquent cortex Before we discuss the different aspects of cortical mapping, it is important to conceptualize the definition of “eloquent cortex” (Berger, 1994; Berger et al., 1997; Marusic et al., 2002). It is intuitive to assume that an eloquent cortical area is an area in which resection would lead to a “significant neurological deficit”. Such a definition is fraught with controversy for reasons that become apparent quickly. “Significant neurological deficit”, as it is often implicit, refers to a readily appreciated deficit in sensory, motor, or speech modalities. However, it could also refer to a deficit of the higher functional modalities of cognition or performance, which become apparent only after a variable length of time and which can be elicited only by sophisticated neuropsychological testing. These possible remote deficits in higher cerebral function do not lend themselves to easy testing and identification within the confines of the time available during a presurgical evaluation. The best that one can do in aiming towards a deficit-free neurological outcome is by sparing those cortical areas that do lend themselves to ready objective testing. We would therefore prefer to elude to eloquent cortex as an area of the cortex, the stimulation of which leads to a reproducibly demonstrable change in neurological function. This change in function could be a positive phenomenon, such as a tonic or clonic movement of a group of muscles, or a negative phenomenon, such as an arrest of speech. From a surgical standpoint, these areas may be relatively dispensable, meaning that their resection would result in a minimal or no deficit, or they may be indispensable for adequate cortical function, implying that their absence would manifest as an obvious focal neurological deficit.
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The following areas of human cortex have been extensively studied in stimulation studies and have demonstrated a relatively stable and reproducible cortical function:
• • • • • • • •
language areas; primary motor area; primary sensory area; supplementary sensory motor area; visual cortex; auditory cortex; negative motor area; dominant angular gyrus (Gerstman syndrome).
3. Methodology The important variables which ensure a safe and meaningful study of cortical function include the selection of electrodes, electrode placement, electrical stimulus which can be reliably delivered to a discrete focal cortical area, and careful and objective recording of responses with clearly specified guidelines. 3.1. Electrodes At our institution, the subdural electrodes used are nonferromagnetic, thin, platinum disks, with the exposed surface measuring 2.3 mm in diameter. Platinum–iridium electrodes may have a theoretical advantage in stability as compared to stainless steel
Fig. 1. Three electrode arrays (8 × 8, 4 × 4, 1 × 8).
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electrodes when current is passed. The interelectrode distance is 1 cm. The array of electrodes could vary from an 8 × 8 to an 1 × 11 and 4 × 4 grid, or any combination thereof, and it is tailored to the cortical area of interest (Fig. 1). After placement, the position of the electrodes on the cortical surface is verified by identifying the electrodes individually on a postoperative 3D MRI acquisition. It is important to ensure that there is an adequate coverage of the cortical area whose function will be evaluated by stimulation. Risk of infection is minimized by observing strict intraoperative and postoperative antiseptic techniques, and by tunneling the wires for a distance under the scalp before their final exit. The experience at our center is that the morbidity in patients undergoing subdural electrode implantation is no greater than that for neurosurgical patients in general when proper care is taken. 3.2. Electrical stimulation The safe delivery of focal electrical stimulation is necessary before we can infer whether an observed response can be attributed to the stimulated area. Nathan et al. studied and found that the current density drops off rapidly with increasing distance from the tissue underlying the stimulating electrodes, by using finite element modeling (FEM; Nathan et al., 1993). Furthermore, recessing the edges of the electrodes in
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the plastic, which embeds them, provides a reliable focal stimulation with a rapid and smooth current drop away from the stimulating site. Figure 1 shows samples of arrays of electrodes embedded in silicone mats used at our institution. Intermittent cortical stimulation carried out over several days for mapping in humans with the current protocols does not result in any cortical damage and is felt to be safe (Gordon et al., 1990). Girvin reported on a patient who had received occipital cortical stimulation over a period of 10 years for the purposes of artificial vision production (Girvin, 1988). No pathologic changes were found when the electrodes were removed. Another concern is that of kindling of the brain with repetitive electrical stimulation, rendering it more epileptogenic after completion of evaluation of cortical function. Although the afterdischarge thresholds may vary over a tested region of the brain with recurrent electrical stimulation on different days, there is no evidence to support any progressive decrease in the afterdischarge threshold which would be expected with a kindling phenomenon (Lesser et al., 1984, 1987). We use stimulus pulses of 0.3-ms duration of alternating polarity (Fig. 2) at the rate of 50 pulses per second. The testing is routinely begun at a low intensity of 1.0 mA and increased gradually by 0.5–1.0 mA until an afterdischarge, clinical response or maximum stimulus strength of the instrument is reached (15 mA with Grass S88 stimulator and 17.5 mA with Grass S12 stimulator). The duration of a stimulus train is usually 5 s for the initial screening. When afterdischarges occur, one can usually repeat testing at the same stimulus inten-
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sity or lower stimulus intensity without the recurrence of afterdischarges. Subsequently, a gradual increase in stimulus intensity far beyond the initial threshold for afterdischarges can be attained, without continued afterdischarges. It is important to bear in mind that the afterdischarge threshold can vary even within adjacent electrodes and from one day to the other, and hence one must establish the afterdischarge threshold for each area tested every time it is tested (Lesser et al., 1984). The tasks given to a patient are tailored to the area that is being stimulated, and the details are described under individual areas. In summary, the current stimulation protocols for cortical mapping are felt to be safe, reliable, and without any lasting adverse effects. 4. Mapping 4.1. Language areas Foerster and Penfield performed the pioneer studies of language mapping intraoperatively in the first half of the 20th century (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957; Penfield and Roberts, 1959). The intraoperative stimulation had to be performed under obvious time constraints. With the development of subdural electrode arrays, extraoperative stimulation of the cortex without the time constraint has been made possible. The speech areas as described by Penfield and Roberts included anterior, posterior, and superior language areas (Penfield and Roberts, 1959). These regions correspond to Broca’s area in the frontal lobe, Wernicke’s area in the posterior temporoparietal region, and the supplementary motor area in the mesial aspect of the superior frontal gyrus. Our group at the Cleveland Clinic reported the presence of a distinct language area in the basal temporal region (L¨uders et al., 1986). These speech areas are shown in Figs. 3 and 4. 4.2. Testing Standard language-related tasks that may be used during the electrical stimulation for evaluation of language include the following:
• Reading aloud: The patients are given words and sen-
Fig. 2. True and effective biphasic waveform of a stimulus pulse.
tences to read. This measures the overall intactness of reading and motor speech output. The words and sentences are selected to be appropriate for the comprehension level of the patient. We often vary the content to maintain the patients’ interest during a particular testing session.
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Fig. 3. Speech areas.
• Object naming: This tests the integrity of systems • •
necessary for the process of visual object identification and name generation. Auditory word repetition: This assesses the normal auditory input to the speech production stage. Auditory and reading comprehension: The patients are asked to carry out commands given verbally or presented on paper. This is sensitive in detecting comprehension deficits.
• Spontaneous speech: This tests the overall integrity of the language production system. 5. Mechanisms of speech arrest elicited by cortical stimulation Any one or a combination of the following mechanisms could give rise to speech arrest during a stimulation study:
• Stimulation of a positive area: Contraction of mus-
•
•
• Fig. 4. Location of the basal temporal language area.
cles responsible or speech production by stimulation of primary motor area 4 may result in difficulty producing speech (Fig. 5). Stimulation of a negative motor area: Stimulation of the primary negative motor area (inferior frontal gyrus immediately in front of the primary face motor area in the dominant hemisphere) or the supplementary negative motor area (anterior to the supplementary sensorimotor area on the mesial aspect of the superior frontal gyrus) could result in impairment of the motor production of speech (Fig. 5). Stimulation of the cortex that elicits other distracting symptoms: A patient may manifest speech disturbance secondary to concurrent production of other symptoms, such as visual or auditory hallucinations. Alteration of consciousness: Partial seizures arising due to cortical stimulation may cause an alteration
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Fig. 5. Location of primary (PNMA) and supplementary negative motor area (SNMA). M1: primary motor area. S1: primary sensory area.
•
of consciousness and hence lead to an observed language impairment. Stimulation of a language area: The mechanisms mentioned above must be excluded before ascribing language function to an area of cortex being stimulated.
