However, it is crucial to note the mathematical assumptions and caveats underlying the VBM approach. Broadly speaking, the notion of intersubject spatial normalization is inherently problem- atic ( 27 ), given the morphometric (especially gyral) variations between individu als. At best, one may assume that there are mini- mal differences in the brains of mesial T LE patients, but those of other groups of patients with focal epilepsy may be even more het - erogeneous. Even within individuals, normalization accuracy is likely to vary between bra in regions, being poorer in more highly convoluted areas of cortex. Furthermore, although t he preprocess- ing of images is largely automated, there is latitude for the experi- menter to vary the method of brain segmentation; the kernel size during spatial smoothing; inters ubject spatial normalization; and the \201 nal methods of statistical analysis. These fac tors likely result in var- ying statistical sensitivity across the brain ( 23 , 28 ), and u nderlie the inconsistencies across studies. Consequently, although VBM remains popular in b asic and clinical neuroscience, it has had very limited application in clinical decision-ma king. In the future, it may be pos- sible to improve speci \201 city of VBM by using large control groups, and by looking for overlapping or coincident abnormalities in the same bra in region with more than one imaging modality ( 29 ). Identi \201 cation of local abnormalities The main applications of DTI in epilepsy are two fold: \201 rst, to iden- tify local abnormalities in the epileptogenic zone; and, second, to identify white matter tracts. With regards to the \201 rst aim, the assumption is tha t diffusion abnormalities will re \202 ect a deranged microstructural arrangement of cereb ral tissue and thus help local- ize epileptic foci in patients with unremarkable structural scans. DTI studies have been conducted in patients following status epi- lepticus or singl e seizures ( 33 \200\22336 ), as well as in the interictal period \200\224 overall, these studies have shown that DTI may indeed confer additional sensitivity over conventional MRI in the identi \201 - cation of occult structural abnormalities ( 37 \200\22339 ). Diffusion tensor imaging and tractography In a routine MRI, the contribution of diffusion o r Brownian motion on the overall signal intensity is relatively small (causing a signal att enuation of <2 % ). However, by incorporating pulsed oxford textbook of epilepsy and epileptic seizures 112 to the central voxel by assessing their diffusion properties, speci \201 - cally with rega rds to their shape (quantitative diffusion anisotropy measures) and orientation (principal eigenvector map) ( 42 ). However, the correlation between diffusion abnormalities and seizure localization with EEG has yielded discrepant \201 ndings ( 40 , 41 ). Broadly speaking, the issue with many of these studies is that they contain only a small number of patients and utilize various meth ods of analysis, which make it dif \201 cult to compare their results. Furthermore, those studies that have examined patients in the immediate postictal period have included patient s who had had varying seizure durations and intervals from seizure to scan; factors which w ould have clearly affected the nature and degree of diffusivity changes. In epilepsy, tractography has been used: ( 1 ) to assess the patho- physiology of chronic e pilepsy on white matter tracts; ( 2 ) to investi- gate the effect of TLE on the reorganizat ion of language function; ( 3 ) to evaluate the structural changes caused by surgery; and ( 4 ) to pre- dict the effects of surgery ( 43 ). Clinically, tractographic data, in com- bi nation with functional activation studies, could potentially guide surgical procedures by d elineating areas of eloquent cortex and prin- cipal white matter connections ( 44 \200\2234 7 ). As an example, one study measured the volume of tracts connected with a frontal lobe s peech region identi \201 ed using fMRI, which allowed the authors to predict the severity of naming de \201 cits after temporal lobe surgery ( 48 ). Similarly, another study showed that damage to the DTI-identi \201 ed tract corresponding to the loop of Meyer correlated with postopera- tive \201 eld defects in mesial TLE (MTLE) patients ( 49 ). The promise of tractography in the future would be to identify the white matter connections that need t o be transected to functionally isolate the sei- zure focus, which may reduce the risks of surgical complications. Tractography A second application of DTI is tractography, which ultimately aims to infer th e structural connectivity between different regions of the brain (Fig. 10.3 ). Tractography is based on the principle that water molecules diffuse along a path parallel, rather than perpendicular, to those of the myelinated nerve \201 bre tracts which contain them. Speci \201 cally, directional information obtained in