- Email: [email protected]
Chapter 52 fMRI and the evaluation of patients with epilepsy
Advances in Clinical Neurophysiology (Supplements 10 Clinical Neurophysiology Vol. 54) Editors: R.C. Reisin, M.R. Nuwer, M. Hallett, C. Medina © 2002 Elsevier Science B.V. AlJ rights reserved.
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Chapter 52
tMRI and the evaluation of patients with epilepsy William Davis Gaillard Comprehensive Pediatric Epilepsy Program, The Children's National Medical Center, Washington, DC (USA) The Epilepsy Research Branch, NINDS, NIH, Bethesda, MD (USA)
Functional imaging plays an increasingly important role in the evaluation of patients with localization related epilepsy. The clinical application of fMRI to the evaluation of epilepsy patients mostly focuses on identifying brain areas to be spared during surgery because they hold eloquent function. Such methods are applied principally to motor and language cortex, and, more recently, to memory function. fMRI has also been used to identify the seizures focus in a few patients, but not as successfully as interictal PET and interictallictal SPECT. The discussion which follows primarily regards fMRI but may also be applied to 150- water-PET as the principles and practical applications in epilepsy populations are similar. PET is limited by the number of injections that can be used for cognitive mapping, and is usually analyzed with group, rather than individual, methods. Newer scanners, however, allow reliable single subject studies. PET is a better marker of capillary flow than blood oxygen level dependent (BOLD) fMRI which derives much ofits signal from draining veins (see below). PET is less sensitive to motion, and can be used in patients who can not enter the MRI environment. Unlike PET, fMRI is not restricted by radiation exposure; as a consequence more paradigms can be studied, and failed studies may be more easily
* Correspondence to: Prof. W.D. Gaillard, The Epilepsy Research Branch, NINDS, NIH, Bethesda, MD, USA. E-mail: [email protected]
repeated. fMRI also has superior signal to noise, spatial, and temporal resolution. Functional MRI (fMRI) using the BOLD technique is an indirect and relative, not absolute, measure ofneuronal activity that occurs during synaptic activity along dendrites (Logothetis et al. 2001). It relies upon detecting alterations in blood flow that follow, by several seconds, regionally specific increases in brain activity associated with task performance (Cohen and Bookheimer 1994). Most BOLD signal derives from hemoglobin (Hgb) which has a different MR signal when oxygenated compared to the deoxygenated state. In the 'activated' state there is a regionally restricted luxury hyperperfusion and concomitant increase in oxyHgb/deoxyHgb ratio in turn detected by fMRI. The temporal resolution offMRI is 2-4 s as there is a delay in the physiologic hemodynamic response to the experimental stimulus (Malonek et al. 1997). The spatial resolution is usually 4-8 mm, though 1-2 mm can be achieved. The temporal resolution is superior to PET, but considerably less than neuronal propagation times; thus, fMRI identifies the neural network involved in cognitive processes but not the regional sequence of activation. BOLD fMRI detects the relative change in signal that occurs between at least two conditions, an experimental and control condition. Arterial spin tagging allows quantitative measure of capillary blood flow, but has not been widely applied (Ye et al. 1998; Lia et al. 2000).
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Most studies employ a block design alternating between a control or rest condition, and an experimental or task condition. Blocks vary in duration from 20-40 s. For these reasons it is imperative that patients can perform the task, and that the control condition is carefully designed so as not to obscure activation. This is particularly problematic when control conditions for language processing involve a language task. For example, comparing reading words to pseudowords may not identify language processing regions because the neural networks that decode written words are also used, especially by unskilled readers, to process pseudowords (Gaillard et al. 2000a; Tagamets et al. 2000). After data acquisition data is corrected for motion and can be analyzed by any number of methods: (1) parametric measures, including the general linear model ofstatistical parametric mapping (SPM; Buchel et al. 1998; Friston et al. 1999); (2) nonparametric tests (Cohen etal. 1994) ofsignal change between conditions; or (3) cross correlation analysis between the experimental signal time course and an ideal wave form (Banditini et al. 1993). These methods yield similar results. The threshold deemed significant for individual as well as group studies is arbitrary and may be affected by patient motion, task performance, positioning in the scanner, and other technical considerations (Gaillard et al. 2001a). Most experimental data sets are analyzed by group means and displayed in a standard template, such as the Talairach and Tournoux atlas (1988). However, such an approach is impracticable for patient populations where heterogeneity is the rule (Steinmetz and Rudiger 1991; Gaillard et al. 2001a). This is a particularly important consideration for language mapping where atypical language representation is common (Rasmussen et al. 1977; Ojemann et al. 1989). Group maps can be used as a standard to which individual activation maps may be compared.