While evaluating any patient, initially we screen for the speech area by asking the patient to read aloud. Whenever a slowing of speech or speech arrest is elicited, additional testing is carried out to exclude any of the other mechanisms (as described above) that might be causing an observed speech impediment. The patient is asked to move their tongue from side to side (to exclude a negative motor response) and to protrude their tongue (to exclude a positive motor phenomenon), and the presence of after-discharges is checked to exclude an alteration of consciousness due to an electrographic seizure. A cortical site is identified as representing a language area only after all the tests identified above are negative. Once such a site is identified, additional testing may be carried out to characterize the precise nature of the language deficit. Additional testing is
also carried out if, on initial screening, the patient does not demonstrate any language deficit, and we are in a location which is likely to harbor language. 6. Anterior language area (Broca’s) Broca’s area resides within the inferior and middle frontal gyrus (Fig. 3). The anterior and posterior borders are 4.0–4.5 cm and 1.5–2.0 cm anterior to the rolandic fissure, respectively. The superior border is about 3.5 cm above the sylvian fissure (Schaffler et al., 1996). Electrical stimulation of the Broca’s area may result in impairment of speech output manifested as speech arrest, slowing of speech, alexia, agraphia, anomia, or paraphasia (Penfield and Jasper, 1954; Penfield and Roberts, 1959).These effects can be observed in isolation or in combination, from one or more electrodes within the area. In addition to the impediment in speech production, electrical stimulation of Broca’s area has also been shown to produce a significant receptive language deficit similar to that defined in Wernicke’s area (Schaffler et al., 1993).
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Thus, although the predominant function of Broca’s area seems to be language production, it also appears to play a significant role in comprehension similar to that in Wernicke’s area (Schaffler et al., 1996). 7. Posterior language area (Wernicke’s) Wernicke’s area resides within the posterior aspect of the superior and middle temporal gyrus, angular gyrus, and supramarginal gyrus (Fig. 3; Penfield and Jasper, 1954; Lesser et al., 1986). The anterior border is thought to be approximately 1 cm behind the junction of the rolandic and sylvian fissures. The posterior border is approximately 5.5–6.5 cm behind this junction. Electrical stimulation of Wernicke’s area leads to comprehension deficits for auditory and visual stimuli. There are no associated negative motor responses in this area, thus suggesting that Wernicke’s area appears to be an exclusive language center and that it is not involved in the organization of voluntary movement. 8. Superior language area During the initial studies of the supplementary motor area, it was found that stimulation led to a speech arrest, implying that this area might subserve speech function (Fig. 3; Penfield and Rasmussen, 1949; Penfield and Rasmussen, 1957). It was referred to as the superior language area as defined by the Montreal group (Penfield and Roberts, 1959). In subsequent studies, it has been demonstrated that the speech impediment produced by stimulating this area is a result of inhibition of movement (Van Buren et al., 1978). In our experience, stimulation studies in the SSMA showed that two-thirds of patients demonstrated a slowing of speech due to inhibition of tongue movement. None of these patients had any impairment in language comprehension or speech impairment without a negative motor response involving the tongue movement. Thus, it is possible that the previous observations designating language function to this area might have been as a result of impaired motor function, which was not properly excluded by adequate testing. 9. Inferior language area (Broca’s temporal language area) The areas most consistently involved with language function in the basal temporal area are the fusiform
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gyrus, inferior temporal gyrus, and the parahippocampal gyrus (Fig. 4) in decreasing order of frequency (Schaffler et al., 1994). The anterior and posterior borders of the basal language area are about 1.1 cm and 6.1 cm posterior to the anterior temporal tip, respectively. The most lateral and mesial borders are thought to be 1.4 cm and 5.9 cm from the lateral edge of the temporal lobe, respectively. Similar to the anterior and posterior speech areas, electrical stimulation of the basal temporal area results in speech arrest as well as impaired comprehension (Van Buren et al., 1978; L¨uders et al., 1986; Burnstine et al., 1990; Schaffler et al., 1994; Krauss et al., 1996; Kluin et al., 1998). This is particularly noticeable at higher stimulus intensities. In patients who underwent resection of the basal temporal language area, after it had been identified by preoperative stimulation studies and who had demonstrated a postoperative language deficit, the language deficit cleared by 6 months after surgery (Krauss et al., 1996). Some other studies have continued to demonstrate changes in language function after resection of the basal temporal language area. Thus, this area appears to subserve a secondary role in controlling language as compared to the anterior or posterior language areas. 9.1. Primary motor and primary sensory areas Direct cortical stimulation of the premotor and motor areas has been widely used to localize human motor function. The main objective is to identify the primary motor cortex so that surgical damage can hopefully be avoided in cases where the anatomical landmarks may have been distorted due to the presence of a lesion or in nonlesional cases where the resection needs to be maximized. The homunculus was first described in 1954 by Penfield (Fig. 5; Penfield and Jasper, 1954). His depiction of the somatotopic distribution of human motor function in the primary motor cortex has stood the test of time with but a few variable patterns observed in individual patients. Using gradual increments in the square wave biphasic stimuli, the patient is observed for motor responses involving contralateral muscle contraction. For the most part, the central sulcus is a reliable demarcation separating motor and sensory cortex, and there is a consistent relationship between tongue, face, thumb, finger, and other parts as one moves up and away from the sylvian fissure (Fig. 5).
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Fig. 6. Lateral view of sensorimotor cortex and neighboring brain areas.
Somatosensory sensation can be elicited from the human brain by electrical stimulation, from three areas – the primary sensory cortex (SI) in the postcentral gyrus, the secondary somatosensory cortex (SII) in the frontal and parietal operculum and the supplementary sensorimotor area in the mesial surface of the frontal and parietal cortex. The primary sensory cortex (SI) can be defined as the postcentral or anterior parietal region consisting of areas 3a, 3b, 2, and 1 (Fig. 6). The clear somatotopy of SI corresponds to that of the motor strip with the exception of the representation of the genitals that is found only in the postcentral cortex (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957). SII is located on the superior bank of the sylvian fissure in the region of the planum infraparietale of the operculum (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957). Stimulation effects in this area consist of sensations of the whole body on the contralateral side and quite often also on the ipsilateral side. The sensations are no different from those obtained by stimulating SI except that there is a whole body representation in SII. Sensory responses obtained from the supplementary sensorimotor area consist of a mixture of bilateral, ipsilateral, and contralateral sensations. The sensory responses are mixed with motor responses. The mesial cortical areas of precuneus, paracentral lobule, superior frontal gyrus, and cingulate gyrus have shown supplementary sensorimotor type responses upon electrical stimulation.
9.2. Supplementary sensorimotor area The mesial aspect of the superior frontal gyrus, just anterior to the primary motor area for the lower limbs, was known to elicit motor responses in monkeys more than a century ago (Horsley and Sch¨afer, 1888). The difficulty in accessing this area of the cortex made it difficult to perform any systematic studies on humans until the second half of the 20th century when implantable depth electrodes and subdural grid electrodes became prevalent (Dinner et al., 1991, 1987; Fried et al., 1991). It has also become apparent that this area has both sensory and motor representation, hence the preferred use of the term supplementary sensorimotor area (Fig. 5; Lim et al., 1994). There are some patterns of responses that are more likely to be obtained upon stimulation of SSMA, and so these are referred to as “SSMA-type responses”. While stimulation of PMA gives rise to predominantly distal and clonic responses, the SSMA leads to predominantly proximal and tonic responses. Other SSMA-type responses include bilateral asymmetric tonic movements of lower or upper extremities, head and eye deviation, and vocalization. Sensory responses consisting of numbness, tingling, or pressure can be elicited contralaterally or bilaterally. Inhibition of movement involving all four extremities and tongue has also been noted after stimulation just anterior to the SSMA (L¨uders et al., 1992; Lim et al., 1994). This supplementary negative motor area is distinct from the primary negative motor area located over the lateral convexity of
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the frontal lobe. The previously reported speech arrest in response to electric stimulation of the SSMA may have been consequent to the stimulation of the supplementary negative motor area. In our studies, the patients who experienced speech impediment during SSMA stimulation did not have any difficulty in language comprehension, and they did not show any speech impediment in the absence of inhibition of tongue movement. Previously, this area was delineated to be on the mesial aspect of the superior frontal gyrus and separated from the primary motor area by a strip of cortex. Since there are no clear anatomic landmarks to define the boundaries, we must rely on the stimulation studies to learn the extent of cortex, which, upon stimulation, gives rise to SSMA-type responses. After careful electrical stimulation studies, experience at our center suggests that SSMA-type responses are obtainable from the mesial surface of the superior frontal gyrus extending to the dorsal convexity, cingulate gyrus, paracentral lobule, and the precuneus (Lim et al., 1994). One hypothesis based on the theory of brain architectonics postulates that the SSMA may be derived from the cingulate gyrus, which would explain the cortical distribution of SSMA-type responses, obtained during stimulation studies. The somatotopic organization of SSMA is posterior to anterior with the representation of the lower extremity followed by the upper extremity followed by the head. A supplementary eye field which causes conjugate contralateral eye deviation is located within the area of head representation (Lim et al., 1994). The significance of SSMA is most likely in providing a supplementary role in motor function, as evidenced by the fact that surgical resection of this area yields only a minimal neurologic deficit (Rostomily et al., 1991; L¨uders et al., 1992; Lim et al., 1994). However, this issue remains to be resolved. A significant bilateral motor neglect, worse on the contralateral side, together with mutism may follow resection of the SSMA. Although most of the neurologic deficit is transient (improvement in speech occurs in days to weeks), some impairment in bimanual coordination may be permanent. Blood-flow studies show an increased perfusion in the SSMA during the phase of planning and execution of complex motor movements, suggesting a supramotor role (Orgogozo and Larsen, 1979; L¨uders et al., 1992; Lim et al., 1994). Additional studies would help in clarifying this controversy.