each voxel is used to generate virtual, t hree-dimensional white matter maps. Each of the surrounding voxels is then considered in tu rn for connection Fig. 10.3 (Also see Color plate 6.) Tractography of the optic radiations in a patient who u nderwent resection of a cavernoma located in the right parieto-occipital cortex. A) Diffusi on-weighted images with 30 directions were acquired and co-registered to the patient \200 \231s MPRAGE, with color fractional anisotropy (FA) corresponding to tensor orientations. B ) Tractography was incorporated into a Stealth neuronavigation system for the operative pro cedure. The optic radiations are indicated in yellow. C) A zoomed region of interest from t he splenium of the corpus callosum is displayed, with the individual superquadratic glyphs from each voxel indicating principal orientation. Each glyph incorporates directional infor mation (blue = inferior/superior; green = anterior \200\223posterior; red = left \200\223ri ght). These orientations are useful in reviewing the quality of tractography results. Repro duced with permission of Simon Vogrin. CHAPTER 10 neuroimaging in the investigation of epilepsy 113 SPECTs, and current data indeed re \202 ect this prediction. Speci \201 cally, studies on patients with TLE have shown sensitivities of between 73 \200\22397 % for ictal SPECTs, co mpared to around 50 % for interictal SPECTs ( 64 \200\22367 ). In some cases, the re-evalua tion of MRI prompted by an abnormal SPECT result has revealed a subtle structural lesion. D espite the promising data for ictal SPECTs in TLE, it is worth noting that the sensitivity of ictal SPECTs appears to be lower with in patients with extratemporal seizure foci ( 66 % ), but fewer data are available ( 66 , 68 ). However, several issues currently limit the more widespread application of tractography. Fr om a practical point of view, DTI and tractography are currently very time-consuming proces ses but, with increases in computing power, this should become less of an issue. Another pr oblem is methodological: typically, the size of a single voxel is 2 \200\2233 mm 3 , a volu me which contains thousands of axons. Most methods assume that \201 bres at each voxel ar e ade- quately described by a single orientation estimate, but the com- plexity of subcorti cal white matter tracts, particularly at points of \201 bre kissing or crossing, may vary between individuals. In recent times, newer algorithms ( 50 ) and diffusion models ( 51 \200\22354 ) have been developed in an attempt to overcome these problems, and improvements in orientation ( 55 ) and spatial resolution ( 56 ) should see advances in this area in th e near future. Nevertheless, it is in principle challenging to validate tractographic metho ds, as prior anatomical knowledge is required to con \201 rm trajectories ( 57 \200\22359 ). It should also be remembered that tractography cannot at present distinguish between aff erent and efferent pathways. Subtraction SPECT In order to maximize the yield of a SPECT study, the pattern of intericta l activity can be subtracted from that of ictal activity ( \200\230sub- traction SPECT \200 \231) to reveal foci of hyperperfusion during the time of the seizure (Fig. 10.4 ). An alte rnative approach is to compare the activity on an ictal SPECT image to that of a control da tabase. These subtraction images can then be co-registered with high-res- olution structura l images on MRI ( \200\230subtraction ictal SPECT coreg- istered to MRI \200\231, SISCOM), which further improves our ability to localize the epileptogenic focus ( 69 \200\22374 ). I n fact, current data show that the SISCOM technique has an impressive positive predictive v alue for surgical outcome if the hyperperfused area is fully resected ( 73 \200\22375 ). In one study, 75 % of patients whose SISCOM \201 ndings fell within the margins of the rese cted tissue or in the disconnected hemisphere were seizure-free following surgery. All (100 % ) of those whose SISCOM \201 ndings fell outside the margins of surgery continued to h ave seizures ( 76 ). It is worth noting, however, that, although SISCOM is a strong predict or of surgical outcome, its relative advantage to other methods (such as MRI or intracrania l EEG) is still debatable (the role of SISCOM in large case series are described in ( 70 , 77 )). Limitations The main practical dif \201 culty of acquiring an accurate ictal SPECT relates to its poor temporal resolution. The value of an ictal SPECT is heavily contingent on the timing of radiocontrast administration due to the rapid propagation of seizure activ ity from the original focus to adjacent areas, and the accompanying rapidly evolving haemod ynamic changes ( 78 ).Speci \201 cally, in temporal lobe epi- lepsy, the initial ictal hyp erperfusion of the mesial and anterotem- poral temporal lobes occurs immediately after seiz ure onset ( 79 ). However, within 1 \200\2232 minutes following the termination