Sensory and motor mapping Motor and sensory mapping result in the most robust hemodynamic response, about 3-5% at 1.5 T, compared 1--2% for cognitive tasks. Tapping
fingers, wiggling tongues or tapping toes, compared to rest, identify the primary motor cortex; brushing the face, hand or foot for sensory, compared to rest, identifies the somatosensory cortex (Kim et al. 1993; Rao et al. 1993, 1995; Hammeke et al. 1994; Lotze et al. 2000). The central sulcus can be identified by using these tasks. Complicated hand movements can be used to identify supplementary motor cortex (Rao et al. 1993). Although used in patients with extratemporallobe epilepsy, these tasks are most commonly reported in patients undergoing resection of tumors (Jack et al. 1994; Yoursey et al. 1995; Atlas et al. 1996; Chapman et al. 1996; Kahn et al. 1996; Righini et al. 1996; Stapleton et al. 1997; Pujol et al. 1998; Schulder et al. 1998; Achten et al. 1999) or vascular malformations (Jack et al. 1994; Latchaw et al. 1995; Yoursey et al. 1995; Chapman et al. 1996; Muelleret al. 1996; Schad et al. 1996; Schlosser et al. 1997; Pujol et al. 1998; Maldjian et al. 1999). The primary visual cortex can be identified with a photic flash (Belliveau et al. 1991; Kwong et al. 1992), and the primary auditory cortex identified by listening to tones (Binder et al. 1994), but such information is rarely used in epilepsy surgery. Motor mapping with fMRl has been confirmed in comparison to evoked response potentials and by cortical stimulation in humans (Puce et al. 1995; Fitzgerald et al. 1997). Agreement between BOLD fMRI and electrocortical stimulation is within 3-5 mm.
Language mapping fMRI is most widely used to identify the dominant hemisphere for language and also the location language processing areas. PET and fMRI have been used in several group averaged studies to identify the anatomic location of receptive and expressive language functions (Peterson et al. 1989; Wise et al. 1991; Howard et al. 1992; Desmond et al. 1995; Binder et al. 1995; Schlosser et al. 1998; Poldrack et al. 1999; Gaillard et al. 2000b, 2001b). These paradigms have been adapted for individual patient studies, in adults and in children as young as 7 years. Data sets are evaluated with a region of interest approach, in order to determine the number
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Fig. 1. tMRI study of a 19-year-old with right temporal lobe dysplasia and right temporal lobe epilepsy. Four tasks are performed: (I) auditory response naming (ARN; clue: 'what is a long yellow fruit,' silent answer 'banana '), compared to rest; (2) read response naming (RRN; the reading version or ARN) compared to viewing a dot pattern; (3) verbal fluency, silently generating words beginning with letters (C, L, F, P, R, W) to letters compared to rest, and (4) fable, reading a series of fables compared to viewing dots. Studies used a 6-cycle block design and were covert and unmonitored. Right image is right brain. All studies confirm left language dominance. Note consistent activation in inferior left MFG, left MFG, and left middle/superior temporal gyrus. The auditory task shows greater bilateral temporal activation (but greater on the left) because an auditory control condition was not used. This study is typical of patients and normal volunteers with left language dominance.
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of activated voxels in each hemisphere or in selected sub-regions, Regional voxel counts are then used to calculate an asymmetry index (AI) that quantitates the degree of regional laterality for task: AI =L- R/L + R; AI > 0.20 left hemisphere dominant; AI <-0.02 right hemisphere dominant, -0.20 < AI < 0.20 bilateral or mixed dominance (Binder et al. 1996; Hertz-Pannier et al. 1997; Yetkin et al. 1998; Benson et al. 1999; Springer et al. 1999; Lehericy et al. 2000). Most investigators find a need to explore different thresholds on some individual patients (Binder et al. 1996; Hertz-Pannier et al. 1997). Paradigms that require verbal fluency or a semantic decision are reliable identifiers of the anterior, 'expressive' language areas: the inferior frontal gyrus (IFG) and middle frontal gyrus (MFG; Fig. 1).They may be implemented with either auditory or visual language stimuli and use block designs. Semantic verbal fluency tasks include generating words that belong to a category, such as 'animals' or 'food' over a block of time, or generating verbs in response to presented nouns, such as 'hit, throw or catch' in response to 'ball.' Phonemic verbal fluency involves generating a list of words beginning with a specified letter such as C, L, or F. All verbal fluency tasks activate the same frontal areas IFG and MFG (BA 44,45,9,46) (Bahn et al. 1997; Fitzgerald et al. 1997; Hertz-Pannier et al. 1997; Stapleton et al. 1997; Grandin et al. 1998; Yetkin et al. 1998; Benson et al. 1999; Lehericy et al. 2000). These tasks are performed silently to minimize motion and are thus unmonitored. Semantic decision tasks have also been used effectively and identify dorsolateral prefrontal cortex (BA 47, 46, 9) (Demb et al. 1995; Binder et al. 1996). They are designed to monitor patient performance by requiring a yes or no decision via a push button response. Examples include determining whether word pairs are abstract or concrete (e.g. love and empathy or stone and snail), or whether a word fits into a category (is the item 'cow' found in the United States and used by humans). These two tasks employ control tasks that require decisions based on non-linguistic stimuli: matching character strings, and identifying a series of tones, respectively. Both verbal fluency and semantic de-