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9.3. Visual cortex Brodmann divided the visual cortex into areas 17, 18, and 19 (Clarke and Miklossy, 1990; Zeki, 1993). Area 17 corresponds to the striate cortex defined by the presence of stria of Gennari, which is clearly identified histologically as a distinctive myelin band. It receives input from the lateral geniculate body and is considered the major gateway for visual information to the cortex. Areas 18 and 19 are visual association areas and are difficult to identify histologically. Primate microelectrode studies have identified different cortical areas for different aspects of vision (Fig. 7; Zeki, 1993). V1 corresponds to the area 17 (striate cortex) and is responsible for color, motion, and position. V2 and V3 surround V1 concentrically and receive input from V1. V4 lies on the inferior occipitotemporal region and has cells that have a large receptive field and respond strongly to color. V5 lies in the lateral aspect of posterior temporal lobe and responds to different kinds of motion. There have been few stimulation studies of the visual cortex owing to the less common origin of surgically treatable epilepsies from this region as well as the difficulty in accessing this area. The visual hallucination responses obtained with electrical stimulation are analogous to the visual auras described in the literature. Simple visual auras are unformed circles of flashing light which may be white or colored. They correspond to “phosphenes” or “elementary” visual hallucinations. Intermediate visual auras are geometric shapes such as diamonds, triangles, or stars, which could be white or colored and flashing. Complex visual auras are formed images which may be clearly drawn. At other times, the patient may find them too fragmentary to draw. Distortion of vision refers to disturbances of visual perception in a localized visual field, without any hallucination of light. Sometimes, they are described as a heat wave or change in distance perception. The responses are localized to the upper or lower quadrant of the contralateral visual field. The switch from upper to lower quadrant corresponded to the calcarine fissure. 9.4. Auditory cortex In humans, the auditory cortical areas are located in the superior temporal gyrus, with the superior aspect buried deep in the sylvian fissure. The primary auditory cortex (area 41) lies in the posteromedial aspect of the gyrus of Heschl. The secondary cortical auditory areas
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Fig. 7. Cortical visual areas of the left hemisphere. (A) Inferomesial view. (B) Posterolateral view. V1–V5: Cortical visual areas.
include the contiguous areas of the transverse gyri of Heschl, which extend dorsally into the planum temporale and ventrally in the region of the superior temporal sulcus (areas 42, 52, and 22). Electrical stimulation is carried out, and the patient is asked to describe the subjective symptoms during and after each stimulus. The stimuli should be separated by a sufficient time interval (5–10 min) such that the local background electrical activity has returned to the prestimulation status before the next stimulus is delivered. Patient responses can be classified as either auditory hallucinations or auditory illusions. The hallucinations are described as ringing sounds or buzzing sounds, and are heard in one (contralateral) or both ears, with often a clear localization in extrapersonal space. The auditory illusions are perceived as a modification of the voice of the patient or the observer with respect
to its tone or intensity. Stimulation of the primary auditory area of the Heschl’s gyrus (area 41) gives rise to high-frequency hallucinations. The secondary auditory area of the Heschl’s gyrus provokes illusions in a majority of patients. Stimulation in the region of planum temporale gives rise to auditory illusions and hallucinations with equal frequency. Interestingly, the left planum temporale gives rise to auditory illusions (perceived contralaterally) and the right to auditory hallucinations (perceived bilaterally). Area 22 provokes all types of illusions as well as hallucinations. 9.5. Negative motor area Penfield and Jasper noted a negative motor affect in selected cases that underwent cortical stimulation (Penfield and Jasper, 1954). Systematic studies have
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now revealed the presence of two regions that, upon stimulation, give rise to a negative motor effect (Fig. 5; L¨uders et al., 1992; Lim et al., 1994): (1) The inferior frontal gyrus, immediately in front of the primary motor face area. Stimulation in this region may result in a negative motor response involving the contralateral and, to a lesser extent, even the ipsilateral muscle groups (L¨uders et al., 1992). (2) The mesial portion of the superior frontal gyrus immediately in front of the face motor area of the supplementary sensory motor area (supplementary negative motor area). Lim et al. found that the negative motor response elicited from the supplementary negative motor area involved the muscles of the tongue as well as all four extremities (Lim et al., 1994). Although the negative motor effect observed after stimulation of the negative motor areas is relevant to the present discussion, it is worth mentioning that the current evidence suggests the existence of two other mechanisms by which cortical stimulation can result in a negative motor phenomenon: (1) The silent period, which is contralateral, has a somatotopic distribution and tends to affect muscles involved in fine movements. The H reflex is not inhibited during the silent period, suggesting that the silent period is generated by a decrease in excitatory input through direct corticospinal neurons on alpha motor neurons of the spinal cord. An increase in calcium-dependent potassium conductance, inhibition of Renshaw cells, and an inhibitory afferent feedback due to muscle contraction are possible explanations underlying the physiology of the silent period. (2) The fast conducting corticuloreticulospinal pathways, which, by the activation of brainstem inhibitory centers, tend to produce bilateral atonia of axial postural muscles. In the context of stimulation of negative motor areas, a negative motor effect is defined as the inability to perform a voluntary movement or to sustain a voluntary motor contraction when the cortex is stimulated at a stimulus intensity that does not produce any positive sign or symptom. It consistently affects the contralateral extremities greater than the ipsilateral extremities, and no interference with muscle tone of the trunk or extremity is noted. For example, the patient might
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be unable to perform rapid alternating movements with their fingers while at the same time being able to maintain the original position of the hand and arm. The stimulation interferes with the function of the cortex being stimulated, but the patient is unaware of the effect until they are asked to perform a specific function. Tests that can be used for screening of a negative motor effect include sticking out the tongue and wiggling it from side to side, rapid alternating horizontal or vertical eye movements, rapid alternating hand or foot movements, or sustained muscle contraction of distal extremities. It is tempting to assume that the negative motor areas subserve the function of organization of fine movement particularly on the opposite side. This hypothesis seems to be supported by animal studies. However, a direct inhibition of the primary motor areas resulting in the observed negative motor effect cannot be ruled out. 9.6. Dominant angular gyrus (Gerstman syndrome) The angular gyrus (Brodmann area 39) forms a part of the temporoparietal heteromodal association cortex along with the supramarginal gyrus (area 40) and the banks of the superior temporal sulcus including Wernicke’s area and the caudal aspects of area 7 in the superior parietal lobule (Fig. 8). Lesions of heteromodal association cortex produce deficits involving higher cortical functions, as opposed to lesions of unimodal association cortex, which lead to deficits specific to a single sensory modality. Lesions of the dominant temporoparietal region sparing Wernicke’s area produce a combination of deficits including Gerstmann syndrome, alexia, anomia, and constructional apraxia. Gerstmann syndrome is characterized by a constellation of acalculia, agraphia, finger agnosia, and left–right disorientation. Hughlings Jackson made the earliest report of stimulation of the dominant temporoparietal region. Since then, several other reports have provided evidence for interference with higher cortical functions upon electrical stimulation of this area. At our institution, we were able to produce alexia and agraphia along with Gerstmann syndrome upon electrical stimulation of the dominant angular gyrus (Fig. 8; Morris et al., 1984). Unlike stimulation of the other cortical areas, association cortex does not produce a readily identifiable positive phenomenon. It is therefore important that the examiner’s interpretation of elicited responses should
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Fig. 8. Temporoparietal association cortex.
be accurate and conservative. Responses that occur at a single site and remain constant over repetitive stimulation should be included. This type of evaluation is obviously labor-intensive but nevertheless important for surgical planning.
standard paradigm and up to 64% lower energy levels. The authors were also able to elicit responses as well as afterdischarges, in some young patients (<5 years), by increasing the stimulus duration after failing to obtain any response at the maximal fixed duration stimulation.
