CHAPTER 10 neuroimaging in the investigation of epilepsy 121 either technology alone. From a research perspective, combining the principles of PET and M RI could also prove a powerful approach. By labeling ligands and tracers with magnetic nano par- ticles, it may be possible to combine the ability of PET to identify speci \201 c rec eptors with the high spatial resolution of MRI. A proof of principle was recently reported with magnetic nanoparticles labeled with AMT in an animal model ( 177 ). of 50 % compared to 92 % for extra-TLE) ( 85 ). This is related to the fact that only 3.5 \200\2234 cm 2 of synchronized activity from the lateral neocortex is required to produce a detectable MEG signal, com- pared to 6 \200\2238 cm 2 in MTLE ( 160 , 172 ). The second role of MEG is to investigate the function of cortical areas near the epileptoge nic focus (similar to evoked potentials and fMRI). In order to avoid postoperative neurolog ical de \201 cits, MEG can be used to delineate adjacent areas of eloquent cortex in senso - rimotor, language, and visual areas. In localizing the primary sen- sorimotor cortex, MEG is able to delineate the central sulcus by identifying the somatosensory-evoked magnetic \201 eld, which is accurate in approximately 90 % of patients when referenced against dire ct cortical stimulation through electrocorticography. Language mapping can be determined by MEG with various language para- digms (e.g. word recognition, silent reading, picture nami ng, verb generation), with similarly high concordant rates of 75 \200\22395 % when referenc ed against Wada testing ( 173 ). With regards to DTI, there have been recent attempts to corre- late diffusion abnormalities with intracranial EEG recordings ( 40 , 178 ), and DTI has also been used to add details t o head models in EEG source localization ( 179 \200\223181 ). The combination of tractogra- phy, EEG and fMRI has been shown to delineate the pathways through which epileptic activit y propagates ( 182 ). Taking parsi- mony to its logical extreme, some authors have even spe culated on the potential for coregistering structural MRI, DTI, SPECT, PET, fMRI, EEG, and MEG across a single platform. The major dif \201 culty in evaluating neuroimaging modalities in the work-up of a patient with epilepsy is the lack of clinical data from large, randomized controlled trials to gui de imaging deci- sions. In fact, very few rigorous studies have examined the cost \200\223 bene \201 t or predictive value of neuroimaging in clinical practice. In 2004, the UK \200 \231s National Institute for Health and Clinical Excellence failed to identify any study of neuroimaging in epilepsy that achieved more than Grade III clinical evidence ( 183 ). Sinc e then, a meta-analysis of localization accuracy, cost-effectiveness, and pre- dictive valu e of neuroimaging in presurgical evaluation was highly critical, commenting on the poor qua lity of all existing studies, which the authors concluded were unable to usefully inform cl ini- cal practice ( 184 ). To this end, an important recent study recruited a large cohort of presurgical patients, who were initially subjected to non-invasive evaluation, followed by intracranial EEG, and \201 nally surgery. This study assessed the additional predictiv e value of FDG-PET, ictal SPECT, and MSI against intracranial EEG ( 185 ) and the outcome o f epilepsy surgery ( 186 ). The data showed that all three modalities were of bene \201 t in predicting seizure-freedom following surgery, but that MSI had the greatest sensitivity for detecting the seizure onset zone as con \201 rmed by intracranial EEG. FDG-PET and ict al SPECT nevertheless had independent predic- tive value for seizure-free postsurgical outc ome. The application of MEG is limited by its availability \200\224 there are only approximatel y 100 MEG installations available for medical use worldwide. Its set-up is limited by the c osts associated in con- structing a shielded room with high-permeability metals to reduce c ompeting ambient magnetic noise, as the epileptiform spikes detected by MEG are 10 \210 \222 9 smaller than environmentally generated magnetic noise. Discussion Approximately 15 % of epileptic surgical candidates are rejected on the basis th at an epileptogenic focus cannot be delineated ( 174 ). With the constant advances in neuro imaging, it is foreseeable that this proportion will drop, and that those who do undergo su rgery will do so with less risk to their areas of eloquent cortex. With the gamut of techno logies that are available to the modern epileptolo- gist, the question of how to approach a patient with epilepsy becomes a dif \201 cult one, and one that varies between institutio ns based on the available expertise and equipment. Each of the tech- niques discussed has i ts limitations. EEG and MEG are insensitive to deeper sources. PET and SPECT reveal