cision tasks show excellent agreement with the intra-carotid amytal test (IAT; Demb et al. 1995; Binder et al. 1996; Hertz-Pannier et al. 1997; Stapleton et al. 1997; Yetkin et al. 1998; Benson et al. 1999; Lehericy et al, 2000). These tasks, however, are relatively poor identifiers of temporal language areas in individual subjects, mostly because the auditory or visual clue is a single word. Some, but inconstant, activation can be seen in temporal cortex. Tasks that require listening to a text or reading sentences are reliable identifiers of temporal 'receptive' language cortex (Fig. 1). Listening to stories is the most commonly used paradigm (Muller et al. 1998; Schlosser et al. 1999; Gaillard et al. 2000c; Lehericy et al. 2000). When coupled with some form of semantic retrieval, frontal activation is also seen. For example, an auditory response naming task requires listening to a sentence that describes an object then silently named: 'What is a long yellow fruit?'; answer 'banana' (Bookheimer et al. 1997; Hunter et al. 1999; Gaillard et al. 2000c). Different auditory controls may be used: a series of tones (Binder 1996), unfamiliar languages (Tamil or Turkish; Mazoyer et al. 1993; Schlosser et al. 1998, 1999), or the task played backwards (Bookheimer et al. 1997; Lehericy et al. 2000). An auditory control is necessary to reduce bilateral activation due to primary and second-order auditory processing. As a result, the use ofthe auditory control enhances the laterality index, but may lower the overall number of patients with activation as some patients may discern speech in the gibberish. Reading text based paradigms is a strong activator of middle and superior temporal cortex, and also evokes MFG and sometimes IFG even in the absence of a semantic decision (Just et al. 1996; Bavalier et al. 1997; Gaillard et al. 2001b) (Fig. 1). In these tasks subjects either read a story or perform a reading version of the auditory response task described above compared to viewing dots or a cross hair; they are very strongly and consistently lateralized (Gaillard et al. 2000a, 200 1b). Studies using single word reading (without requiring a semantic decision), object naming, or repetition, have not proved useful on an individual basis for patients (Benson et al. 1999; Lehericy et
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a1. 2000). This is unfortunate as most electrocortical stimulation and IAT procedures rely heavily on object naming tasks. As they do not directly compare the same tasks, direct comparison between IAT and fMRI is problematic. Most comparison studies between IAT and fMRI for identifying hemispheric dominance for language show excellent agreement. These studies have included several patients with right and mixed dominance. However, many investigators find partial disagreement in about 5% of cases, where one modality shows unilateral language dominance in one, the other method bilateral language representation. It is difficult to know which method is better, as both have known methodological and technical limitations and the same tasks are not directly comparable. There also have been too few reports from anyone center including mixed results to analyze the discrepancies in a meaningful way. There are two reports of discordant functional studies with IAT; in both instances the imaging study correctly identified language areas. We have also successfully performed fMRI when patients had aberrant vascular supply that precluded successful IAT or did not tolerate the lAT.Yet there are other instances (see below) where fMRI may provide falsely localizing information. We have also had a patient who became claustrophobic for fMRI but who tolerated IAT. There are few studies that have directly compared localization oflanguage function using PET (Bookheimer et a1. 1997a) or fMRI (Fitzgerald et a1. 1997; Ruge et a1. 1999; Lurito et a1. 2000) to electrocortica1 stimulation. They find excellent but not complete agreement between the two modalities. The activation seen during functional studies is the same area, within 5-8 mm, disrupted by cortical stimulation. These are the only studies that have validated the basis of functional imaging approaches for mapping cognitive networks. There is a small error in co-registration programs and a few mm difference may be accounted for by draining vein activation. Not all areas activated can be tested by stimulation with either grids or intra-operative corticography; fMRI can also identify language areas in a sulcus not typically stimulated through grids (Rutten et a1. 1999). More impor-
tantly, not all areas activated during functional imaging paradigms are necessarily critical to language function (for example the common identification ofcingulate and supplementary motor cortex in most language tasks), and not all critical areas are identified by functional imaging paradigms. Motion, poor patient performance, poor paradigm design, or not being able to elicit the hemodynamic response may affect activation maps. Furthermore, any single paradigm is unlikely to encompass the many varied aspects of language processing. Although the correlation between functional imaging and either IAT or electrocortical stimulation is excellent, there are circumstances when false localization information is obtained. It is important to recall that even when tasks are strongly lateralized the non-dominant hemisphere still exhibits 10-30% of activation. When tumors are large the mass effect and edema may alter and obscure the hemodynamic response and the typical nondominant activation may be falsely interpreted (Bookheimer et a1. 1997b; Gaillard et a1. 2000a). AVMs may also result in a vascular steel that also obscures the BOLD response. Thus, null activation must be cautiously interpreted (Gaillard et a1. 2000a). Negative studies, or atypical results, should be confirmed by repeat studies or by other means. It is important to make sure the patient can perform the task, and when in-scanner monitoring of performance is not possible, that some form of post or pre task performance is obtained. When there is disagreement between functional imaging and IAT it is difficult to know which is correct. For most patients there is good agreement; and fMRI may be used to determine the dominant hemisphere for language in most patients when a panel of tasks is used (Fig. 1). Further investigation is necessary to understand the few instances of disagreement.