10. Special considerations in children 10.1. Testing paradigms Cortical mapping in children poses additional unique challenges. The changes inherent to a developing nervous system and absence of firm guidelines for electrical safety necessitate that the energy and charge requirements be kept to a minimum. In addition, the cooperation from pediatric patients is commensurate with the age and level of development and as such is somewhat limited. This makes it challenging to obtain a reproducible objective study of cortical stimulation. The stimulation paradigm based on a fixed pulse duration of 0.3 ms (used successfully in adults) is rarely effective in infants and young children, and yields inconsistent results in older children. The longer chronaxies characteristic of immature cortex and poorly myelinated nervous system require increments of both stimulus intensity and pulse duration in order to approach the chronaxie while minimizing the energy required to elicit a response. In a study based on such a dual increment paradigm (Jayakar et al., 1992), clinical responses and/or afterdischarges were successfully elicited at thresholds 5–8 mA below the
Biphasic pulse stimuli are delivered at 50 Hz for 3–5 s (motor mapping) or 5–10 s (language mapping). Monopolar stimulation is preferred, with an electrode distant from the site being stimulated used as an anode. This minimizes the chance of shunting of current as might result with bipolar stimulation. Stimulation is begun at a low intensity (1.0 mA) and gradually increased in increments of 0.5–1.0 mA, until the after-discharge, clinical response, or stimulation ceiling of the instrument is reached (15 mA for Grass S88, or 17.5 mA for Grass S12 stimulator). Pulse durations are increased from a starting level of 0.3 ms, up to a maximum of 1.0 ms. Jayakar et al. were also able to demonstrate that most clinical responses in children were obtained at or above the after-discharge threshold (Jayakar et al., 1992). This was felt to be a result of maturational factors giving rise to variations in the coupling of functional responses to after-discharges. Faced with an absence of clinical response in the presence of
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after-discharge therefore does not exclude the presence of eloquent cortex under that electrode. It is possible and worthwhile to retest at the same or slightly lower intensities and avoid the occurrence of after-discharges in many cases. Subsequently, the stimulus intensity could be gradually increased to current settings beyond the after-discharge threshold without eliciting after-discharges. Specific language, memory, and motor tasks administered must be tailored to the patient’s age and neurocognitive status. The team has to be sensitive to the relatively short attention span and limited amount of patience natural to the pediatric patients. A creative participation of the personnel involved could result in a very fruitful mapping study. We have, for example, obtained excellent cooperation by incorporating an ongoing cartoon channel on TV or card and board games in carrying out common tasks to test language, memory, and motor skills. 10.2. Response characteristics Motor movements are obtained at all age groups with some ontogenic trends. In children younger than 2 years of age, tongue movements are difficult to elicit, and they may demonstrate bilateral rather than unilateral responses from the lower face when the lower rolandic region is stimulated. Individual finger movements are usually first manifest at or after 3 years of age. Clonic finger movements appear after tonic finger movements. These observations are likely to be a result of the maturing systems in cortical area 4. Children with developmental disorders or disorders with aberrant cortical formation are more likely to show atypical distribution of the motor or language cortex. In as much as is feasible, it is imperative that a correlation of results of cortical stimulation be carried out together with data obtained from metabolic and functional neuroimaging studies to unravel the mysteries of the developing neuronal systems. References Berger, MS (1994) Lesions in functional (“eloquent”) cortex and subcortical white matter. Clin. Neurosurg., 41: 444–463. Berger, MS, Stieg, PE, Danks, RA, Schwartz, RB and Folkerth, RD (1997) Lesions in eloquent cortex. Neurosurgery, 40: 1059–1063.
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Bittar, RG, Olivier, A, Sadikot, AF, Andermann, F, Pike, GB and Reutens, DC (1999) Presurgical motor and somatosensory cortex mapping with functional magnetic resonance imaging and positron emission tomography. J. Neurosurg., 91: 915–921. Burnstine, TH, Lesser, RP, Hart, J, Jr, Uematsu, S, Zinreich, SJ, Krauss, GL, Fisher, RS, Vining, EP and Gordon, B (1990) Characterization of the basal temporal language area in patients with left temporal lobe epilepsy. Neurology, 40: 966–970. Clarke, S and Miklossy, J (1990) Occipital cortex in man: organization of callosal connections, related myelo- and cytoarchitecture, and putative boundaries of functional visual areas. J. Comp. Neurol., 298: 188–214. Cordes, D, Haughton, VM, Arfanakis, K, Wendt, GJ, Turski, PA, Moritz, CH, Quigley, MA and Meyerand, ME (2000) Mapping functionally related regions of brain with functional connectivity MR imaging. Am. J. Neuroradiol., 21: 1636–1644. Dinner, DS, L¨uders, H and Morris, HH (1987) Human supplementary motor area (SMA): Electrical stimulation study. Epilepsia, 28: 619. Dinner, DS, Lim, SH and L¨uders, H (1991) Supplementary eye field in humans defined by electrical stimulation of mesial frontal cortex. Neurology, 41: 402. Duncan, JD, Moss, SD, Bandy, DJ, Manwaring, K, Kaplan, AM, Reiman, EM, Chen, K, Lawson, MA and Wodrich, DL (1997) Use of positron emission tomography for presurgical localization of eloquent brain areas in children with seizures. Pediatr. Neurosurg., 26: 144– 156. Dymarkowski, S, Sunaert, S, Van Oostende, S, Van Hecke, P, Wilms, G, Demaerel, P, Nuttin, B, Plets, C and Marchal, G (1998) Functional MRI of the brain: localisation of eloquent cortex in focal brain lesion therapy. Eur. Radiol., 8: 1573–1580. Fried, I, Katz, A and Sass, KJ (1991) Functional organization of human supplementary motor cortex studied by electrical stimulation. J. Neurosci., 11: 3656–3666. Girvin, JP (1988) Current status of artificial vision by electrocortical stimulation. Can. J. Neurol. Sci., 15: 58– 62. Gordon, B, Lesser, RP, Rance, NE, Hart, J, Jr, Webber, R, Uematsu, S and Fisher, RS (1990) Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation. Electroencephalogr. Clin. Neurophysiol., 75: 371–377. Horsley, V and Sch¨afer, EA (1888) A record of experiments upon the functions of the cerebral cortex. Philos. Trans. R. Soc. London [Biol.], 179: 1–45. Jayakar, P, Alvarez, LA, Duchowny, MS and Resnick, TJ (1992) A safe and effective paradigm to functionally map the cortex in childhood. J. Clin. Neurophysiol., 9: 288–293.
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Kluin, K, Abou-Khalil, B and Hood, T (1998) Inferior speech area in patients with temporal lobe epilepsy. Neurology, 38(Suppl. 1): 227. Krauss, GL, Fisher, R, Plate, C, Hart, J, Uematsu, S, Gordon, B and Lesser, RP (1996) Cognitive effects of resecting basal temporal language areas. Epilepsia, 37: 476– 483. Latchaw, RE and Hu, X (1995) Functional MR imaging in the evaluation of the patient with epilepsy. Functional localization. Neuroimag. Clin. North Am., 5: 683– 693. Lesser, RP, L¨uders, H, Klem, G, Dinner, DS, Morris, HH and Hahn, J (1984) Cortical afterdischarge and functional response thresholds: results of extraoperative testing. Epilepsia, 25: 615–621. Lesser, RP, L¨uders, H, Morris, HH, Dinner, DS, Klem, G, Hahn, J and Harrison, M (1986) Electrical stimulation of Wernicke’s area interferes with comprehension. Neurology, 36: 658–663. Lesser, RP, L¨uders, H, Klem, G, Dinner, DS, Morris, HH, Hahn, JF and Wyllie, E (1987) Extraoperative cortical functional localization in patients with epilepsy. J. Clin. Neurophysiol., 4: 27–53. Lim, SH, Dinner, DS, Pillay, PK, L¨uders, H, Morris, HH, Klem, G, Wyllie, E and Awad, IA (1994) Functional anatomy of the human supplementary sensorimotor area: results of extraoperative electrical stimulation. Electroencephalogr. Clin. Neurophysiol., 91: 179–193. L¨uders, H, Lesser, RP, Hahn, J, Dinner, DS, Morris, H, Resor, S and Harrison, M (1986) Basal temporal language area demonstrated by electrical stimulation. Neurology, 36: 505–510. L¨uders, HO, Lesser, RP, Dinner, DS, Morris, HH, Wyllie, E and J and Hahn, JH (1992) A negative motor response elicited by electrical stimulation of the human frontal cortex. Adv. Neurol., 57: 149–157. Maestu, C, Gomez-Utrero, E, Pineiro, R and Sola, RG (1999) Magnetoencephalography: a new functional diagnostic technique for the neurosciences. Rev. Neurol., 28: 1077–1090. Marusic, P, Najm, IM, Ying, Z, Prayson, R, Rona, S, Nair, D, Hadar, E, Kotagal, P, Bej, MD, Wyllie, E, Bingaman, W and L¨uders, H (2002) Focal cortical dysplasias in eloquent cortex: functional characteristics and correlation with MRI and histopathologic changes. Epilepsia, 43: 27–32. McDonald, JD, Chong, BW, Lewine, JD, Jones, G, Burr, RB, McDonald, PR, Koehler, SB, Tsuruda, J, Orrison, WW and Heilbrun, MP (1999) Integration of preoperative and intraoperative functional brain mapping in a frameless stereotactic environment for lesions near eloquent cortex. Technical note. J. Neurosurg., 90: 591–598. Minassian, BA, Otsubo, H, Weiss, S, Elliott, I, Rutka, JT and Snead, OC, III (1999) Magnetoencephalographic