regiona l, rather than local, abnormalities, and lack the spatial resolution of MRI. MRI has the be st spatial resolution in detecting structural lesions, but may still miss more subtle lesio ns ( 10 ). Furthermore, a lesion that is detected does not necessarily indicate an epilepti c focus and, conversely, patients without an identi \201 able structural lesion on MRI can nevertheless be successful surgical candidates ( 175 ). Future studies along similar lines will be important in \201 lling the existing evidence gap, especially given resource limitations which behoove us to establish which investigatio ns are cost-effective, and which are optional or even redundant. However, in practice, meas - uring non-invasive techniques against the yardstick of intracranial EEG is not possible, as many patients do not undergo invasive studies, and in any case intracranial EEGs sample only a limited part of the brain. Furthermore, there is the dif \201 culty of designing la rge-scale randomized controlled trials to recruit a suf \201 cient number of patients and achieve adequate follow-up when the back- ground is that of an ever-changing neuroimaging l andscape. Thus, the rapid advances in neuroimaging imply that a long-term study examining s urgical outcome may only inform the use of outdated technology by the time it is completed. This fact notwithstanding, such studies could nevertheless prove useful, as is evidenced b y our current ongoing use of older imaging modalities such as PET and SPECT. The issue that will become even more relevant in the future will be how to establish which lesions identi \201 ed with more advanced MRI technology are epileptogenic. Combining the strengths and weaknesses of each modality could potentially result in more robust data comp ared to each modality on their own, and in fact current attempts at seizure localization us ually involve multiple technolo- gies, either separately (e.g. SISCOM, MSI) or concurrently (e.g. EEG-fMRI, EEG-MEG), with the aim of \201 nding converging evi- dence for a single, resectable seizure focus. High-resolution structural MRI forms the basis on which the \201 ndings of other function al imaging modalities can be coregis- tered. SISCOM, of course, is a long-established techn ique, but there have also been attempts to coregister FDG-PET and MRI prior to surgical res ection ( 176 ) (Fig. 10.5 ), which has shown potential for improved sensitivity and speci \201 city compared to The advances in neuroimaging techniques have also made the standardization of studies dif \201 cult. The wide variations in data analysis for many of the more modern modalities have led to many oxford textbook of epilepsy and epileptic seizures 122 methodological inconsistencies between studies. Future studies need to clarify not only the sensitivity and speci \201 city of individual techniques and analysis algorithms, but als o the reproducibility of \201 ndings both within and between centers, the positive predic tive value for important clinical outcomes, the economic value of each modality, and, more broadly, the independent value of neuroimag- ing over other modalities (such as EEG and neu ropsychometry). Although many clinicians would feel disinclined to merely repli- cate previ ous \201 ndings, it can only be with such replication that one can establish a genuine tr end, especially given the small numbers of subjects that are usually involved. Thus, future studies will proba- bly see multicentre collaborations in order to recruit suf \201 cient numbers of patients and to pool collective resources. 12 . Urbach H . Imaging of the epilepsies . European Radiol 2005 ; 15 : 494 \200\223 500 . 13 . Elster A , Mirza W . MR imaging in chronic partial epilepsy: role of contrast enhancem ent . Am J Neuroradiol 1991 ; 12 ( 1 ): 165 \200\223 70 . 14 . Widjaja E , Raybaud C . Adv ances in neuroimaging in patients with epilepsy . Neurosurg Focus 2008 ; 25 ( 3: E3 ): 1 \200\223 11 . 15 . Salmenpera T , Duncan J . Imaging in epilepsy . J Neurol Neurosurg Psychiat ry 2005 ; 76 ( Suppl III ): 2 \200\223 10 . 16 . Eriksson SH , Thom M , Bartlett PA , Symms MR , McEvoy AW , Sisodiya SM , et al . PROPELLER MRI visualizes detailed pathology of hippocampal sclerosis . Epilepsia 2008 ; 49 ( 1 ): 33 \200\223 9 . 17 . Bonilha L , Halford JJ , Rorden C , Roberts DR , Rumboldt Z , Eckert MA . Automated MRI analysis for identi \201 cation of hippocampal atrophy in temporal lobe epilepsy . Epilepsia 2008 ; 50 ( 2 ): 228 \200\223 33 . 18 . Knake S , Triantafyllou C , Wald LL , Wiggins G , Kirk GP , Larsson PG , et al . 