Memory mapping For epilepsy populations about to undergo temporallobe surgery the capacity for the hippocampus to sustain memory is clinically important. Little is known, and no imaging studies have been per-
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formed, that examine working memory systems in epilepsy populations. The integrity of the hippocampal formation to sustain memory has been much more difficult to assess than language. It is difficult to assess hippocampal function because the high 'resting' hippocampal activity and 'resting' blood flow make it difficult to achieve a contrast between paradigm conditions. Most memory studies successful in activating hippocampus and parahippocampal areas have been performed in small populations and analyzed using group methods to enhance signal over noise (Stern et a1. 1996; Gabrielli et al. 1997: Brewer et ai. 1998). One study in epilepsy patients using group analysis methods compared activation between right and left temporal lobe epilepsy groups taking advantage of passive verbal encoding during an auditory semantic decision task described above (Binder et al. 1996; Bellgowan et al. 1998). This study found right temporal lobe patients activated middle left hippocampus and parahippocampal gyrus but found no activation in this region in the left temporal group. Task performance was comparable suggesting that the left TLE group maintained the capacity to perform the task. Two studies have identified hippocampal activation in individual epilepsy patients; both relied on viewing complex images (Detre et al. 1998; Bellgowan et al. 2000). In one study, ten patients explicitly memorized complex visual scenes; during the control task patients viewed blurred images (Detre et al. 1998). The other study used an implicit memory design involving 28 patients and 70 normal volunteers. Participants determined whether a complex picture represented an indoor scene; during the control task subjects compared matching scattergram images. Both tasks activate bilateral hippocampus and parahipppocampal areas and likely include visual and verbal memory from verbal encoding of visual features. Currently employed fMRI tasks do not distinguish types of memory that may be preferentially mediated by one hippocampus over another. The laterality index of hippocampal activation in both studies had good but incomplete correlation (70-80%) with IAT memory laterality; the agreement is not as strong as for language studies. Preliminary evidence also sug-
gests ipsilateral hippocampal activation may predict postoperative memory performance (Cassanto et al. 2001). Although both tasks are compared to the lAT as the general standard, the lAT also has known limitations when assessing memory . Techniques designed to improve imaging of mesial temporal structures and event related design that allows independent analysis of items poorly or well recalled, may enhance memory studies conducted on individual patients (Wagner et al. 1998; Constable et al. 2000). fMRI memory paradigms are not yet reliable tools to assess memory integrity but advances in memory assessment are likely to occur in the next few years.
Ictal and interictal mapping Blood flow studies comparing ictal and interictal perfusion patterns using SPECT are useful for identifying the ictal focus in temporal and extratemporal lobe epilepsy. Thus it is not surprising that fMRI BOLD studies can identify the ictal source. Furthermore fMRl provides a temporal resolution that can sometimes be used to examine the propagation of ictal activity (Jackson et al. 1994). Unfortunately, fMRI ictal studies are rare; they have occurred in patients who serendipitously had a seizure in the scanner, allowing post hoc analysis, or had frequent seizures that could be clinically identified to assist MRI data analysis (Jackson et al. 1994; Detre et al. 1995; Schwartz et al. 1998; Kubota et al. 2000). One child had Rasmussen's encephalitis and frequent facial motor seizures that could be clinically identified, one teenager had dysplastic cleft in sensory motor cortex, and an adult had a glioma. A condition for all ictal studies is that the seizures caused little movement to distort images. Thus, fMRl can be used to identify the ictal source, but it is rare and impracticable. The location of interictal spike activity is easier to achieve with fMRl. Event related paradigms may be used to identify the perfusion changes associated with interictal activity (Seeck et al. 1998; Krakow et a1. 1999,2001; Symms et al. 1999). Event related paradigms take advantage ofthe temporal delay in signal change associated with a brief
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event, such an EEG interictal EEG spike. The EEG is monitored while subjects are in the scanner. As the peak BOLD response is 4-8 s after the physiological event, the EEG is screened to identify interictal spikes and the data is acquired after a spike is seen. The signal change following a spike is compared to epochs with quiet EEG. Approximately 50 events are required, so patients must have frequent spikes (Krakow et al. 1999). Approximately 30% individual spikes elicit a BOLD response (Krakow et al. 2001). Sixty percent of patients will show regional increase in signal. Interictal fMRI methods appear reliable and replicable and may be used to identify activity at the margin ofmass lesions, in dysplastic cortex, in mesial temporallobe (mesial temporal sclerosis), and in structurally normal brain (Krakow et al. 1999). The clinical utility depends upon the relationship of interictal activity to the seizure focus.
Summary
fMRI may be used to identify the ictal source, but such events are uncommon. More promising is the use of fMRI to identify regional specific changes in blood flow associated with interictal activity. The greatest use of fMRI, however, is to identify what is to be spared in the evaluation of patients for epilepsy. Memory studies are in their infancy but are promising. Language paradigms are reliable for language lateralization in most patients, and can be used as a guide for localization in planning surgery. It appears best to use a panel of task paradigms. fMRllanguage studies should be interpreted cautiously. Atypical or null studies should be repeated or confirmed by other means.