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localization in pediatric epilepsy surgery: comparison with invasive intracranial electroencephalography. Ann. Neurol., 46: 627–633. Morris, HH, L¨uders, H, Lesser, RP, Dinner, DS and Hahn, J (1984) Transient neuropsychological abnormalities (including Gerstmann’s syndrome) during cortical stimulation. Neurology, 34: 877–883. Nathan, SS, Sinha, SR, Gordon, B, Lesser, RP and Thakor, NV (1993) Determination of current density distributions generated by electrical stimulation of the human cerebral cortex. Electroencephalogr . Clin. Neurophysiol., 86: 183–192. Orgogozo, JM and Larsen, B (1979) Activation of the supplementary motor area during voluntary movement in man suggests it works as a supramotor area. Science, 206: 847–850. Otsubo, H, Ochi, A, Elliott, I, Chuang, SH, Rutka, JT, Jay, V, Aung, M, Sobel, DF and Snead, OC (2001) MEG predicts epileptic zone in lesional extrahippocampal epilepsy: 12 pediatric surgery cases. Epilepsia, 42: 1523– 1530. Penfield, W and Jasper, H (1954) Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown. Penfield, W and Rasmussen, T (1949) Vocalization and arrest of speech. Arch. Neurol. Psychiatry, 61: 21– 27. Penfield, W and Rasmussen, T (1957) The Cerebral Cortex of Man. A Clinical Study of Localization of Function. Macmillan, New York, pp. 118–130. Penfield, W and Roberts, L (1959) Speech and Brain Mechanisms. Princeton University Press, Princeton, NJ. Puce, A, Constable, RT, Luby, ML, McCarthy, G, Nobre, AC, Spencer, DD, Gore, JC and Allison, T (1995) Functional magnetic resonance imaging of sensory and motor cortex: comparison with electrophysiological localization. J. Neurosurg., 83: 262–270. Pujol, J, Conesa, G, Deus, J, Lopez-Obarrio, L, Isamat, F and Capdevila, A (1998) Clinical application of functional magnetic resonance imaging in presurgical identification of the central sulcus. J. Neurosurg., 88: 863– 869. Risinger, MW and Gumnit, RJ (1995) Intracranial electrophysiologic studies. Neuroimag. Clin. North Am., 5: 559–573. Rostomily, RC, Berger, MS, Ojemann, GA and Lettich, E (1991) Postoperative deficits and functional recovery following removal of tumors involving the dominant hemisphere supplementary motor area. J. Neurosurg., 75: 62–68. Schaffler, L, L¨uders, HO, Dinner, DS, Lesser, RP and Chelune, GJ (1993) Comprehension deficits elicited by electrical stimulation of Broca’s area. Brain, 116(Pt. 3): 695–715.
286 Schaffler, L, L¨uders, HO, Morris, HH, Jr and Wyllie, E (1994) Anatomic distribution of cortical language sites in the basal temporal language area in patients with left temporal lobe epilepsy. Epilepsia, 35: 525– 528. Schaffler, L, L¨uders, HO and Beck, GJ (1996) Quantitative comparison of language deficits produced by extraoperative electrical stimulation of Broca’s, Wernicke’s, and basal temporal language areas. Epilepsia, 37: 463– 475.
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Van Buren, JM, Fedio, P and Frederick, GC (1978) Mechanism and localization of speech in the parietotemporal cortex. Neurosurgery, 2: 233–239. Vinas, FC, Zamorano, L, Mueller, RA, Jiang, Z, Chugani, H, Fuerst, D, Muzik, O, Mangner, TJ and Diaz, FG (1997) [15 O]-water PET and intraoperative brain mapping: a comparison in the localization of eloquent cortex. Neurol. Res., 19: 601–608. Zeki, S (1993) A Vision of the Brain. Blackwell Scientific, Oxford.
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CHAPTER 2.19
Cortical stimulation in the definition of eloquent cortical areas Deepak K. Lachhwania,∗ and Dudley S. Dinnerb Department of Neurology, a Division of Pediatric Epilepsy and b Section of Epilepsy and Sleep Disorders, S-90 Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
1. Introduction Ideally, epilepsy surgery should render a patient with medically refractory epilepsy seizure-free with no consequent neurological deficits. Functional mapping of the different areas of the brain therefore forms an integral step towards realization of this goal (Risinger and Gumnit, 1995). It provides a road map of crucial information for the surgeon, which helps to avoid inadvertent resection of areas serving important functions while planning a surgical strategy. Since the dawn of epilepsy surgery, many pioneers in this field have pursued the study of cortical function with relentless zeal, implementing newer modalities as they have become available. The turn of the 20th century saw the evolution of systematic electrical stimulation as a method to perform functional mapping of the cortex. The intervening century has witnessed the invention of several other methods of charting cortical function. Some of these methods are fMRI (Latchaw and Hu, 1995; Puce et al., 1995; Dymarkowski et al., 1998; Pujol et al., 1998; McDonald et al., 1999), functional connectivity MRI (Cordes et al., 2000), magnetic resonance spectroscopy (MRS), positron emission tomography (PET; Duncan et al., 1997; Vinas et al., 1997; Bittar et al., 1999), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG; Maestu et al., 1999; Minassian et al., 1999; Otsubo et al., 2001). Although these different modalities have been instrumental in contributing to the body of evidence in support of incriminating a candidate epileptogenic area in any given patient, they have only been able to provide supplementary information in ascribing function to any given cortical area. In this regard, electrical stim∗
Correspondence to: Deepak K. Lachhwani MBBS, MD. E-mail address: [email protected] Tel.: +1-216-445-9818.
ulation of the brain continues to be the gold standard and hence the preferred method to map eloquent cortical areas. 2. Eloquent cortex Before we discuss the different aspects of cortical mapping, it is important to conceptualize the definition of “eloquent cortex” (Berger, 1994; Berger et al., 1997; Marusic et al., 2002). It is intuitive to assume that an eloquent cortical area is an area in which resection would lead to a “significant neurological deficit”. Such a definition is fraught with controversy for reasons that become apparent quickly. “Significant neurological deficit”, as it is often implicit, refers to a readily appreciated deficit in sensory, motor, or speech modalities. However, it could also refer to a deficit of the higher functional modalities of cognition or performance, which become apparent only after a variable length of time and which can be elicited only by sophisticated neuropsychological testing. These possible remote deficits in higher cerebral function do not lend themselves to easy testing and identification within the confines of the time available during a presurgical evaluation. The best that one can do in aiming towards a deficit-free neurological outcome is by sparing those cortical areas that do lend themselves to ready objective testing. We would therefore prefer to elude to eloquent cortex as an area of the cortex, the stimulation of which leads to a reproducibly demonstrable change in neurological function. This change in function could be a positive phenomenon, such as a tonic or clonic movement of a group of muscles, or a negative phenomenon, such as an arrest of speech. From a surgical standpoint, these areas may be relatively dispensable, meaning that their resection would result in a minimal or no deficit, or they may be indispensable for adequate cortical function, implying that their absence would manifest as an obvious focal neurological deficit.
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The following areas of human cortex have been extensively studied in stimulation studies and have demonstrated a relatively stable and reproducible cortical function:
• • • • • • • •
language areas; primary motor area; primary sensory area; supplementary sensory motor area; visual cortex; auditory cortex; negative motor area; dominant angular gyrus (Gerstman syndrome).
3. Methodology The important variables which ensure a safe and meaningful study of cortical function include the selection of electrodes, electrode placement, electrical stimulus which can be reliably delivered to a discrete focal cortical area, and careful and objective recording of responses with clearly specified guidelines. 3.1. Electrodes At our institution, the subdural electrodes used are nonferromagnetic, thin, platinum disks, with the exposed surface measuring 2.3 mm in diameter. Platinum–iridium electrodes may have a theoretical advantage in stability as compared to stainless steel
Fig. 1. Three electrode arrays (8 × 8, 4 × 4, 1 × 8).