of the sei- zure, the lateral temporal neocortex becomes intensely hypoper- fused, and this hypoperfus ion then spreads over the next few minutes to the mesial temporal areas (the \200\230posti ctal switch \200\231 ( 80 )). Over the next 15 minutes, perfusion in these areas is then re stored until it reaches the interictal state of mild hypoperfusion. A challenge surrounds the dif \201 culty in quantifying tractographic data. Until recently , tractographic analysis has relied on visual assess- ment of \201 bre trajectories and c omparison with control subjects or atlases (i.e. it is necessary to have prior anatomical k nowledge ( 59 )). Several recent studies have made important advances in this regard ( 60 , 61 ). Nevertheless, an ongoing methodological constraint is the lack of an absolute metric to evaluate connectivity, given the wide intersubject variation and intrasubject uncertain ty with respect to the course and trajectory of the major white matter tracts ( 61 ). Functional modalities Single-photon emission computed tomography Functional imaging has the advantage of localizing epileptogenic foci even in areas that are morphologically inconspi cuous. In a single-photon emission computed tomography (SPECT) study, patients are injected with a photon-emitting radioisotope attached to molecules designed to label the brain area s of interest ( 62 ). The distribution of radioisotope is then detected by a gamma camera, which allows a quantitative assessment of regional cerebral blood \202 ow. All of the rad iolabelled compounds that are in use today share the common properties of having a small mo lecular size and being lipophilic. These properties allow them to readily cross the blood \200\223 brain barrier and subsequently accumulate in the brain paren- chyma for long enoug h to permit image acquisition ( 63 ). In practice, the vast majority of studies use radiola belled technetium (Tc), in the form of 99m Tc-hexamethylpropyleneamineoxime ( 99m Tc-HMPAO) or 99m Tc-ethyl cysteinate diethylester ( 99m Tc- ECD). The peak uptake of these compounds occurs at approxi- mately 2 minutes after injection. Importantly, they are not redistribut ed to other brain areas, and therefore the administration of these tracers provides us with a snapshot of the cerebral circula- tion at the time of injection. These tracers remain st able for up to at least two hours, thus permitting delayed acquisition of the SPECT images. This implies a very narrow window within which the radioiso- tope needs to be administered. In practice, there is usually a delay before the delivery of the tracer, which takes a fur ther 30 seconds to cross the blood \200\223brain barrier if it is administered peripherally . Furthermore only 70 % of the radioisotope will be taken up at \201 rst pass. One study suggested that an injection time of less than 20 seconds after seizure onset is an importan t predictor of accurate localization, which is obviously dif \201 cult to achieve in pract ice ( 77 ). Ictal versus interictal SPECT The radiolabelled tracer can be delivered either during a sei zure (ictal SPECT) or in the absence of seizure activity (interictal SPECT) (Fig. 10.4 ). A priori, one might expect ictal SPECTs to result in greater yields of seizure localization than interictal In summary, therefore, in those cases in which the administra- tion of radiotracer is less than optimal, the interpretation of the subsequent SPECT images becomes complicated by two issues. First, the ictal SPECT hyperperfusion patterns often contain both oxford textbook of epilepsy and epileptic seizures 114 Fig. 10.4 (Also see Color plate 7.) SISCOM data from a patient with focal epilepsy of the r ight temporal lobe. Interictal 99m Tc-ECD SPECT activity was subtracted from ictal activity , and then co-registered to the patient \200\231s MRI. Reproduced with permission of Simon Vogrin. The most common radioisotope in clinical use today is 2-( 18 F) \202 uoro-2-deoxy-D-gluco se (( 18 F) FDG). FDG follows the topo- graphic distribution of glucose uptake in the brain , and therefore provides an estimate of the rate of regional glucose metabolism. It is ther efore considered an indirect marker of neuronal activity. In contrast to SPECT, PET isotope s emit positrons, which travel a short distance before colliding with an electron. These pa rticles are then mutually annihilated, resulting in the emission of a pair of photons which travel in diametrically opposite directions, and which are detected by the PET scanners. the ictal onset zone and the seizure propagation pathways ( 81 ). In practice, the ictal on set zone is often considered the region with the largest and most intense hyperperfusion, b ut the false positive results that subsequently occur therefore make SPECT less reliable th an other imaging modalities in predicting surgical outcome. Second, postictal switching can result in false localization or later- alization of the ictal focus when the