Acknowledgeme nts
Many thanks to Lyn Balsamo and Ben Xu, and to Suzanne Reigle for assistance in preparing the manuscript. Supported by NTNDS K08-NS 1663,the Epilepsy Research Branch, and a grant form the Board of Lady Visitors, Children's National Medical Center.
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Chapter 52
tMRI and the evaluation of patients with epilepsy William Davis Gaillard Comprehensive Pediatric Epilepsy Program, The Children's National Medical Center, Washington, DC (USA) The Epilepsy Research Branch, NINDS, NIH, Bethesda, MD (USA)
Functional imaging plays an increasingly important role in the evaluation of patients with localization related epilepsy. The clinical application of fMRI to the evaluation of epilepsy patients mostly focuses on identifying brain areas to be spared during surgery because they hold eloquent function. Such methods are applied principally to motor and language cortex, and, more recently, to memory function. fMRI has also been used to identify the seizures focus in a few patients, but not as successfully as interictal PET and interictallictal SPECT. The discussion which follows primarily regards fMRI but may also be applied to 150- water-PET as the principles and practical applications in epilepsy populations are similar. PET is limited by the number of injections that can be used for cognitive mapping, and is usually analyzed with group, rather than individual, methods. Newer scanners, however, allow reliable single subject studies. PET is a better marker of capillary flow than blood oxygen level dependent (BOLD) fMRI which derives much ofits signal from draining veins (see below). PET is less sensitive to motion, and can be used in patients who can not enter the MRI environment. Unlike PET, fMRI is not restricted by radiation exposure; as a consequence more paradigms can be studied, and failed studies may be more easily
* Correspondence to: Prof. W.D. Gaillard, The Epilepsy Research Branch, NINDS, NIH, Bethesda, MD, USA. E-mail: [email protected]
repeated. fMRI also has superior signal to noise, spatial, and temporal resolution. Functional MRI (fMRI) using the BOLD technique is an indirect and relative, not absolute, measure ofneuronal activity that occurs during synaptic activity along dendrites (Logothetis et al. 2001). It relies upon detecting alterations in blood flow that follow, by several seconds, regionally specific increases in brain activity associated with task performance (Cohen and Bookheimer 1994). Most BOLD signal derives from hemoglobin (Hgb) which has a different MR signal when oxygenated compared to the deoxygenated state. In the 'activated' state there is a regionally restricted luxury hyperperfusion and concomitant increase in oxyHgb/deoxyHgb ratio in turn detected by fMRI. The temporal resolution offMRI is 2-4 s as there is a delay in the physiologic hemodynamic response to the experimental stimulus (Malonek et al. 1997). The spatial resolution is usually 4-8 mm, though 1-2 mm can be achieved. The temporal resolution is superior to PET, but considerably less than neuronal propagation times; thus, fMRI identifies the neural network involved in cognitive processes but not the regional sequence of activation. BOLD fMRI detects the relative change in signal that occurs between at least two conditions, an experimental and control condition. Arterial spin tagging allows quantitative measure of capillary blood flow, but has not been widely applied (Ye et al. 1998; Lia et al. 2000).
342
Most studies employ a block design alternating between a control or rest condition, and an experimental or task condition. Blocks vary in duration from 20-40 s. For these reasons it is imperative that patients can perform the task, and that the control condition is carefully designed so as not to obscure activation. This is particularly problematic when control conditions for language processing involve a language task. For example, comparing reading words to pseudowords may not identify language processing regions because the neural networks that decode written words are also used, especially by unskilled readers, to process pseudowords (Gaillard et al. 2000a; Tagamets et al. 2000). After data acquisition data is corrected for motion and can be analyzed by any number of methods: (1) parametric measures, including the general linear model ofstatistical parametric mapping (SPM; Buchel et al. 1998; Friston et al. 1999); (2) nonparametric tests (Cohen etal. 1994) ofsignal change between conditions; or (3) cross correlation analysis between the experimental signal time course and an ideal wave form (Banditini et al. 1993). These methods yield similar results. The threshold deemed significant for individual as well as group studies is arbitrary and may be affected by patient motion, task performance, positioning in the scanner, and other technical considerations (Gaillard et al. 2001a). Most experimental data sets are analyzed by group means and displayed in a standard template, such as the Talairach and Tournoux atlas (1988). However, such an approach is impracticable for patient populations where heterogeneity is the rule (Steinmetz and Rudiger 1991; Gaillard et al. 2001a). This is a particularly important consideration for language mapping where atypical language representation is common (Rasmussen et al. 1977; Ojemann et al. 1989). Group maps can be used as a standard to which individual activation maps may be compared.