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electrodes when current is passed. The interelectrode distance is 1 cm. The array of electrodes could vary from an 8 × 8 to an 1 × 11 and 4 × 4 grid, or any combination thereof, and it is tailored to the cortical area of interest (Fig. 1). After placement, the position of the electrodes on the cortical surface is verified by identifying the electrodes individually on a postoperative 3D MRI acquisition. It is important to ensure that there is an adequate coverage of the cortical area whose function will be evaluated by stimulation. Risk of infection is minimized by observing strict intraoperative and postoperative antiseptic techniques, and by tunneling the wires for a distance under the scalp before their final exit. The experience at our center is that the morbidity in patients undergoing subdural electrode implantation is no greater than that for neurosurgical patients in general when proper care is taken. 3.2. Electrical stimulation The safe delivery of focal electrical stimulation is necessary before we can infer whether an observed response can be attributed to the stimulated area. Nathan et al. studied and found that the current density drops off rapidly with increasing distance from the tissue underlying the stimulating electrodes, by using finite element modeling (FEM; Nathan et al., 1993). Furthermore, recessing the edges of the electrodes in
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the plastic, which embeds them, provides a reliable focal stimulation with a rapid and smooth current drop away from the stimulating site. Figure 1 shows samples of arrays of electrodes embedded in silicone mats used at our institution. Intermittent cortical stimulation carried out over several days for mapping in humans with the current protocols does not result in any cortical damage and is felt to be safe (Gordon et al., 1990). Girvin reported on a patient who had received occipital cortical stimulation over a period of 10 years for the purposes of artificial vision production (Girvin, 1988). No pathologic changes were found when the electrodes were removed. Another concern is that of kindling of the brain with repetitive electrical stimulation, rendering it more epileptogenic after completion of evaluation of cortical function. Although the afterdischarge thresholds may vary over a tested region of the brain with recurrent electrical stimulation on different days, there is no evidence to support any progressive decrease in the afterdischarge threshold which would be expected with a kindling phenomenon (Lesser et al., 1984, 1987). We use stimulus pulses of 0.3-ms duration of alternating polarity (Fig. 2) at the rate of 50 pulses per second. The testing is routinely begun at a low intensity of 1.0 mA and increased gradually by 0.5–1.0 mA until an afterdischarge, clinical response or maximum stimulus strength of the instrument is reached (15 mA with Grass S88 stimulator and 17.5 mA with Grass S12 stimulator). The duration of a stimulus train is usually 5 s for the initial screening. When afterdischarges occur, one can usually repeat testing at the same stimulus inten-
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sity or lower stimulus intensity without the recurrence of afterdischarges. Subsequently, a gradual increase in stimulus intensity far beyond the initial threshold for afterdischarges can be attained, without continued afterdischarges. It is important to bear in mind that the afterdischarge threshold can vary even within adjacent electrodes and from one day to the other, and hence one must establish the afterdischarge threshold for each area tested every time it is tested (Lesser et al., 1984). The tasks given to a patient are tailored to the area that is being stimulated, and the details are described under individual areas. In summary, the current stimulation protocols for cortical mapping are felt to be safe, reliable, and without any lasting adverse effects. 4. Mapping 4.1. Language areas Foerster and Penfield performed the pioneer studies of language mapping intraoperatively in the first half of the 20th century (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957; Penfield and Roberts, 1959). The intraoperative stimulation had to be performed under obvious time constraints. With the development of subdural electrode arrays, extraoperative stimulation of the cortex without the time constraint has been made possible. The speech areas as described by Penfield and Roberts included anterior, posterior, and superior language areas (Penfield and Roberts, 1959). These regions correspond to Broca’s area in the frontal lobe, Wernicke’s area in the posterior temporoparietal region, and the supplementary motor area in the mesial aspect of the superior frontal gyrus. Our group at the Cleveland Clinic reported the presence of a distinct language area in the basal temporal region (L¨uders et al., 1986). These speech areas are shown in Figs. 3 and 4. 4.2. Testing Standard language-related tasks that may be used during the electrical stimulation for evaluation of language include the following:
• Reading aloud: The patients are given words and sen-
Fig. 2. True and effective biphasic waveform of a stimulus pulse.
tences to read. This measures the overall intactness of reading and motor speech output. The words and sentences are selected to be appropriate for the comprehension level of the patient. We often vary the content to maintain the patients’ interest during a particular testing session.
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Fig. 3. Speech areas.
• Object naming: This tests the integrity of systems • •
necessary for the process of visual object identification and name generation. Auditory word repetition: This assesses the normal auditory input to the speech production stage. Auditory and reading comprehension: The patients are asked to carry out commands given verbally or presented on paper. This is sensitive in detecting comprehension deficits.
• Spontaneous speech: This tests the overall integrity of the language production system. 5. Mechanisms of speech arrest elicited by cortical stimulation Any one or a combination of the following mechanisms could give rise to speech arrest during a stimulation study:
• Stimulation of a positive area: Contraction of mus-
•
•
• Fig. 4. Location of the basal temporal language area.
cles responsible or speech production by stimulation of primary motor area 4 may result in difficulty producing speech (Fig. 5). Stimulation of a negative motor area: Stimulation of the primary negative motor area (inferior frontal gyrus immediately in front of the primary face motor area in the dominant hemisphere) or the supplementary negative motor area (anterior to the supplementary sensorimotor area on the mesial aspect of the superior frontal gyrus) could result in impairment of the motor production of speech (Fig. 5). Stimulation of the cortex that elicits other distracting symptoms: A patient may manifest speech disturbance secondary to concurrent production of other symptoms, such as visual or auditory hallucinations. Alteration of consciousness: Partial seizures arising due to cortical stimulation may cause an alteration
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Fig. 5. Location of primary (PNMA) and supplementary negative motor area (SNMA). M1: primary motor area. S1: primary sensory area.
•
of consciousness and hence lead to an observed language impairment. Stimulation of a language area: The mechanisms mentioned above must be excluded before ascribing language function to an area of cortex being stimulated.
While evaluating any patient, initially we screen for the speech area by asking the patient to read aloud. Whenever a slowing of speech or speech arrest is elicited, additional testing is carried out to exclude any of the other mechanisms (as described above) that might be causing an observed speech impediment. The patient is asked to move their tongue from side to side (to exclude a negative motor response) and to protrude their tongue (to exclude a positive motor phenomenon), and the presence of after-discharges is checked to exclude an alteration of consciousness due to an electrographic seizure. A cortical site is identified as representing a language area only after all the tests identified above are negative. Once such a site is identified, additional testing may be carried out to characterize the precise nature of the language deficit. Additional testing is
also carried out if, on initial screening, the patient does not demonstrate any language deficit, and we are in a location which is likely to harbor language. 6. Anterior language area (Broca’s) Broca’s area resides within the inferior and middle frontal gyrus (Fig. 3). The anterior and posterior borders are 4.0–4.5 cm and 1.5–2.0 cm anterior to the rolandic fissure, respectively. The superior border is about 3.5 cm above the sylvian fissure (Schaffler et al., 1996). Electrical stimulation of the Broca’s area may result in impairment of speech output manifested as speech arrest, slowing of speech, alexia, agraphia, anomia, or paraphasia (Penfield and Jasper, 1954; Penfield and Roberts, 1959).These effects can be observed in isolation or in combination, from one or more electrodes within the area. In addition to the impediment in speech production, electrical stimulation of Broca’s area has also been shown to produce a significant receptive language deficit similar to that defined in Wernicke’s area (Schaffler et al., 1993).
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Thus, although the predominant function of Broca’s area seems to be language production, it also appears to play a significant role in comprehension similar to that in Wernicke’s area (Schaffler et al., 1996). 7. Posterior language area (Wernicke’s) Wernicke’s area resides within the posterior aspect of the superior and middle temporal gyrus, angular gyrus, and supramarginal gyrus (Fig. 3; Penfield and Jasper, 1954; Lesser et al., 1986). The anterior border is thought to be approximately 1 cm behind the junction of the rolandic and sylvian fissures. The posterior border is approximately 5.5–6.5 cm behind this junction. Electrical stimulation of Wernicke’s area leads to comprehension deficits for auditory and visual stimuli. There are no associated negative motor responses in this area, thus suggesting that Wernicke’s area appears to be an exclusive language center and that it is not involved in the organization of voluntary movement. 8. Superior language area During the initial studies of the supplementary motor area, it was found that stimulation led to a speech arrest, implying that this area might subserve speech function (Fig. 3; Penfield and Rasmussen, 1949; Penfield and Rasmussen, 1957). It was referred to as the superior language area as defined by the Montreal group (Penfield and Roberts, 1959). In subsequent studies, it has been demonstrated that the speech impediment produced by stimulating this area is a result of inhibition of movement (Van Buren et al., 1978). In our experience, stimulation studies in the SSMA showed that two-thirds of patients demonstrated a slowing of speech due to inhibition of tongue movement. None of these patients had any impairment in language comprehension or speech impairment without a negative motor response involving the tongue movement. Thus, it is possible that the previous observations designating language function to this area might have been as a result of impaired motor function, which was not properly excluded by adequate testing. 9. Inferior language area (Broca’s temporal language area) The areas most consistently involved with language function in the basal temporal area are the fusiform
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gyrus, inferior temporal gyrus, and the parahippocampal gyrus (Fig. 4) in decreasing order of frequency (Schaffler et al., 1994). The anterior and posterior borders of the basal language area are about 1.1 cm and 6.1 cm posterior to the anterior temporal tip, respectively. The most lateral and mesial borders are thought to be 1.4 cm and 5.9 cm from the lateral edge of the temporal lobe, respectively. Similar to the anterior and posterior speech areas, electrical stimulation of the basal temporal area results in speech arrest as well as impaired comprehension (Van Buren et al., 1978; L¨uders et al., 1986; Burnstine et al., 1990; Schaffler et al., 1994; Krauss et al., 1996; Kluin et al., 1998). This is particularly noticeable at higher stimulus intensities. In patients who underwent resection of the basal temporal language area, after it had been identified by preoperative stimulation studies and who had demonstrated a postoperative language deficit, the language deficit cleared by 6 months after surgery (Krauss et al., 1996). Some other studies have continued to demonstrate changes in language function after resection of the basal temporal language area. Thus, this area appears to subserve a secondary role in controlling language as compared to the anterior or posterior language areas. 9.1. Primary motor and primary sensory areas Direct cortical stimulation of the premotor and motor areas has been widely used to localize human motor function. The main objective is to identify the primary motor cortex so that surgical damage can hopefully be avoided in cases where the anatomical landmarks may have been distorted due to the presence of a lesion or in nonlesional cases where the resection needs to be maximized. The homunculus was first described in 1954 by Penfield (Fig. 5; Penfield and Jasper, 1954). His depiction of the somatotopic distribution of human motor function in the primary motor cortex has stood the test of time with but a few variable patterns observed in individual patients. Using gradual increments in the square wave biphasic stimuli, the patient is observed for motor responses involving contralateral muscle contraction. For the most part, the central sulcus is a reliable demarcation separating motor and sensory cortex, and there is a consistent relationship between tongue, face, thumb, finger, and other parts as one moves up and away from the sylvian fissure (Fig. 5).