delay between seizure onset and tracer application is too long. For example, a recent study showed that patients with supplementary motor area seizures had ictal SPECTs which falsely localized to bilateral anterior cingulate cortex ( 82 ). Together, this implies that patients may need their epi- leptogenic focus to be more precisely delineated with other meth- ods, such as i ntracranial EEG. Focal areas of reduced FDG uptake tend to correlate with the focus of seizure activity, eve n in the presence of grossly normal structural imaging with MRI ( 83 , 84 ) (Fig. 10.5 ). I n TLE, comparison with the contralateral side has been useful in localizing the epileptogen ic focus. The sensitivity of PET in patients with TLE is in the order of 70 \200\22390 % ( 85 \200\22390 ). Much of this variability is related to the heteroge- neity of the epilepsy , rather than technical factors such as differences in quality or speci \201 cations of th e PET camera ( 91 ). Some reports suggest that the sensitivity of PET is increased when sei zures are more frequent or when performed soon after a seizure has occurred. In contrast to patients with TLE, the sensitivity for seizure locali- zation in extra-TLE is signi \201 cantly lower, in the order of 30 \200\22360 % ( 86 , 92 \200\22396 ). An exception may be p atients with cortical dysplasia, in whom the reported sensitivity of PET varies between 60 \200\22392 % . In general, however, the sample sizes tend to be smaller in this population of extra-TLE patients, and less data are available. Positron emission tomography As with SPECT, positron emission tomography (PET) potentially provides information about seizure localization that may not be gleaned from conventional M RI sequences alone. The goal of a PET study is to detect areas of relative hypometabolism, which are presumed to re \202 ect focal functional disturbances of cerebral activ- ity ass ociated with the ictal onset zone. The underlying pathophys- iology leading to this hypomet abolism is incompletely understood, and has been related to neuronal loss, diaschisis, inhi bitory proc- esses, or a reduction in synaptic density. In a PET study, patients are injected with a radioactive ligand, the nature of which is det ermined by the target areas to be imaged. CHAPTER 10 neuroimaging in the investigation of epilepsy 115 Fig. 10.5 (Also see Color plate 8.) Multimodal imaging used in the presurgical planning of a patient with temporal lobe epilepsy. A) Coronal, sagittal, and axial slices from the pati ent \200\231s ( 18 F) FDG PET study, co-registered with the patient \200\231s MRI to plan f or the placement of intracranial electrodes (blue dots). These images demonstrate reduced F DG tracer uptake in the left temporal lobe. B) Cortical reconstruction demonstrating the ve nous distribution (purple) from a magnetic resonance venogram co-registered to the same pat ient \200\231s 3D MPRAGE volume. Reproduced with permission of Simon Vogrin. PET ligands other than ( 18 F) FDG In addition to ( 18 F) FDG, several other radioisotopes are used to better understand the neurobiology and functional changes associ- ated with dif ferent subtypes of epilepsy, although most of these are not used in routine clinical practi ce. These radiotracers differ according to the target receptor to which the tracer is sensi tive. For example, alpha-methyl-L-tryptophan (AMT) is a tracer for tryp- tophan metabolism ( 83 ); and other ligands have been used which bind to opioid receptors ( 97 ), histamine H 1 receptors ( 98 ), N-methyl-D-aspartate (NMDA) receptors ( 99 ), and peripheral benzodiaze pine receptors ( 100 ). Consequently, 11 C- \202 umazenil-PET is not routine, and its clinical utility remains con troversial ( 106 , 107 ). Nevertheless, regardless of whether 11 C- \202 umazenil is super ior to ( 18 F) FDG-PET, it may pro- vide useful data complementary to those of ( 18 F) FDG- PET and MRI ( 86 ). Limitations As in SPECT, the extent of ( 18 F) FDG uptake usually extends beyond the seizur e focus, and it is limited by weak temporal and spatial resolution. For example, it is not unusual for patients with TLE to also demonstrate hypometabolism of their frontal lobes, wh ich may represent inhibitory phenomena induced by the epilep- togenic focus ( 108 ). The au thors of one study compared pre- and postoperative ( 18 F) FDG-PET scans in patients with M TLE- hippocampal sclerosis who were rendered seizure-free after surgery ( 109 ). In this st udy, there were postoperative increases in ( 18 F) FDG metabolism in the propagation pathwa ys of ictal and interic- tal epileptic discharges (e.g. temporal white matter, inferior pre - central gyrus, anterior cingulate gyrus), suggesting that hypometabolism in these regions was functional, seizure-related, and reversible. Thus, a \200\230PETectomy \200\231 (i.e. resecting the area of tem- poral lobe hypometabolism visible on a PET ( 110 )) would resul t in resection of larger areas of tissue than is necessary. In general, these data suggest that PET alone is less useful for precise neuroanatomi- cal localization. 