Sensory and motor mapping Motor and sensory mapping result in the most robust hemodynamic response, about 3-5% at 1.5 T, compared 1--2% for cognitive tasks. Tapping
fingers, wiggling tongues or tapping toes, compared to rest, identify the primary motor cortex; brushing the face, hand or foot for sensory, compared to rest, identifies the somatosensory cortex (Kim et al. 1993; Rao et al. 1993, 1995; Hammeke et al. 1994; Lotze et al. 2000). The central sulcus can be identified by using these tasks. Complicated hand movements can be used to identify supplementary motor cortex (Rao et al. 1993). Although used in patients with extratemporallobe epilepsy, these tasks are most commonly reported in patients undergoing resection of tumors (Jack et al. 1994; Yoursey et al. 1995; Atlas et al. 1996; Chapman et al. 1996; Kahn et al. 1996; Righini et al. 1996; Stapleton et al. 1997; Pujol et al. 1998; Schulder et al. 1998; Achten et al. 1999) or vascular malformations (Jack et al. 1994; Latchaw et al. 1995; Yoursey et al. 1995; Chapman et al. 1996; Muelleret al. 1996; Schad et al. 1996; Schlosser et al. 1997; Pujol et al. 1998; Maldjian et al. 1999). The primary visual cortex can be identified with a photic flash (Belliveau et al. 1991; Kwong et al. 1992), and the primary auditory cortex identified by listening to tones (Binder et al. 1994), but such information is rarely used in epilepsy surgery. Motor mapping with fMRl has been confirmed in comparison to evoked response potentials and by cortical stimulation in humans (Puce et al. 1995; Fitzgerald et al. 1997). Agreement between BOLD fMRI and electrocortical stimulation is within 3-5 mm.
Language mapping fMRI is most widely used to identify the dominant hemisphere for language and also the location language processing areas. PET and fMRI have been used in several group averaged studies to identify the anatomic location of receptive and expressive language functions (Peterson et al. 1989; Wise et al. 1991; Howard et al. 1992; Desmond et al. 1995; Binder et al. 1995; Schlosser et al. 1998; Poldrack et al. 1999; Gaillard et al. 2000b, 2001b). These paradigms have been adapted for individual patient studies, in adults and in children as young as 7 years. Data sets are evaluated with a region of interest approach, in order to determine the number
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Fig. 1. tMRI study of a 19-year-old with right temporal lobe dysplasia and right temporal lobe epilepsy. Four tasks are performed: (I) auditory response naming (ARN; clue: 'what is a long yellow fruit,' silent answer 'banana '), compared to rest; (2) read response naming (RRN; the reading version or ARN) compared to viewing a dot pattern; (3) verbal fluency, silently generating words beginning with letters (C, L, F, P, R, W) to letters compared to rest, and (4) fable, reading a series of fables compared to viewing dots. Studies used a 6-cycle block design and were covert and unmonitored. Right image is right brain. All studies confirm left language dominance. Note consistent activation in inferior left MFG, left MFG, and left middle/superior temporal gyrus. The auditory task shows greater bilateral temporal activation (but greater on the left) because an auditory control condition was not used. This study is typical of patients and normal volunteers with left language dominance.
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of activated voxels in each hemisphere or in selected sub-regions, Regional voxel counts are then used to calculate an asymmetry index (AI) that quantitates the degree of regional laterality for task: AI =L- R/L + R; AI > 0.20 left hemisphere dominant; AI <-0.02 right hemisphere dominant, -0.20 < AI < 0.20 bilateral or mixed dominance (Binder et al. 1996; Hertz-Pannier et al. 1997; Yetkin et al. 1998; Benson et al. 1999; Springer et al. 1999; Lehericy et al. 2000). Most investigators find a need to explore different thresholds on some individual patients (Binder et al. 1996; Hertz-Pannier et al. 1997). Paradigms that require verbal fluency or a semantic decision are reliable identifiers of the anterior, 'expressive' language areas: the inferior frontal gyrus (IFG) and middle frontal gyrus (MFG; Fig. 1).They may be implemented with either auditory or visual language stimuli and use block designs. Semantic verbal fluency tasks include generating words that belong to a category, such as 'animals' or 'food' over a block of time, or generating verbs in response to presented nouns, such as 'hit, throw or catch' in response to 'ball.' Phonemic verbal fluency involves generating a list of words beginning with a specified letter such as C, L, or F. All verbal fluency tasks activate the same frontal areas IFG and MFG (BA 44,45,9,46) (Bahn et al. 1997; Fitzgerald et al. 1997; Hertz-Pannier et al. 1997; Stapleton et al. 1997; Grandin et al. 1998; Yetkin et al. 1998; Benson et al. 1999; Lehericy et al. 2000). These tasks are performed silently to minimize motion and are thus unmonitored. Semantic decision tasks have also been used effectively and identify dorsolateral prefrontal cortex (BA 47, 46, 9) (Demb et al. 1995; Binder et al. 1996). They are designed to monitor patient performance by requiring a yes or no decision via a push button response. Examples include determining whether word pairs are abstract or concrete (e.g. love and empathy or stone and snail), or whether a word fits into a category (is the item 'cow' found in the United States and used by humans). These two tasks employ control tasks that require decisions based on non-linguistic stimuli: matching character strings, and identifying a series of tones, respectively. Both verbal fluency and semantic de-