3T phased array MRI improves the presu rgical evaluation in focal epilepsies: a prospective study . Neurology 2005 ; 65 : 1026 \200\223 31 . It is certainly an exciting time for neuroimaging in epilepsy. However, the translation of the many small studies in the literature into clinical practice should proceed cautiously, due to the limita- tions of each modality, and the lack of a strong (Class I) evidence base for any given approach. For now, the newer neuroimaging modalities remain auxiliary techni ques as part of a multimodality and multidisciplinary assessment, which should include a th or- ough clinical evaluation, neuropsychological testing, neuropsychi- atric evaluation, in terictal and ictal EEG recordings, optimal conventional imaging with MRI, and possibly MEG, PET, or SPECT scanning. 19 . Strandberg M , Larsson EM , Backman S , K ll n K . Pre-surgical epilepsy evaluation using 3T MRI . Do surface coils provide additional information? Epilept ic Disord 2008 ; 10 ( 2 ): 83 \200\223 92 . 20 . Duncan J . The current status of neuroimaging for epilepsy . Curr Opin Neurol 2009 ; 22 : 179 \200\223 84 . 21 . Deblaere K , Achten E . Structural magnetic resonance imaging in epilepsy . European Radiol 2008 ; 18 : 119 \200\223 29 . 22 . Wright IC , McGuire PK , Poline JB , Travere JM , Murray RM , Frith CD , et al . A voxel-based method for the statistical analysis of gray and white matter den sity applied to schizophrenia . Neuroimage 1995 ; 2 : 244 \200\223 52 . Acknowledgements The authors wish to thank Simon Vogrin for contributing Figs 10.3 \200 \223 10. 7 and 10.9 to this chapter. 23 . Ashburner J , Friston K . Voxel-based morphometry \200\224 the methods . Neuroimage 2000 ; 11 : 805 \200\223 21 . 24 . Chung MK , Worsley KJ , Paus T , Cherif C , Collins DL , Giedd JN , et al . A uni \201 ed statistical approach to deformation-based morphometry . Neuroimage 2001 ; 14 ( 3 ): 595 \200\223 606 . References 25 . Abbott DF , Pell GS , Pardoe H , Jackson GD . Voxel-based iterative sensitiviy (VBIS) analysis: methods and a validation of intensity scaling for T2-weighted i maging of hippocampal sclerosis . Neuroimage 2009 ; 44 : 812 \200\223 19 . 1. L ders H , Awad I. Conceptual considerations . In: L ders H (ed) Epilepsy Surgery , p. 51 \200\223 62 . New York : Raven Press , 1992 . 2 . Rosenow F , L ders H . Presurgical evaluation of epilepsy . Brain 2001 ; 26 . Riederer F , Lanzenberger R , Kaya M , Prayer D , Serles W , 124 : 1683 \200\223 700 . Baumgartner C . Network atrophy in temporal lobe epilepsy . Neurology 2008 ; 71 ( 6 ): 419 \200\223 25 . 3 . Gastaut H , Gastaut J . Computerized transverse axial tomography in epilepsy . Epilepsia 1976 ; 17 : 325 \200\223 64 . 27 . Bookstein F . \200\230Voxel-based morphometry \200\231 should not be used with imperf ectly registered images . Neuroimage 2001 ; 14 : 1454 \200\223 62 . 4 . International League Against Epilepsy . Recommendations for neuroimaging of patients with epilepsy. Commission on neuroimaging of the International Lea gue Against Epilepsy . Epilepsia 1997 ; 38 : 1255 \200\223 6 . 28 . Crum WR , Grif \201 n LD , Hill DL , Hawkes DJ . Zen and the art of medical image registration: correspondence, homology, and quality . Neuroimage 2003 ; 20 ( 3 ): 142 5 \200\223 37 . 5 . Berg AT , Testa FM , Levy SR , Shinnar S . Neuroimaging in children 29 . Richardson M . Current themes in neuroimaging of epilepsy: Brain networks, dynamic phe nomena, and clinical evidence . Clin Neurophysiol 2010 ; 121 : 1153 \200\223 75 . with newly diagnosed epilepsy: A community-based study . Pediatrics 2000 ; 106 : 527 \200 \223 32 . 6 . King MA , Newton MR , Jackson GD , Fitt GJ , Mitchell LA , Silvapulle MJ , et al . Epil eptology of the \201 rst-seizure presentation: a clinical, electroencephalogrpahic, and m agnetic resonance imaging study of 300 consecutive patients . Lancet 1998 ; 352 ( 9133 ): 1 007 \200\223 11 . 7 . Cakirer S , Ba ak M , Mutlu A , Galip GM . MR imaging in the 30 . Keller SS , Wieshmann UC , Mackay CE , Denby CE , Webb J , Roberts N . Voxel based morphometry of gray matter abnormalities in patients with medically intract able temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration . J Neu rol Neurosurg Psychiatry 2002 ; 73 ( 6 ): 648 \200\223 55 . presurgical workup of patients with drug-resistant epilepsy . Am J Neuroradiol 2004 ; 25 : 919 \200\223 26 . 31 . Hajnal J , Doran M , Hall AS , Collins AG , Oatridge A , Pennock JM , et al . MR imaging of anisotropically restricted diffusion of water in the nervous system: technical, anatomic, and pathologic considerations . J Comput Assist Tomogr 1991 ; 15 ( 1 ) : 1 \200\223 18 . 8 . Cakirer S , Ba ak M , Mutlu A , Galip GM . MR imaging in epilepsy that is refractory to medical therapy . European Radiol 2002 ; 12 : 549 \200\223 58 . 9 . Matsuda K , Mihara T , Tottori T , Otubo T , Usui N , Baba K , et al . 32 . Rugg-Gunn F . Diffusion imaging in epilepsy . Expert Rev Neurother Magnetic resonance imaging in 120 patients with intractable partial seizures: a preoperativ e assessment . Neuroradiology 2005 ; 47 : 352 \200\223 61 . 2007 ; 7 ( 8 ): 1043 \200\223 54 . 