11 C- \202 umazenil is notable for its capacity to bind to the GABA A receptor complex, th e concentration of which appears to be lower in epileptogenic foci relative to the homologo us region on the con- tralateral hemisphere and the remaining neocortex ( 101 ). Some data show that the distribution of 11 C- \202 umazenil PET was more accurate than ( 18 F) FDG-P ET for the localization of seizure onset in patients with extra-TLE ( 102 ), and suggests 1 1 C- \202 umazenil to be a viable alternative or adjunct marker in identifying epileptogen ic regions ( 103 ). Furthermore, the degree of gamma-aminobutyric acid (GABA) receptor redu ction showed a positive correlation with seizure frequency. This implies that inhibitory me chanisms are dis- turbed in the epileptogenic focus ( 104 ), and that 11 C- \202 umazenil could act as a biochemical marker of epileptogenicity. However, 11 C- \202 umazenil abnormalities tend to be functional, transient, and seizure-r elated. In particular, one study showed that the most accurate seizure localization with 11 C- \202 umazenil occurred with scans that occurred at the shortest interictal period ( 10 5 ). This is related to the short half-life of 11 C (20 minutes), which necessi- tates rapi d acquisition of the PET scan after seizure onset. Furthermore, it is worth noting the temporal limitations of PET imaging. First, the tempora l dynamics of PET are slower than the blood \202 ow changes detected with SPECT. In addit ion, the half-life of the 18 F label (110 minutes) is relatively short and, in contrast to the radiolabelled technetium used in SPECT, there is prolonged oxford textbook of epilepsy and epileptic seizures 116 cerebral uptake of ( 18 F) FDG, which leads to signi \201 cant contami- nation caused by s eizure propagation. Together, these imply that PETs can only reliably image the interictal state, unlike SPECT. Some authors have, however, attempted to obtain ictal PETs in rare cas es of epilepsia partialis continua. Functional magnetic resonance imaging There are many cases in which the epileptogenic zone is near the eloquent cortex, in which case it is likely that the resection margin will encr oach upon functional brain tissue, and there is a risk of postoperative neurological de \201 cit. Although the gold standard for functional mapping remains intraoperative cortical stimulation, this is often impractical. Functional magnetic resonance imaging (fMRI) has b ecome a widely acceptable technique to non-inva- sively map brain function in normal and di seased brains. It involves detecting dynamic changes in the relative concentrations of oxy- and deoxyhaemoglobin during brain activity, and to use these microvascular blood-oxygen le vel dependent (BOLD) changes as a surrogate measure for neuronal function. In the epilepsy popula- tion, it has been used to non-invasively map sensory, motor, lan- guage, and memory functions for presurgical planning. One of the key uses of fMRI in epilepsy is to lateralize language function, a goal which ha s been traditionally accomplished with the intracortical amobarbital (Wada) test. The repor ted concordance between fMRI and the Wada test is variable, but is generally 90 % or higher , and fMRI is currently thought of as a valid alternative to the latter test ( 111 \200\223 115 ). Various paradigms are in use, including verbal \202 uency and language comprehensi on. The most reliable fMRI data are in sensory and motor tasks ( 116 \200\223118 ), which r esult in excellent agreement with intraoperative cortical mapping ( 119 , 120 ) (Fig. 10.6 ). In addition, fMRI may be able to visualize the func- tional anatomy of memory tasks ( 12 1 ), the assessment of which is critical prior to planning anterior temporal lobe resection . Fig. 10.6 (Also see Color plate 9.) FMRI scans acquired from an individual subject during a \201 nger-tapping task. Coronal, sagittal, and axial sections, as well as a rendered who le brain, show motor regions which are active during tapping with \201 ngers of the left (blue) and right (red) hands. Images were acquired with a 1.5 T MRI scanner, and activation s are shown at a statistical cluster threshold of z = 3.0. Subject \200\231s right is \201 gure left. Reproduced with permission of Simon Vogrin. Third, the nature of the task, and the selection of an appropriate baseline condition, is c ritical in deriving accurate activations, espe- cially when it comes to more complex cognit ive functions, such as language or memory. FMRI has been used extensively in the cogni- tiv e neuroscience literature, and there are a multitude of tasks that have been devised to pro be the various cognitive domains. A priori, one may expect different paradigms to activate different brain region, and indeed the lack of protocol standardization for the var- ious c ognitive functions