cision tasks show excellent agreement with the intra-carotid amytal test (IAT; Demb et al. 1995; Binder et al. 1996; Hertz-Pannier et al. 1997; Stapleton et al. 1997; Yetkin et al. 1998; Benson et al. 1999; Lehericy et al, 2000). These tasks, however, are relatively poor identifiers of temporal language areas in individual subjects, mostly because the auditory or visual clue is a single word. Some, but inconstant, activation can be seen in temporal cortex. Tasks that require listening to a text or reading sentences are reliable identifiers of temporal 'receptive' language cortex (Fig. 1). Listening to stories is the most commonly used paradigm (Muller et al. 1998; Schlosser et al. 1999; Gaillard et al. 2000c; Lehericy et al. 2000). When coupled with some form of semantic retrieval, frontal activation is also seen. For example, an auditory response naming task requires listening to a sentence that describes an object then silently named: 'What is a long yellow fruit?'; answer 'banana' (Bookheimer et al. 1997; Hunter et al. 1999; Gaillard et al. 2000c). Different auditory controls may be used: a series of tones (Binder 1996), unfamiliar languages (Tamil or Turkish; Mazoyer et al. 1993; Schlosser et al. 1998, 1999), or the task played backwards (Bookheimer et al. 1997; Lehericy et al. 2000). An auditory control is necessary to reduce bilateral activation due to primary and second-order auditory processing. As a result, the use ofthe auditory control enhances the laterality index, but may lower the overall number of patients with activation as some patients may discern speech in the gibberish. Reading text based paradigms is a strong activator of middle and superior temporal cortex, and also evokes MFG and sometimes IFG even in the absence of a semantic decision (Just et al. 1996; Bavalier et al. 1997; Gaillard et al. 2001b) (Fig. 1). In these tasks subjects either read a story or perform a reading version of the auditory response task described above compared to viewing dots or a cross hair; they are very strongly and consistently lateralized (Gaillard et al. 2000a, 200 1b). Studies using single word reading (without requiring a semantic decision), object naming, or repetition, have not proved useful on an individual basis for patients (Benson et al. 1999; Lehericy et
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a1. 2000). This is unfortunate as most electrocortical stimulation and IAT procedures rely heavily on object naming tasks. As they do not directly compare the same tasks, direct comparison between IAT and fMRI is problematic. Most comparison studies between IAT and fMRI for identifying hemispheric dominance for language show excellent agreement. These studies have included several patients with right and mixed dominance. However, many investigators find partial disagreement in about 5% of cases, where one modality shows unilateral language dominance in one, the other method bilateral language representation. It is difficult to know which method is better, as both have known methodological and technical limitations and the same tasks are not directly comparable. There also have been too few reports from anyone center including mixed results to analyze the discrepancies in a meaningful way. There are two reports of discordant functional studies with IAT; in both instances the imaging study correctly identified language areas. We have also successfully performed fMRI when patients had aberrant vascular supply that precluded successful IAT or did not tolerate the lAT.Yet there are other instances (see below) where fMRI may provide falsely localizing information. We have also had a patient who became claustrophobic for fMRI but who tolerated IAT. There are few studies that have directly compared localization oflanguage function using PET (Bookheimer et a1. 1997a) or fMRI (Fitzgerald et a1. 1997; Ruge et a1. 1999; Lurito et a1. 2000) to electrocortica1 stimulation. They find excellent but not complete agreement between the two modalities. The activation seen during functional studies is the same area, within 5-8 mm, disrupted by cortical stimulation. These are the only studies that have validated the basis of functional imaging approaches for mapping cognitive networks. There is a small error in co-registration programs and a few mm difference may be accounted for by draining vein activation. Not all areas activated can be tested by stimulation with either grids or intra-operative corticography; fMRI can also identify language areas in a sulcus not typically stimulated through grids (Rutten et a1. 1999). More impor-
tantly, not all areas activated during functional imaging paradigms are necessarily critical to language function (for example the common identification ofcingulate and supplementary motor cortex in most language tasks), and not all critical areas are identified by functional imaging paradigms. Motion, poor patient performance, poor paradigm design, or not being able to elicit the hemodynamic response may affect activation maps. Furthermore, any single paradigm is unlikely to encompass the many varied aspects of language processing. Although the correlation between functional imaging and either IAT or electrocortical stimulation is excellent, there are circumstances when false localization information is obtained. It is important to recall that even when tasks are strongly lateralized the non-dominant hemisphere still exhibits 10-30% of activation. When tumors are large the mass effect and edema may alter and obscure the hemodynamic response and the typical nondominant activation may be falsely interpreted (Bookheimer et a1. 1997b; Gaillard et a1. 2000a). AVMs may also result in a vascular steel that also obscures the BOLD response. Thus, null activation must be cautiously interpreted (Gaillard et a1. 2000a). Negative studies, or atypical results, should be confirmed by repeat studies or by other means. It is important to make sure the patient can perform the task, and when in-scanner monitoring of performance is not possible, that some form of post or pre task performance is obtained. When there is disagreement between functional imaging and IAT it is difficult to know which is correct. For most patients there is good agreement; and fMRI may be used to determine the dominant hemisphere for language in most patients when a panel of tasks is used (Fig. 1). Further investigation is necessary to understand the few instances of disagreement.