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Fig. 6. Lateral view of sensorimotor cortex and neighboring brain areas.
Somatosensory sensation can be elicited from the human brain by electrical stimulation, from three areas – the primary sensory cortex (SI) in the postcentral gyrus, the secondary somatosensory cortex (SII) in the frontal and parietal operculum and the supplementary sensorimotor area in the mesial surface of the frontal and parietal cortex. The primary sensory cortex (SI) can be defined as the postcentral or anterior parietal region consisting of areas 3a, 3b, 2, and 1 (Fig. 6). The clear somatotopy of SI corresponds to that of the motor strip with the exception of the representation of the genitals that is found only in the postcentral cortex (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957). SII is located on the superior bank of the sylvian fissure in the region of the planum infraparietale of the operculum (Penfield and Jasper, 1954; Penfield and Rasmussen, 1957). Stimulation effects in this area consist of sensations of the whole body on the contralateral side and quite often also on the ipsilateral side. The sensations are no different from those obtained by stimulating SI except that there is a whole body representation in SII. Sensory responses obtained from the supplementary sensorimotor area consist of a mixture of bilateral, ipsilateral, and contralateral sensations. The sensory responses are mixed with motor responses. The mesial cortical areas of precuneus, paracentral lobule, superior frontal gyrus, and cingulate gyrus have shown supplementary sensorimotor type responses upon electrical stimulation.
9.2. Supplementary sensorimotor area The mesial aspect of the superior frontal gyrus, just anterior to the primary motor area for the lower limbs, was known to elicit motor responses in monkeys more than a century ago (Horsley and Sch¨afer, 1888). The difficulty in accessing this area of the cortex made it difficult to perform any systematic studies on humans until the second half of the 20th century when implantable depth electrodes and subdural grid electrodes became prevalent (Dinner et al., 1991, 1987; Fried et al., 1991). It has also become apparent that this area has both sensory and motor representation, hence the preferred use of the term supplementary sensorimotor area (Fig. 5; Lim et al., 1994). There are some patterns of responses that are more likely to be obtained upon stimulation of SSMA, and so these are referred to as “SSMA-type responses”. While stimulation of PMA gives rise to predominantly distal and clonic responses, the SSMA leads to predominantly proximal and tonic responses. Other SSMA-type responses include bilateral asymmetric tonic movements of lower or upper extremities, head and eye deviation, and vocalization. Sensory responses consisting of numbness, tingling, or pressure can be elicited contralaterally or bilaterally. Inhibition of movement involving all four extremities and tongue has also been noted after stimulation just anterior to the SSMA (L¨uders et al., 1992; Lim et al., 1994). This supplementary negative motor area is distinct from the primary negative motor area located over the lateral convexity of
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the frontal lobe. The previously reported speech arrest in response to electric stimulation of the SSMA may have been consequent to the stimulation of the supplementary negative motor area. In our studies, the patients who experienced speech impediment during SSMA stimulation did not have any difficulty in language comprehension, and they did not show any speech impediment in the absence of inhibition of tongue movement. Previously, this area was delineated to be on the mesial aspect of the superior frontal gyrus and separated from the primary motor area by a strip of cortex. Since there are no clear anatomic landmarks to define the boundaries, we must rely on the stimulation studies to learn the extent of cortex, which, upon stimulation, gives rise to SSMA-type responses. After careful electrical stimulation studies, experience at our center suggests that SSMA-type responses are obtainable from the mesial surface of the superior frontal gyrus extending to the dorsal convexity, cingulate gyrus, paracentral lobule, and the precuneus (Lim et al., 1994). One hypothesis based on the theory of brain architectonics postulates that the SSMA may be derived from the cingulate gyrus, which would explain the cortical distribution of SSMA-type responses, obtained during stimulation studies. The somatotopic organization of SSMA is posterior to anterior with the representation of the lower extremity followed by the upper extremity followed by the head. A supplementary eye field which causes conjugate contralateral eye deviation is located within the area of head representation (Lim et al., 1994). The significance of SSMA is most likely in providing a supplementary role in motor function, as evidenced by the fact that surgical resection of this area yields only a minimal neurologic deficit (Rostomily et al., 1991; L¨uders et al., 1992; Lim et al., 1994). However, this issue remains to be resolved. A significant bilateral motor neglect, worse on the contralateral side, together with mutism may follow resection of the SSMA. Although most of the neurologic deficit is transient (improvement in speech occurs in days to weeks), some impairment in bimanual coordination may be permanent. Blood-flow studies show an increased perfusion in the SSMA during the phase of planning and execution of complex motor movements, suggesting a supramotor role (Orgogozo and Larsen, 1979; L¨uders et al., 1992; Lim et al., 1994). Additional studies would help in clarifying this controversy.
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9.3. Visual cortex Brodmann divided the visual cortex into areas 17, 18, and 19 (Clarke and Miklossy, 1990; Zeki, 1993). Area 17 corresponds to the striate cortex defined by the presence of stria of Gennari, which is clearly identified histologically as a distinctive myelin band. It receives input from the lateral geniculate body and is considered the major gateway for visual information to the cortex. Areas 18 and 19 are visual association areas and are difficult to identify histologically. Primate microelectrode studies have identified different cortical areas for different aspects of vision (Fig. 7; Zeki, 1993). V1 corresponds to the area 17 (striate cortex) and is responsible for color, motion, and position. V2 and V3 surround V1 concentrically and receive input from V1. V4 lies on the inferior occipitotemporal region and has cells that have a large receptive field and respond strongly to color. V5 lies in the lateral aspect of posterior temporal lobe and responds to different kinds of motion. There have been few stimulation studies of the visual cortex owing to the less common origin of surgically treatable epilepsies from this region as well as the difficulty in accessing this area. The visual hallucination responses obtained with electrical stimulation are analogous to the visual auras described in the literature. Simple visual auras are unformed circles of flashing light which may be white or colored. They correspond to “phosphenes” or “elementary” visual hallucinations. Intermediate visual auras are geometric shapes such as diamonds, triangles, or stars, which could be white or colored and flashing. Complex visual auras are formed images which may be clearly drawn. At other times, the patient may find them too fragmentary to draw. Distortion of vision refers to disturbances of visual perception in a localized visual field, without any hallucination of light. Sometimes, they are described as a heat wave or change in distance perception. The responses are localized to the upper or lower quadrant of the contralateral visual field. The switch from upper to lower quadrant corresponded to the calcarine fissure. 9.4. Auditory cortex In humans, the auditory cortical areas are located in the superior temporal gyrus, with the superior aspect buried deep in the sylvian fissure. The primary auditory cortex (area 41) lies in the posteromedial aspect of the gyrus of Heschl. The secondary cortical auditory areas
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Fig. 7. Cortical visual areas of the left hemisphere. (A) Inferomesial view. (B) Posterolateral view. V1–V5: Cortical visual areas.