has led to greater variability in functional localization. For example, no standardized fMRI paradigm has been validated which can identify the ability of the unre sected side to sustain memory postoperatively and predict postoperative memory performance. More broadly, a shortcoming of fMRI is that the activations that are identi \201 ed in an y given task imply that those areas are implicated in that task, but a causal relationship cannot be drawn. When compared with the \200\230gold standard \200\231 of electrocortical stim- ulation, th e speci \201 city of fMRI in one study was 67 % and sensitiv- ity greater than 90 % ( 122 ). Differences may have been due to the inability of electrocortical stimulation to map dee p sulcal areas, coregistration errors in fMRI, BOLD identi \201 cation of draining veins r ather than capillaries, or the threshold used for processing the fMR images. Although the use of fMRI has become widespread, it is worth noting several caveats in the i nterpretation of its data. First, there are the limitations imposed by the neurophysiologic al underpin- nings of the fMRI technique. The BOLD signal depends on a com- plex cascade of phenomena which couple a change in neuronal activity to a change in cerebral haemodynamics . Thus, the BOLD response is merely a surrogate measure of synaptic activity and, in the pa thological brain, it is unclear whether the normal mechanisms of neurovascular coupling sti ll hold. In addition, an altered BOLD response can be the result of alterations in the bloo d \202 ow to an area (such as occurs with vascular malformations ( 123 ), a large tumor w ith mass effect and oedema ( 112 ), or in the postictal state ( 124 )). Such alterations in cerebral haemodynamics could therefore be misinterpreted as functional activation of a par ticular area ( 125 ). Finally, the analysis of the tasks themselves is far from standard- ized, and the activatio ns will vary depending on such factors as the haemodynamic response function model that is chosen ( 129 ), and the statistical threshold that is arbitrarily set by the particular lab o- ratory. More broadly on this point, one should not neglect the philosophical differences in analyzing fMRI data between the clini- cal and research domains \200\224 the emphasis in research is to avoid false positive (Type I) errors, which leads to more conservative st a- tistical thresholds being favored. Conversely, in clinical neurol- ogy, the priority is to identify all brain regions involved in a particular task, and as a result more liberal s tatistical thresholds may be set to avoid false negatives. A second group of factors are technical. Some of the brain regions of most interest in epil epsy, such as the inferior frontal lobes and mesial temporal lobes (including the hippocamp us), are suscepti- ble to geometric distortions and signal loss during typical fMRI acquisi tion sequences, especially at higher \201 eld strength ( 126 \200\223128 ). CHAPTER 10 neuroimaging in the investigation of epilepsy 117 EEG-fMRI Simultanous EEG and fMRI is a rapidly evolving technique which offers the hope of combining two modalities with complementary strengths. EEG, of course, has excellent tempor al resolution, in the order of milliseconds, but has poor spatial resolution, as the exact location of neuronal currents varies with individual geometry and conductivity, and the lim ited number of EEG channels. In com- parison, fMRI has good spatial resolution, but its tem poral resolu- tion is limited by the haemodynamic (BOLD) response, which typically follows a neural stimulus by 2 \200\2236 seconds. Each of these modalities is bas ed on fundamentally different neurophysiological principles (with EEG measuring electrical activity and fMRI meas- uring BOLD responses); thus, applied together, they may be able to offer converging evidence in seizure localization. The general approach to EEG-fMRI is to map regional changes in BOLD signal that are time-lo cked to interictal epileptiform dis- charges (IEDs) identi \201 ed on the simultaneously r ecorded EEG ( 129 , 130 ) (Fig. 10.7 ). Of course, there are inherent technical Fig. 10.7 (Also see Color plate 10.) Upper panel) EEG-fMRI \201 ndings from a patient wit h left temporal lobe epilepsy. 