Memory mapping For epilepsy populations about to undergo temporallobe surgery the capacity for the hippocampus to sustain memory is clinically important. Little is known, and no imaging studies have been per-
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formed, that examine working memory systems in epilepsy populations. The integrity of the hippocampal formation to sustain memory has been much more difficult to assess than language. It is difficult to assess hippocampal function because the high 'resting' hippocampal activity and 'resting' blood flow make it difficult to achieve a contrast between paradigm conditions. Most memory studies successful in activating hippocampus and parahippocampal areas have been performed in small populations and analyzed using group methods to enhance signal over noise (Stern et a1. 1996; Gabrielli et al. 1997: Brewer et ai. 1998). One study in epilepsy patients using group analysis methods compared activation between right and left temporal lobe epilepsy groups taking advantage of passive verbal encoding during an auditory semantic decision task described above (Binder et al. 1996; Bellgowan et al. 1998). This study found right temporal lobe patients activated middle left hippocampus and parahippocampal gyrus but found no activation in this region in the left temporal group. Task performance was comparable suggesting that the left TLE group maintained the capacity to perform the task. Two studies have identified hippocampal activation in individual epilepsy patients; both relied on viewing complex images (Detre et al. 1998; Bellgowan et al. 2000). In one study, ten patients explicitly memorized complex visual scenes; during the control task patients viewed blurred images (Detre et al. 1998). The other study used an implicit memory design involving 28 patients and 70 normal volunteers. Participants determined whether a complex picture represented an indoor scene; during the control task subjects compared matching scattergram images. Both tasks activate bilateral hippocampus and parahipppocampal areas and likely include visual and verbal memory from verbal encoding of visual features. Currently employed fMRI tasks do not distinguish types of memory that may be preferentially mediated by one hippocampus over another. The laterality index of hippocampal activation in both studies had good but incomplete correlation (70-80%) with IAT memory laterality; the agreement is not as strong as for language studies. Preliminary evidence also sug-
gests ipsilateral hippocampal activation may predict postoperative memory performance (Cassanto et al. 2001). Although both tasks are compared to the lAT as the general standard, the lAT also has known limitations when assessing memory . Techniques designed to improve imaging of mesial temporal structures and event related design that allows independent analysis of items poorly or well recalled, may enhance memory studies conducted on individual patients (Wagner et al. 1998; Constable et al. 2000). fMRI memory paradigms are not yet reliable tools to assess memory integrity but advances in memory assessment are likely to occur in the next few years.
Ictal and interictal mapping Blood flow studies comparing ictal and interictal perfusion patterns using SPECT are useful for identifying the ictal focus in temporal and extratemporal lobe epilepsy. Thus it is not surprising that fMRI BOLD studies can identify the ictal source. Furthermore fMRl provides a temporal resolution that can sometimes be used to examine the propagation of ictal activity (Jackson et al. 1994). Unfortunately, fMRI ictal studies are rare; they have occurred in patients who serendipitously had a seizure in the scanner, allowing post hoc analysis, or had frequent seizures that could be clinically identified to assist MRI data analysis (Jackson et al. 1994; Detre et al. 1995; Schwartz et al. 1998; Kubota et al. 2000). One child had Rasmussen's encephalitis and frequent facial motor seizures that could be clinically identified, one teenager had dysplastic cleft in sensory motor cortex, and an adult had a glioma. A condition for all ictal studies is that the seizures caused little movement to distort images. Thus, fMRl can be used to identify the ictal source, but it is rare and impracticable. The location of interictal spike activity is easier to achieve with fMRl. Event related paradigms may be used to identify the perfusion changes associated with interictal activity (Seeck et al. 1998; Krakow et a1. 1999,2001; Symms et al. 1999). Event related paradigms take advantage ofthe temporal delay in signal change associated with a brief
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event, such an EEG interictal EEG spike. The EEG is monitored while subjects are in the scanner. As the peak BOLD response is 4-8 s after the physiological event, the EEG is screened to identify interictal spikes and the data is acquired after a spike is seen. The signal change following a spike is compared to epochs with quiet EEG. Approximately 50 events are required, so patients must have frequent spikes (Krakow et al. 1999). Approximately 30% individual spikes elicit a BOLD response (Krakow et al. 2001). Sixty percent of patients will show regional increase in signal. Interictal fMRI methods appear reliable and replicable and may be used to identify activity at the margin ofmass lesions, in dysplastic cortex, in mesial temporallobe (mesial temporal sclerosis), and in structurally normal brain (Krakow et al. 1999). The clinical utility depends upon the relationship of interictal activity to the seizure focus.
Summary
fMRI may be used to identify the ictal source, but such events are uncommon. More promising is the use of fMRI to identify regional specific changes in blood flow associated with interictal activity. The greatest use of fMRI, however, is to identify what is to be spared in the evaluation of patients for epilepsy. Memory studies are in their infancy but are promising. Language paradigms are reliable for language lateralization in most patients, and can be used as a guide for localization in planning surgery. It appears best to use a panel of task paradigms. fMRllanguage studies should be interpreted cautiously. Atypical or null studies should be repeated or confirmed by other means.
Acknowledgeme nts
Many thanks to Lyn Balsamo and Ben Xu, and to Suzanne Reigle for assistance in preparing the manuscript. Supported by NTNDS K08-NS 1663,the Epilepsy Research Branch, and a grant form the Board of Lady Visitors, Children's National Medical Center.
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