include the contiguous areas of the transverse gyri of Heschl, which extend dorsally into the planum temporale and ventrally in the region of the superior temporal sulcus (areas 42, 52, and 22). Electrical stimulation is carried out, and the patient is asked to describe the subjective symptoms during and after each stimulus. The stimuli should be separated by a sufficient time interval (5–10 min) such that the local background electrical activity has returned to the prestimulation status before the next stimulus is delivered. Patient responses can be classified as either auditory hallucinations or auditory illusions. The hallucinations are described as ringing sounds or buzzing sounds, and are heard in one (contralateral) or both ears, with often a clear localization in extrapersonal space. The auditory illusions are perceived as a modification of the voice of the patient or the observer with respect
to its tone or intensity. Stimulation of the primary auditory area of the Heschl’s gyrus (area 41) gives rise to high-frequency hallucinations. The secondary auditory area of the Heschl’s gyrus provokes illusions in a majority of patients. Stimulation in the region of planum temporale gives rise to auditory illusions and hallucinations with equal frequency. Interestingly, the left planum temporale gives rise to auditory illusions (perceived contralaterally) and the right to auditory hallucinations (perceived bilaterally). Area 22 provokes all types of illusions as well as hallucinations. 9.5. Negative motor area Penfield and Jasper noted a negative motor affect in selected cases that underwent cortical stimulation (Penfield and Jasper, 1954). Systematic studies have
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now revealed the presence of two regions that, upon stimulation, give rise to a negative motor effect (Fig. 5; L¨uders et al., 1992; Lim et al., 1994): (1) The inferior frontal gyrus, immediately in front of the primary motor face area. Stimulation in this region may result in a negative motor response involving the contralateral and, to a lesser extent, even the ipsilateral muscle groups (L¨uders et al., 1992). (2) The mesial portion of the superior frontal gyrus immediately in front of the face motor area of the supplementary sensory motor area (supplementary negative motor area). Lim et al. found that the negative motor response elicited from the supplementary negative motor area involved the muscles of the tongue as well as all four extremities (Lim et al., 1994). Although the negative motor effect observed after stimulation of the negative motor areas is relevant to the present discussion, it is worth mentioning that the current evidence suggests the existence of two other mechanisms by which cortical stimulation can result in a negative motor phenomenon: (1) The silent period, which is contralateral, has a somatotopic distribution and tends to affect muscles involved in fine movements. The H reflex is not inhibited during the silent period, suggesting that the silent period is generated by a decrease in excitatory input through direct corticospinal neurons on alpha motor neurons of the spinal cord. An increase in calcium-dependent potassium conductance, inhibition of Renshaw cells, and an inhibitory afferent feedback due to muscle contraction are possible explanations underlying the physiology of the silent period. (2) The fast conducting corticuloreticulospinal pathways, which, by the activation of brainstem inhibitory centers, tend to produce bilateral atonia of axial postural muscles. In the context of stimulation of negative motor areas, a negative motor effect is defined as the inability to perform a voluntary movement or to sustain a voluntary motor contraction when the cortex is stimulated at a stimulus intensity that does not produce any positive sign or symptom. It consistently affects the contralateral extremities greater than the ipsilateral extremities, and no interference with muscle tone of the trunk or extremity is noted. For example, the patient might
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be unable to perform rapid alternating movements with their fingers while at the same time being able to maintain the original position of the hand and arm. The stimulation interferes with the function of the cortex being stimulated, but the patient is unaware of the effect until they are asked to perform a specific function. Tests that can be used for screening of a negative motor effect include sticking out the tongue and wiggling it from side to side, rapid alternating horizontal or vertical eye movements, rapid alternating hand or foot movements, or sustained muscle contraction of distal extremities. It is tempting to assume that the negative motor areas subserve the function of organization of fine movement particularly on the opposite side. This hypothesis seems to be supported by animal studies. However, a direct inhibition of the primary motor areas resulting in the observed negative motor effect cannot be ruled out. 9.6. Dominant angular gyrus (Gerstman syndrome) The angular gyrus (Brodmann area 39) forms a part of the temporoparietal heteromodal association cortex along with the supramarginal gyrus (area 40) and the banks of the superior temporal sulcus including Wernicke’s area and the caudal aspects of area 7 in the superior parietal lobule (Fig. 8). Lesions of heteromodal association cortex produce deficits involving higher cortical functions, as opposed to lesions of unimodal association cortex, which lead to deficits specific to a single sensory modality. Lesions of the dominant temporoparietal region sparing Wernicke’s area produce a combination of deficits including Gerstmann syndrome, alexia, anomia, and constructional apraxia. Gerstmann syndrome is characterized by a constellation of acalculia, agraphia, finger agnosia, and left–right disorientation. Hughlings Jackson made the earliest report of stimulation of the dominant temporoparietal region. Since then, several other reports have provided evidence for interference with higher cortical functions upon electrical stimulation of this area. At our institution, we were able to produce alexia and agraphia along with Gerstmann syndrome upon electrical stimulation of the dominant angular gyrus (Fig. 8; Morris et al., 1984). Unlike stimulation of the other cortical areas, association cortex does not produce a readily identifiable positive phenomenon. It is therefore important that the examiner’s interpretation of elicited responses should
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Fig. 8. Temporoparietal association cortex.
be accurate and conservative. Responses that occur at a single site and remain constant over repetitive stimulation should be included. This type of evaluation is obviously labor-intensive but nevertheless important for surgical planning.
standard paradigm and up to 64% lower energy levels. The authors were also able to elicit responses as well as afterdischarges, in some young patients (<5 years), by increasing the stimulus duration after failing to obtain any response at the maximal fixed duration stimulation.
10. Special considerations in children 10.1. Testing paradigms Cortical mapping in children poses additional unique challenges. The changes inherent to a developing nervous system and absence of firm guidelines for electrical safety necessitate that the energy and charge requirements be kept to a minimum. In addition, the cooperation from pediatric patients is commensurate with the age and level of development and as such is somewhat limited. This makes it challenging to obtain a reproducible objective study of cortical stimulation. The stimulation paradigm based on a fixed pulse duration of 0.3 ms (used successfully in adults) is rarely effective in infants and young children, and yields inconsistent results in older children. The longer chronaxies characteristic of immature cortex and poorly myelinated nervous system require increments of both stimulus intensity and pulse duration in order to approach the chronaxie while minimizing the energy required to elicit a response. In a study based on such a dual increment paradigm (Jayakar et al., 1992), clinical responses and/or afterdischarges were successfully elicited at thresholds 5–8 mA below the
Biphasic pulse stimuli are delivered at 50 Hz for 3–5 s (motor mapping) or 5–10 s (language mapping). Monopolar stimulation is preferred, with an electrode distant from the site being stimulated used as an anode. This minimizes the chance of shunting of current as might result with bipolar stimulation. Stimulation is begun at a low intensity (1.0 mA) and gradually increased in increments of 0.5–1.0 mA, until the after-discharge, clinical response, or stimulation ceiling of the instrument is reached (15 mA for Grass S88, or 17.5 mA for Grass S12 stimulator). Pulse durations are increased from a starting level of 0.3 ms, up to a maximum of 1.0 ms. Jayakar et al. were also able to demonstrate that most clinical responses in children were obtained at or above the after-discharge threshold (Jayakar et al., 1992). This was felt to be a result of maturational factors giving rise to variations in the coupling of functional responses to after-discharges. Faced with an absence of clinical response in the presence of
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after-discharge therefore does not exclude the presence of eloquent cortex under that electrode. It is possible and worthwhile to retest at the same or slightly lower intensities and avoid the occurrence of after-discharges in many cases. Subsequently, the stimulus intensity could be gradually increased to current settings beyond the after-discharge threshold without eliciting after-discharges. Specific language, memory, and motor tasks administered must be tailored to the patient’s age and neurocognitive status. The team has to be sensitive to the relatively short attention span and limited amount of patience natural to the pediatric patients. A creative participation of the personnel involved could result in a very fruitful mapping study. We have, for example, obtained excellent cooperation by incorporating an ongoing cartoon channel on TV or card and board games in carrying out common tasks to test language, memory, and motor skills. 10.2. Response characteristics Motor movements are obtained at all age groups with some ontogenic trends. In children younger than 2 years of age, tongue movements are difficult to elicit, and they may demonstrate bilateral rather than unilateral responses from the lower face when the lower rolandic region is stimulated. Individual finger movements are usually first manifest at or after 3 years of age. Clonic finger movements appear after tonic finger movements. These observations are likely to be a result of the maturing systems in cortical area 4. Children with developmental disorders or disorders with aberrant cortical formation are more likely to show atypical distribution of the motor or language cortex. In as much as is feasible, it is imperative that a correlation of results of cortical stimulation be carried out together with data obtained from metabolic and functional neuroimaging studies to unravel the mysteries of the developing neuronal systems. References Berger, MS (1994) Lesions in functional (“eloquent”) cortex and subcortical white matter. Clin. Neurosurg., 41: 444–463. Berger, MS, Stieg, PE, Danks, RA, Schwartz, RB and Folkerth, RD (1997) Lesions in eloquent cortex. Neurosurgery, 40: 1059–1063.
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