128-channel EEG recorded in the MRI scanner showing left tem poral spikes (A). The large gradient artifact was \201 ltered, leaving, nevertheless, som e transient waveforms. The epileptic discharges of this patient could be identi \201 ed un ambiguously from their morphology and spatial distribution (B). Lower panel) During a 35 mi nute simultanous EEG-fMRI session, there were 11 interictal discharges which were localized to the left superior temporal gyrus (C). These activations were modeled using a multi-haem odynamic response function approach, including regressors for head movement. Three principa l clusters were found \200\224 in the left superior temporal gyrus, the left precentral gy rus, and right frontal lobe, with the former two activations correlating with the patient \200\231s seizure semiology. With permission from Vogrin, S. et al. ESI and fMRI of interic tal and ictal epileptic discharges. International Journal of Bioelectromagnetism 2011; 13( 4 ):S261 \200\2237. oxford textbook of epilepsy and epileptic seizures 118 dif \201 culties related to minimizing the electromagnetic noise during simultanous acquis ition of EEG and fMRI data. Traditionally, conventional \200\230spike-triggered \200\231 s tudies involve an expert observer visually identifying interictal epileptiform activity on scalp EEG, and manually triggering image acquisition ( 131 \200\223133 ). Those EEG events are then convolved with a model of the haemodynamic response function, which provides a reg ressor for a general linear model analysis of the fMRI data. Images associated with interic tal discharges are then compared to those without visible interictal discharges. The next a dvance in data acquisition was periodic imaging, in which fMRI image acquisition was altern ated with EEG epochs in order to minimize image artifact ( 134 ). Such protocols have allow ed high-frequency EEG (in the gamma range or higher) to be recorded and mapped to thalamoco rtical circuits in normals ( 135 ), and these high-frequency oscillations may potentially b e of relevance in epilepsy as well. Today we are able to record simulta- neous EEG-fMRI wit hout gaps in the acquisition sequence. With these new techniques have also come newer analy sis algorithms, such as independent components analysis and wavelet analysis ( 136 ), which are able to minimize the subjectivity in IED classi \201 ca- tion by automating that proc ess. ( 131 , 138 ), but this could very well represent a selection bias. In a recent paper, even ts were captured in only 40 % of patients ( 137 ). In sum, the precise clinical role of EEG-fMRI remains to be de \201 ned. While the aforeme ntioned imaging modalities are inform- ative in the majority of patients, at present the gr eatest utility of EEG-fMRI is in patients for whom other source localization tech- niques h ave failed to identify a single circumscribed focus. Magnetic resonance spectroscopy As has been clear from the experience with PET and SPECT, b io- chemical and metabolic abnormalities can occur in the absence of visible structural abn ormalities on MRI. Magnetic resonance spec- troscopy (MRS) is a tool that aims to detect ch anges in cerebral energy metabolism, which may occur in the absence of any obvious structur al changes. It is based on the hypothesis that the epilep- togenic focus is associated with long-term changes of metabolite concentrations ( 152 ). By detecting the magnetic resonanc e signals from phosphorus ( 31 P) or single proton ( 1 H) entities ( 153 ), MRS aims to inf er the presence of various neural metabolites, such as N-acetylaspartate (NAA), creatine (C r), choline compounds (signal intensities of \200\223CH 3 groups), glutamate (Glu), glutam ine (Gln), lac- tate (-CH doublet), and GABA (Fig. 10.8 ). In order to validate the EEG-fMRI approach, most studies have studied IED-correlated BOLD s ignal change with invasive and non-invasive methods of localizing the seizure onset zone ( 137 ), with the \200\230gold standard \200\231 for validation being intracranial EEG. Comp arison of the IED-BOLD activation maps with electro-clini- cal data on seizure onset has re vealed BOLD changes which corre- spond to the source of spiking activity and presumed irrit ative zone, with a concordance rate of approximately 70 % ( 130 , 131 , 138 \200\223141 ). This implies, however, that distant positive BOLD responses have also been found in areas u nrelated or not impli- cated in the individual patient \200\231s pathology \200\224 for ex ample, one study showed occipital coactivation with frontal IEDs ( 142 ). The assump- tion in most studies is that positive BOLD changes generally re \202 ect increases in neuronal activity, and in fact previous reports suggest seizures and IEDs are indeed associated with a positive BOLD response ( 143 ). This has led some authors to focus their attention on re gions with the most signi \201 cant BOLD response to assess con- cordance ( 138 ), while o thers considered all areas with a positive BOLD response ( 130 , 131 , 140 ). However, the relationship between BOLD and IED is not clear-cut, and lack of activation does not allow a ny \201 rm inferences to be drawn. It is worth noting also that the signi \201 cance and neurophysiological mechanism of negative BOLD responses, especially with respect to IEDs, remains unclear, and its localizing value is contentious ( 144 \200\223149 ). Proton MRS can lateralize an epileptic lesion in more than 85 % of MTL epilepsies, but its ability to lateralize extra-TLE is some- what less (e.g. around 50 % in one study of patien ts with frontal lobe epilepsy ( 154 )). NAA is generally considered a marker