33 . Chu K , Kang DW , Kim JY , Chang KH , Lee SK . Diffusion-weighted 10 . Matsuda K , Mihara T , Tottori T , Otubo T , Usui N , Baba K , et al . magnetic resonance imaging in nonconvulsive status epilepticus . Arch Neurol 2001 ; 58 ( 6 ): 993 \200\223 8 . Neuroradiologic \201 ndings in focal cortical dysplasia: histologic correlation with surg ically resected specimens . Epilepsia 2001 ; 42 (s 6 ): 29 \200\223 36 . 34 . Kim JA , Chung JI , Yoon PH , Kim DI , Chung TS , Kim EJ , et al . Transient MR signal changes in patients with generalized tonicoclonic seizure or status epi lepticus: periictal diffusion-weighted imaging . Am J Neuroradiol 2001 ; 22 ( 6 ): 1149 \200\223 60 . 11 . von Oertzen J , Urbach H , Bl mcke I , Reuber M , Tr ber F , Peveling T , et al . Ti me-ef \201 cient relaxometry of the entire hippocampus is feasible in temporal lobe epilep sy . Neurology 2002 ; 58 : 257 \200\223 64 . CHAPTER 10 neuroimaging in the investigation of epilepsy 123 57 . Hagmann P , Thiran JP , Jonasson L , Vandergheynst P , Clarke S , 35 . Parmar H , Lim SH , Tan NC , Lim CC . Acute symptomatic seizures and hippocampus damag e: DWI and MRS \201 ndings . Neurology 2006 ; 66 ( 11 ): 1732 \200\223 35 . Maeder P , et al . DTI mapping of human brain connectivity: statistical \201 bre tracking and virtual dissection . Neuroimage 2003 ; 19 ( 3 ): 545 \200\223 54 . 58 . Parker GJ , S tephan KE , Barker GJ , Rowe JB , MacManus DG , Wheeler- Kingshott CA , et al . Initial dem onstration of in vivo tracing of axonal projections in the macaque brain and comparison wit h the human brain using diffusion tensor imaging and fast marching tractography . Neuroimag e 2002 ; 15 ( 4 ): 797 \200\223 809 . 36 . Diehl B , Symms MR , Boulby PA , Salmenpera T , Wheeler-Kingshott CA , Barker GJ , et al . Postictal diffusion tensor imaging . Epilepsy Res 2005 ; 65 ( 3 ): 137 \200\223 46 . 37 . Salmenpera TM , Simister RJ , Bartlett P , Symms MR , Boulby PA , et al . High-resolut ion diffusion tensor imaging of the hippocampus in temporal lobe epilepsy . Epilepsy Res 20 06 ; 71 : 102 \200\223 6 . 59 . Hagler DJ Jr , Ahmadi ME , Kuperman J , Holland D , McDonald CR , Halgren E , et al . Automated white-matter tractography using a probabilistic diffusion tensor atlas: Applicati on to temporal lobe epilepsy . Hum Brain Mapp 2009 ; 30 ( 5 ): 1535 \200\223 47 . 38 . Goncalves Pereira P , Oliveira E , Rosado P . Apparent diffusion coef \201 cient mapping of the hippocampus and the amygdala in the pharmaco-resistant temp oral lobe epilepsy . Am J Neuroradiol 2006 ; 27 : 671 \200\223 83 . 60 . Ciccarelli O , Parker GJ , Toosy AT , Wheeler-Kingshott CA , Barker GJ , Boulby PA , et al . From diffusion tractography to quantitative white matter tract measures : a reproducibility study . Neuroimage 2003 ; 18 : 348 \200\223 59 . 39 . Kimiwada T , Juh sz C , Makki M , Muzik O , Chugani DC , Asano E , et al . Hippocampal and thalamic diffusion abnormalities in children with temporal lobe epi lepsy . Epilepsia 2006 ; 47 : 167 \200\223 75 . 61 . Jones D . Determining and visualizing uncertainty in estimates of \201 ber orientati on from diffusion tensor MRI . Magn Res Med 2003 ; 49 : 7 \200\223 12 . 62 . la Foug re C , Rominger A , F rster S , Geisler J , Bartenstein P . PET and SPECT in epilepsy: A criti cal review . Epilepsy Behav 2009 ; 15 : 50 \200\223 5 . 63 . Neirinckx RD , Canning LR , P iper IM , Nowotnik DP , Pickett RD , 40 . Guye M , Ranjeva JP , Bartolomei F , Confort-Gouny S , McGonigal A , R gis J , et al . What is the signi \201 cance of interictal water diffusion changes in frontal lobe epile psies? Neuroimage 2007 ; 35 : 28 \200\223 37 . 41 . Thivard L , Hombrouck J , du Montcel ST , Delmaire C , Cohen L , Samson S , et al . Productive and perceptive language reorganization in temporal lobe epile psy . Neuroimage 2005 ; 24 : 841 \200\223 51 . Holmes RA , et al . Technetium-99m d,l-HM-PAO: A new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion . J Nucl Med 1987 ; 28 ( 2 ): 191 \200\223 202 . 42 . Mori S , van Zijl P . Fiber tracking: principles and strategies \200\224 a technical review . NMR in Biomedicine 2002 ; 15 : 468 \200\223 80 . 64 . Spanaki MV , Spencer SS , Corsi M , MacMullan J , Seibyl J , Zubal IG . Sensitivity an d speci \201 city of quantitate difference SPECT analysis in seizure localization . J Nucl Med 1999 ; 40 : 730 \200\223 6 . 43 . Yogarajah M , Duncan J . Diffusion-based magnetic resonance imaging and tractography in epilepsy . Epilepsia 2008 ; 49 ( 2 ): 189 \200\223 200 . 44 . Stefan H , Nimsky C , Scheler G , Rampp S , Hopfeng rtner R , Hammen 65 . Devous MD Sr , Thisted RA , Morgan GF , Leroy RF , Rowe CC . SPECT T , et al . Periventricular nodular heterotopia: a challenge for epilepsy surgery . Seizure 2007 ; 16 ( 1 ): 81 \200\223 6 . brain imaging in epilepsy: a meta-analysis . J Nucl Med 1998 ; 39 : 285 \200\223 93 . 45 . Nimsky C , Ganslandt O , Merhof D , Sorensen AG , Fahlbusch R . Intraoperative visuali zation of the pyramidal tract by diffusion- tensor-imaging-based \201 ber tracking . Neur oimage 2006 ; 30 ( 4 ): 1219 \200\223 29 . 66 . Weil S , Noachtar S , Arnold S , Yousry TA , Winkler PA , Tatsch K . Ictal ECD-SPECT d ifferentiates between temporal and extratemporal epilepsy: con \201 rmation by excellent p ostoperative seizure control . Nucl Med Commun 2001 ; 22 : 233 \200\223 7 . 46 . Catani M , Howard RJ , Pajevic S , Jones DK . Virtual in vivo interactive 67 . Zaknun JJ , Bal C , Maes A , Tepmongkol S , Vazquez S , Dupont P , et al . Comparative analysis of MR imaging, ictal SPECT and EEG in temporal lobe epilepsy: a prospective IAEA multi-center study . Eur J Nucl Med Mol Imaging 2008 ; 35 : 107 \200\223 15 . dissection of white matter fasciculi in the human brain . Neuroimage 2002 ; 17 ( 1 ): 77 \200\223 94 . 47 . Guye M , Parker GJ , Symms M , Boulby P , Wheeler-Kingshott CA , Salek-Haddadi A , et al . Combined functional MRI and tractography to demonstrate the conne ctivity of the human primary motor cortex in vivo . Neuroimage 2003 ; 19 ( 4 ): 1349 \200 \223 60 . 68 . Lee JJ , Lee SK , Lee SY , Park KI , Kim DW , Lee DS , et al . Seizure, Frontal lobe epilepsy: clinical characteristics, surgical outcomes and diagnostic modalitie s . Seizure 2008 ; 17 : 514 \200\223 23 . 48 . Powell HW , Parker GJ , Alexander DC , Symms MR , Boulby PA , Barker GJ , et al . Imag ing language pathways predicts postoperative naming defects . J Neurol Neurosurg Psychiatry 2008 ; 79 : 327 \200\223 30 . 69 . Ahnlide JA , Ros n I , Lind n-Mickelsson Tech P , K ll n K. Does SISCOM contribute to favorable seizure outcome after epilepsy surgery? Epilepsia 2007 ; 48 : 579 \200\223 8 8 . 49 . Powell HW , Parker GJ , Alexander DC , Symms MR , Boulby PA , 70 . Matsuda H , Matsuda K , Nakamura F , Kameyama S , Masuda H , Wheeler-Kingshott CA , et al . MR tractography predicts visual \201 eld defects following temporal lobe resection . Neurology 2005 ; 65 : 596 \200\223 9 . 50 . Parker G , Alexande r D . Probabilistic anatomical connectivity derived Otsuki T , et al . Contribution of subtraction ictal SPECT coregistered to MRI to epilepsy surgery: a multicenter study . Ann Nucl Med 2009 ; 23 : 283 \200\223 91 . from the microscopic persistent angular structure of cerebral tissue . Philos Trans R Soc L ond B Biol Sci 2005 ; 460 : 893 \200\223 902 . 71 . Kaiboriboon K , Lowe VJ , Chantarujikapong SI , Hogan RE . The usefulness of subtraction ictal SPECT coregistered to MRI in single- and dual-headed SPECT cameras in partial epilepsy . Epilepsia 2002 ; 43 : 408 \200\223 14 . 51 . Tournier JD , Calamante F , Gadian DG , Connelly A . Direct estimation of the \201 b er orientation density function from diffusion-weighted MRI data using spherical deconvolut ion . Neuroimage 2004 ; 23 : 1176 \200\223 85 . 72 . O \200\231Brien T . SPECT: methodology . Adv Neurol 2002 ; 83 : 11 \200\223 32 . 73 . O \200\231Brien TJ , So EL , Cascino GD , Hauser MF , Marsh WR , Meyer FB , 52 . Tuch D . Q-ball imaging . Magn Res Med 2004 ; 52 : 1358 \200\223 72 . 53 . Alexander D . Multiple- \201 ber reconstruction algorithms for diffusion et al . Subtraction SPECT coregistered to MRI in focal malformations of cortical developmen t: localization of the epileptogenic zone in epilepsy surgery candidates . Epilepsia 2004 ; 45 : 367 \200\223 76 . MRI . Ann N Y Acad Sci 2005 ; 1064 : 113 \200\223 33 . 54 . Perrin M , Poupon C , Rieul B , Leroux P , Constantinesco A , Mangin JF , et al . Validation of q-ball imaging with a diffusion \201 bre-crossing phant om on a clinical scanner . Philos Trans R Soc Lond B Biol Sci 2005 ; 360 : 881 \200\223 91 . 74 . O \200\231Brien TJ , So EL , Mullan BP , Cascino GD , Hauser MF , Brinkmann BH , et al . Subtraction peri-ictal SPECT is predictive of extratemporal epilepsy surgery outcome . N eurology 2000 ; 55 : 1668 \200\223 77 . 55 . Tuch DS , Reese TG , Wiegell MR , Makris N , Belliveau JW , 75 . O \200\231Brien TJ , So EL , Mullan BP , Hauser MF , Brinkmann BH , Bohnen NI , et al . Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in loc alizing the surgical seizure focus . Neurology 1998 ; 50 : 445 \200\223 54 . Wedeen VJ . High angular resolution diffusion imaging reveals intravoxel white matter \201 ber heterogeneity . Magn Res Med 2002 ; 48 : 577 \200\223 82 . 56 . Nunes RG , Jezzard P , Behrens TE , Clare S . Self-navigates multishot echo-planar pul se sequence for high-resolution diffusion-weighted imaging . Magn Res Med 2005 ; 53 : 1474 \200\223 8 . 76 . Wichert-Ana L , de Azevedo-Marques PM , Oliveira LF , Terra- Bustamante VC , Fernandes RM , Santos AC , et al . Interictal hyperemia oxford textbook of epilepsy and epileptic seizures 124 97 . Frost JJ , Mayberg HS , Fisher RS , Douglass KH , Dannals RF , correlates with epileptogenicity in polymicrogyric cortex . Epilepsy Res 2008 ; 79 : 39 \200\223 48 . Links JM , et al . Mu-opiate receptors measured by positron emission tomography are increas ed in temporal lobe epilepsy . Ann Neurol 1988 ; 23 : 231 \200\223 7 . 