for neuronal d isease and is usually reduced in pathological conditions that lead to neuronal damage. In t he initial studies on epilepsy, the critical \201 nding was reduced signal intensities of NAA on the side ipsilateral to the seizure focus relative to the contralateral side. This focal reduction of NAA seems to correlate well with EEG abnor- malities and the severity of cell loss, as veri \201 ed by histological sam- ples obtained from the resected hippocamp i of patients with MTS. Although the proportion of neurons in MTS that are lost is between 30 \200\22350 % , there may, in addition, be underlying neuronal and glial dysfunction that contribute to the NAA changes on MRS. Glutamate and glutamine have also been found to be e levated in the temporal lobe ipsilateral to the seizure focus, including in patients with n ormal structural scans. It is important to note, how- ever, that the spatial resolution of MRS is low. MRS has also been used to measure the changes in neural metab- olites as a result of antico nvulsant medications or surgical resection. For example, GABA is the major inhibitory neuro transmitter in humans, and is the target of several anticonvulsant drugs (e.g. viga- batrin , gabapentin, topiramate, zonisamide). In contrast, glutamate is a key excitatory neurotran smitter, and intracellular glutamate concentrations are elevated in the epileptogenic human hippocam- pus and neocortex ( 153 ). Although the precise \202 uctuations in neu- rotran smitter concentrations with long-term anticonvulsant therapy are still unclear, in the futu re GABA and glutamate imaging may allow us to individualize anticonvulsant therapy. For exa mple, a patient with low GABA levels may bene \201 t from an anticonvulsant that increases cellular GABA or decreases cellular glutamate. Just as simultanous EEG-fMRI has the potential to combine the strengths of each modality, s o are its limitations ampli \201 ed. The analysis of combined EEG-fMRI data relies on the assumption that there is normal haemodynamic response function (HRF)-coupling in generalize d spike-wave discharges (for which there actually appears to be some preliminary evidence ( 150 )). In addition, as in standalone fMRI, the \201 nal outcome depends on the speci \201 c HRF that is chosen to model the data ( 129 ). Furthermore, while EEG may complement the poor temporal resolution of fMRI, ultimately, the delay of the HRF still limits interpr etation of the data. Simultanous EEG-fMRI relies on recordings of IEDs which occur during t he scanning period (a problem shared with MEG and standard EEG), and therefore requires pat ients to have a reasonably active resting EEG. In most studies reported, this is often the case Currently, the clinical application of MRS is limited by several technical factors, not lea st of which is lack of availability and exper- tise. Despite the relative success of MRS in the research domain, it continues to have problems with sensitivity when applied to clini- cal populations. Examples of factors which limit its widespread application as a diagnosti c tool include long acquisition times CHAPTER 10 neuroimaging in the investigation of epilepsy 119 Fig. 10.8 (Also see Color plate 11.) Magnetic resonance spectroscopy data from a single sub ject. A) NAA/Cr images at 7 axial slices. B) T2-weighted images corresponding to the center of the metabolite image slice. C) z -score images for NAA/Cr in the standard spatial refer ence frame. D) T2-MRI following af \201 ne registration to the standard spatial reference frame. E) Spectra from the locations indicated in (B). From Maudsley A, et al. Application of volumetric MR spectroscopic imaging for localization of neocortical epilepsy. Epilepsy R es 2010; 88( 2 \200\2233 ):127 \200\22338. uses a superconducting quantum interference device (SQUID) to amplify the small magnetic \201 elds generated by small intraneuronal electric currents. In contrast to EEG, which is sensitive to both radial and tangential activity, MEG is maximally sensitive to dipoles ori ented tangentially to the brain surface, which therefore corre- spond to sulcal activity. B eing complementary techniques, EEG and MEG may also be simultaneously performed to provide con- verging evidence in localizing a seizure focus (Fig. 10.9 ). when using conventional phase-encoding; loss of spectral informa- tion from magnetic-suscep tibility-induced spectral line broaden- ing; image distortions extending from the large sub cutaneous lipid signals or unsuppressed water; and limitations on signal quality and spatia l resolution due to poor detection sensitivity. Magnetoencephalography In conjunction with the aforementioned techniques, magnetoen- cephal ography (MEG) is emerging as an important tool in identi- fying the source of interictal di scharges ( 156 ). EEG and MEG are complementary techniques \200\224 whereas scalp EEG dete cts extracel- lular volume currents produced by post-synaptic potentials, MEG