77 . Lee SK , Lee SY , Yun CH , Lee HY , Lee JS , Lee DS . Ictal SPECT in neocortical epile psies: clinical usefulness and factors affecting the pattern of hyperperfusion . Neuroradio logy 2006 ; 48 : 678 \200\223 84 . 78 . Van Paesschen W . Ictal SPECT . Epilepsia 2004 ; 4 5 (Suppl. 4 ): 35 \200\223 40 . 79 . Kazemi N , O \200\231Brien TJ , Cascino GD , So LS. S ingle photon emission computed tomography . In: Engel J Jr , Pedley T (eds) Epilepsy: A Com prehensive Textbook , pp. 965 \200\223 74 . Philadelphia , PA : Lippincott Williams & Wilk ins , 2008 . 98 . Iinuma K , Yokoyama H , Otsuki T , Yanai K , Watanabe T , Ido T , et al . Histamine H1 -receptors are increased in parietal epilepsy: A PET Study . Lancet 1993 ; 341 : 238 . 99 . Kumlien E , Hartvig P , Valind S , Oye I , Tedroff J , L ngstr m B . NMDA-receptor activity visualized with (S)-(N-methyl-11C) ketamine and positron emission to mography in patients with medial temporal lobe epilepsy . Epilepsia 1999 ; 40 ( 1 ): 30 \200\223 7 . 80 . Newton MR , Berkovic SF , Austin MC , Reutens DC , McKay WJ , Bladin 100 . Sauvageau A , Desjardins P , Lozeva V , Rose C , Hazell AS , Bouthillier A , PF . Dystonia, clinical lateralization, and regional blood \202 ow changes in temporal lo be seizures . Neurology 1992 ; 42 : 371 \200\223 7 . et al . Increased expression of \200\230peripheral-type \200\231 benzodiazepine receptors in human temporal lobe epilepsy: Implications for PET imaging of hippocampal sclerosis . Me tab Brain Dis 2002 ; 17 ( 1 ): 3 \200\223 11 . 81 . Dupont P , Van Paesschen W , Palmini A , Ambayi R , Van Loon J , Gof \201 n J , et al . Ictal perfusion patterns associated with single MRI- visible focal dysplastic lesions: I mplications for the noninvasive delineation of the epileptogenic zone . Epilepsia 2006 ; 47 ( 9 ): 1550 \200\223 7 . 82 . Fukuda M , Masuda H , Honma J , Kameyama S , Tanaka R . Ict al SPECT analyzed by three-dimensional stereotactic surface projection in frontal lobe epil epsy patients . Epilepsy Res 2006 ; 68 : 95 \200\223 102 . 101 . Savic I , Persson A , Roland P , Pauli S , Sedvall G , Wid n L . In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci . Lancet 1 988 ; 2 : 863 \200\223 6 . 102 . Muzik O , da Silva EA , Juhasz C , Chugani DC , Shah J , Nagy F , et al . Intracranial EEG versus \202 umazenil and glucose PET in children with extratemporal lobe epilepsy . Neurology 2000 ; 54 : 171 \200\223 9 . 83 . Chugani DC , Chugani HT , Muzik O , Shah JR , Shah AK , Canady A , et al . Imaging epileptogenic tubers in children with tuberous sclerosis complex using alph a-(11C)methyl-L-tryptophan positron emission tomography . Ann Neurol 1998 ; 44 : 858 \200 \223 66 . 103 . Savic I , Thorell J , Roland P . (11C)Flumazenil positron emission tomography visualizes frontal epileptogenic regions . Epilepsia 1995 ; 36 : 1225 \200\223 32 . 84 . da Silva EA , Chugani DC , Muzik O , Chugani HT . Identi \201 cation of frontal lobe epileptic foci in children using positron emission tomography . Epilepsia 1997 ; 38 : 1198 \200\223 1208 . 104 . Savic I , Svanborg E , Thorell J . Cortical benzodiazepine receptor changes are related to frequency of partial seizures: a positron emission tomography study . Epilepsia 1996 ; 37 : 236 \200\223 44 . 85 . Knowlton RC , Laxer KD , Aminoff MJ , Roberts TP , Wong ST , Rowley 105 . Bouvard S , Costes N , Bonnefoi F , Lavenne F , Maugui re F , Delforge J , et al . S eizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a (11 C) \202 umazenil-PET study . Brain 2005 ; 128 : 1330 \200\223 43 . HA . Magnetoencephalography in partial epilepsy: clinical yield and localization accuracy . Ann Neurol 1997 ; 42 : 622 \200\223 31 . 86 . Ryvlin P , Bouvard S , Le Bars D , De Lam rie G , Gr goire MC , Kahane P , et al . Clinical utility of \202 umazenil-PET versus (18F) \202 uorodeoxyglucose-PE T and MRI in refractory partial epilepsy: a prospective study in 100 patients . Brain 1998 ; 121 ( 11 ): 2067 \200\223 81 . 87 . Valk PE , Laxer KD , Barbaro NM , Knezevic S , Dillo n WP , Budinger TF . High-resolution (2.6 mm) PET in partial complex epilepsy associated wi th mesial temporal sclerosis . Radiology 1993 ; 186 : 55 \200\223 8 . 88 . Gaillard WD , B hatia S , Bookheimer SY , Fazilat S , Sato S , Theodore 106 . Koepp MJ , Hammers A , Labb C , Woermann FG , Brooks DJ , Duncan JS . 11C- \202 um azenil PET in patients with refractory temporal lobe epilepsy and normal MRI . Neurology 20 00 ; 54 : 332 \200\223 9 . 107 . Kaneko K , Sasaki M , Morioka T , Koga H , Abe K , Sawamoto H , et al . Pre-surgical identi \201 cation of epileptogenic areas in temporal lobe epilepsy by 123I-iomazenil SPEC T: a comparison with IMP SPECT and FDG PET . Nucl Med Comm 2006 ; 2006 ( 27 ): 893 \200 \223 9 . WH . FDG-PET and volumetric MRI in the evaluation of patients with partial epilepsy . Neuro logy 1995 ; 45 : 123 \200\223 6 . 108 . Nelissen N , Van Paesschen W , Baete K , Van Laere K , Palmini A , et al . Correlatio ns of interictal FDG-PET metabolism and ictal SPECT perfusion changes in human temporal lob e epilepsy with hippocampal sclerosis . Neuroimage 2006 ; 32 ( 2 ): 684 \200\223 95 . 89 . Ryvlin P , Philippon B , Cinotti L , Froment JC , Le Bars D , Maugui re F . Functional neuroimaging strategy in temporal lobe epilepsy: a comparative study of 18 FDG-P ET and 99m Tc-HMPAO-SPECT . Ann Neurol 1992 ; 31 : 650 \200\223 6 . 109 . Joo EY , Hong SB , Han HJ , Tae WS , Kim JH , Han SJ , et al . Postoperative alteration of cerebral glucose metabolism in mesial temporal lobe epilepsy . Brain 2005 ; 128 ( 8 ): 1802 \200\223 10 . 90 . Swartz B , Tomiyasu U , Delgado E . Neuroimaging in temporal lobe epilepsy: test sensitivity and relationships to pathology and postoperative outcome . Epile psia 1992 ; 33 : 624 \200\223 34 . 110 . Vinton AB , Carne R , Hicks RJ , Desmond PM , Kilpatrick C , Kaye AH , et al . The ex tent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy . Brai n 2006 ; 130 ( 2 ): 548 \200\223 60 . 111 . Benson RR , FitzGerald DB , LeSueur LL , Kenne dy DN , Kwong KK , 91 . Henry T , Engel J , Mazziotta J . Clinical evaluation of interictal \202 uorine- 18- \202 uorodeoxyglucose PET in partial epilepsy . J Nucl Med 1993 ; 34 : 1892 \200\223 8 . Buchbinder BR , et al . Language dominance determined by whole brain functional MRI in pati ents with brain lesions . Neurology 1999 ; 52 : 798 \200\223 809 . 92 . Drzezga A , Arnold S , Minoshima S , Noachtar S , Szecsi J , Winkler P , et al . 18F-F DG PET studies in patients with extratemporal and temporal epilepsy: evaluation of an obser ver-independent analysis . J Nucl Med 1999 ; 40 : 737 \200\223 46 . 112 . Gaillard WD , Balsamo L , Xu B , Grandin CB , Braniecki SH , Papero PH , et al . Language dominance in partial epilepsy patients identi \201 ed with an fMRI r eading task . Neurology 2002 ; 59 : 256 \200\223 65 . 93 . Arnold S , Schlaug G , Niemann H , Ebner A , L ders H , Witte OW , et al . Topography of interictal glucose hypometabolism in unilateral mesiotemporal epilepsy . Neur ology 1996 ; 46 : 1422 \200\223 30 . 113 . Leh ricy S , Cohen L , Bazin B , Samson S , Giacomini E , Rougetet R , et al . Functional MR evaluation of temporal and frontal language dominance compared with t he Wada test . Neurology 2000 ; 54 : 1625 \200\223 33 . 94 . Gambhir S , Singh Sethi R , Deswal S . Incidental detection of a single brain metastas is from breast carcinoma during Tc-99m MIBI scintimammography . Clin Nucl Med 2001 ; 26 : 8 83 \200\223 4 . 114 . Woermann FG , Jokeit H , Luerding R , Freitag H , Schulz R , Guertler S , 95 . Juh sz C , Chugani DC , Muzik O , Shah A , Shah J , Watson C , et al . Relationship o f \202 umazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome . N eurology 2001 ; 56 : 1650 \200\223 8 . 96 . Won HJ , Chang KH , Cheon JE , Kim HD , Lee DS , Han MH , et al . et al . Language lateralization by Wada test and fMRI in 100 patients with epilepsy . Neuro logy 2003 ; 61 : 699 \200\223 701 . 115 . Yetkin FZ , Swanson S , Fischer M , Akansel G , Morris G , Mueller W , et al . Functional MR of frontal lobe activation: comparison with Wada language results . A m J Neuroradiol 1998 ; 19 ( 6 ): 1095 \200\223 8 . Comparison of MR imaging with PET and ictal SPECT in 118 patients with intractable epilepsy . Am J Neuroradiol 1999 ; 20 : 593 \200\223 9 . CHAPTER 10 neuroimaging in the investigation of epilepsy 125 135 . Ritter P , Freyer F , Curio G , Villringer A . High-frequency (600 Hz) 116 . Hammeke TA , Yetkin FZ , Mueller WM , Morris GL , Haughton VM , population spikes in human EEG delineate thalamic and cortical fMRI activation sites . Neur oimage 2008 ; 42 : 483 \200\223 90 . Rao SM , et al . Functional magnetic resonance imaging of somatosensory stimulation . Neuro surgery , 1994 ; 35 : 677 \200\223 81 . 136 . Formaggio E , Storti SF , Bertoldo A , Manganotti P , Fiaschi A , Toffolo GM . Integr ating EEG and fMRI in epilepsy . Neuroimage 2011 ; 54 : 2719 \200\223 31 . 117 . Kim SG , Ashe J , Georgopoulos AP , Merkle H , Ellermann JM , Menon RS , et al . Func tional imaging of human motor cortex at high magnetic \201 eld . J Neurophysiol 1993 ; 69 ( 1 ): 297 \200\223 302 . 137 . Thornton R , Laufs H , Rodionov R , Cannadathu S , Carmichael DW , Vulliemoz S , et a l . EEG correlated functional MRI and postoperative outcome in focal epilepsy . J Neurol Ne urosurg Psychiatry 2010 ; 81 : 922 \200\223 7 . 118 . Rao SM , Binder JR , Bandettini PA , Hammeke TA , Yetkin FZ , Jesmanowicz A , et al . Functional magnetic resonance imaging of complex human movements . Neurology 1993 ; 42 : 2311 \200\223 18 . 119 . Yetkin FZ , Mueller WM , Morris GL , McAuliffe TL , Ulmer JL , Cox RW , et al . Funct ional MR activation correlated with intraoperative cortical mapping . Am J Neuroradiol 1997 ; 18 : 1311 \200\223 15 . 138 . Salek-Haddadi A , Diehl B , Hamandi K , Merschhemke M , Liston A , Friston K , et al . Hemodynamic correlates of epileptiform discharges: an EEG-fMRI study of 63 patients with focal epilepsy . Brain Res 2006 ; 1088 : 148 \200\223 66 . 120 . Yousry TA , Schmid UD , Jassoy AG , Schmidt D , Eisner WE , Reulen HJ , et al . Topog raphy of the cortical motor hand area: prospective study with functional MR imaging and dir ect motor mapping at surgery . Radiology 1995 ; 195 : 23 \200\223 9 . 139 . B nar CG , Grova C , Kobayashi E , Bagshaw AP , Aghakhani Y , Dubeau F , et al . EEG -fMRI of epileptic spikes: Concordance with EEG source localization and intracranial EEG . Neuroimage 2006 ; 30 : 1161 \200\223 70 . 121 . Binder JR , Swanson SJ , Sabsevitz DS , Hammeke TA , Raghavan M , Mueller WM . A comp arison of two fMRI methods for predicting verbal memory decline after left temporal lobecto my: language lateralization versus hippocampal activation asymmetry . Epilepsia 2010 ; 51 ( 4 ): 618 \200\223 26 . 140 . Lazeyras F , Blanke O , Perrig S , Zimine I , Golay X , Delavelle J , et al . EEG-tri ggered functional MRI in patients with pharmacoresistant epilepsy . J Magn Res Imaging 2000 ; 12 : 177 \200\223 85 . 141 . Zimine I , Seghier ML , Seeck M , Lazeyras F . Brain activation using triggered event -related fMRI . Neuroimage 2003 ; 18 : 410 \200\223 15 . 142 . Kobayashi E , Bagshaw AP , B nar CG , Aghakhani Y , Andermann F , 122 . Bookheimer SY , Zef \201 ro TA , Blaxton T , Malow BA , Gaillard WD , Sato S , et al . A direct comparison of PET activation and electrocortical stimulation mapping for langua ge localization . Neurology 1997 ; 48 : 1056 \200\223 65 . Dubeau F , et al . Temporal and extratemporal BOLD responses to temporal lobe interictal sp ikes . Epilepsia 2006 ; 2 : 343 \200\223 54 . 143 . Salek-Haddadi A , Friston KJ , Lemieux L , Fish DR . Studying 123 . Leh ricy S , Biondi A , Sourour N , Vlaicu M , du Montcel ST , Cohen L , et al . Arteriovenous brain malformations: is functional MR imaging reliable for studying l anguage reorganization in patients? Initial observations . Radiology 2002 ; 223 : 672 \200 \223 82 . spontaneous EEG activity with fMRI . Brain Res Rev 2003 ; 43 : 110 \200\223 33 . 144 . Carmichael DW , Hamandi K , Laufs H , Duncan JS , Thomas DL , Lemieux L . An investigation of the relationship between BOLD and perfusion signal changes during epileptic generalized spike wave activity . Magn Res Imaging 2008 ; 26 : 870 \200 \223 3 . 124 . Jayakar P , Bernal B , Santiago Medina L , Altman N . False lateralization of language cortex on functional MRI after a cluster of focal seizures . Neurology 2002 ; 5 8 : 490 \200\223 2 . 145 . Kobayashi E , Bagshaw AP , Grova C , Gotman J , Dubeau F . Gray matter heterotopia: w hat EEG-fMRI can tell us about epileptogenicity of neuronal migration disorders . Brain 200 6 ; 129 ( 2 ): 366 \200\223 74 . 146 . Stefanovic B , Warnking JM , Kobayashi E , Bagshaw AP , Hawco C , 125 . Wellmer J , Weber B , Urbach H , Reul J , Fernandez G , Elger CE . Cerebral lesions c an impair fMRI-based language lateralization . Epilepsia 2009 ; 50 ( 10 ): 2213 \200\223 2 3 . 126 . Jezzard P , Clare S . Sources of distortion in functional MRI data . Dubeau F , et al . Hemodynamic and metabolic responses to activation, deactivation and epil eptic discharges . Neuroimage 2005 ; 28 : 205 \200\223 15 . Hum Brain Mapp 1999 ; 8 : 80 \200\223 5 . 127 . Ances BM , Leontiev O , Perthen JE , Liang C , Lansing AE , Buxton RB . 147 . Shmuel A , Yacoub E , Pfeuffer J , Van de Moortele PF , Adriany G , Hu Regional differences in the coupling of cerebral blood \202 ow and oxygen metabolism chan ges in response to activation: implications for BOLD-fMRI . Neuroimage 2008 ; 39 : 1510 \200\223 21 . X , et al . Sustained negative BOLD, blood \202 ow and oxygen consumption response and it s coupling to the positive response in the human brain . Neuron 2002 ; 36 : 1195 \200\223 210 . 128 . Restom K , Perthen JE , Liu TT . Calibrated fMRI in the medial 148 . Parkes LM , Fries P , Kerskens CM , Norris DG . Reduced BOLD response to periodic vis ual stimulation . Neuroimage 2004 ; 21 ( 1 ): 236 \200\223 43 . temporal lobe during a memory-encoding task . Neuroimage 2008 ; 40 : 1495 \200\223 502 . 129 . B nar CG , Gross DW , Wang Y , Petre V , Pike B , Dubeau F , et al . The BOLD respon se to interictal epileptiform discharges . Neuroimage 2002 ; 3 : 1182 \200\223 92 . 149 . Kobayashi E , Bagshaw AP , Grova C , Dubeau F , Gotman J . Negative BOLD responses to epileptic spikes . Hum Brain Mapp 2006 ; 27 : 488 \200\223 97 .