Video EEG monitoring In the past, patients were usually referred to an epilepsy center with a video EEG monitoring unit for a presurgical evaluation assuming that they are potential surgical candidates. However, selection cri- teria who constitutes a good surgical candidat e (e.g. suspected epi- leptogenic zone based on semiology and interictal EEG, lesion on epi lepsy protocol MRI), depend on a high level of expertise and technical infrastructure. It h as become evident that 25 % of patients oxford textbook of epilepsy and epileptic seizures 104 to surgery and the ability to include the patient in the informed consent process after all data are obtained further adds to the ben- e \201 t of extraoperative recording (Fig. 9.8 ). The typical length of stay is around 3 \200\2235 days which allows the recording of seizure s in approximately 70 % of patients ( 25 ). Complications are rare and related to falls, st atus epilepticus, pos- tictal psychosis, and, in rare events, SUDEP ( 26 ). Advanced EEG techniques EEG source localization With conventional visual analysis of focal EEG activity, where the observer attempts to de \201 ne the source of this activity, certa in assumptions are made. It is assumed that ( 1 ) the source lies close to the electrode th at has maximum negativity or minimum positivity; ( 2 ) that focal sources produce focal epi leptiform abnormalities; and ( 3 ) that broad potential \201 elds are indicative of diffu se or multi- focal generators ( 27 ) However, this is not always true and clear exceptions to these assumptions are frequently found in clinical practice when depth electrodes are us ed to localize EEG activity because generators of EEG activity are dipolar with a \201 el d potential of one polarity at the active synaptic site (current sink) and a \201 eld of the opposite polarity at a distant site (current source) ( 28 ). What is seen on the surfac e therefore, may arise from a distant and/or deep source. An example of this is the mesial temporal EEG spike of hippocampal sclerosis. These spikes can be demonstrated to arise from the hippocampal \200\223amygdalar complex with depth elec- trodes. Voltage distribution ma ps of simultanous scalp recordings of these same spikes with a standard surface EEG montage will show these to arise from the anterior temporal or antero-basal temporal lobe (electro des F7, T3, FT9). EEG source localization (EEG source imaging, ESI) is therefore aimed at l ocating the true generator of electrical activity as a direct or indirect indicator of the individual \200\231s epileptogenic zone. This is important in the charac- terization of a f ocal epilepsy although ESI techniques are also capa- ble of source localizing eloquent cort ex through analysis of evoked potentials. See Figs 9.9 and 9.10. Invasive EEG Intraoperative electrocorticography Intraoperative ECoG with subdural and, les s commonly, stereotactic depth electrodes attempts to capture interictal abnormalities to f ur- ther delineate the irritative cortex (as indicated by spikes) or the area of dysfunctio n (represented by slowing or attenuation of normal activ- ity). The additional procedural r isk of intraoperative ECoG is compa- rably small and usually extends the time of surgery by not more than 30 \200\22360 minutes. In many lesional (mesial temporal sclerosis (MTS), ca vernous malformations, low grade tumors) and non-lesional (non-dominant) temporal lobe case s, intraoperative ECoG can be a useful adjustment to delineate the extent of the surgical r esection without the risks associated with extraoperative invasive recordings. For these patients, functional mapping can be often accom- plished preoperatively through W ada testing or functional MRI (fMRI). If necessary, the relation to eloquent cortex can be further defined through central sulcus mapping with somatosensory evoked potentials or elec trical cortical stimulation under anaesthe- sia (recording motor response from EMG electrod es) or in the awake patient (for language mapping). Extraoperative invasive recording Extraoperative invasive monitoring either through subdura l elec- trode placement or a depth electrode exploration with \200\230stereo \200\231-EEG is the preferred approach to invasive epilepsy surgery in many adult centers ( 7 , 8 ). Par ticularly non-lesional extratemporal, dominant temporal, or bitemporal lobe cases and the g roup of patients with suspected dual pathology, post-traumatic epilepsy, or focal cortical dysplasia bene \201 t from the invasive de \201 nition of the ictal onset area. Sampling of interictal epileptiform activity to delineate the irrita- tive cortex is often more reli able outside the operation room with all its pitfalls in terms of time constraint and the e ffect of anaesthe- sia. A more systematic and reproducible functional mapping prior Sophisticated mathematical modeling techniques and algo- rithms are used to determine ESI a nd several commercially availa- ble software programs incorporate these for clinical and re search usage. With both ESI and source imaging with magnetoencepha- lography, two important concepts require consideration \200\224 the for- ward and inverse problems; the \200\230 solutions \200\231 to which add complexity Electrocorticography Location Extratemporal Temporal Dominant Non-dominant Extraoperative Intraoperative Noninvasive Fig. 9.8 Intra- vs. extraoperative electrocorticography. The decision between non-invasive and intraoperative or extraoperative invasive recording for epilepsy surgery depends on loc ation and etiology. The suspected etiology of a lesion determines the overlap between irrit ative cortex, ictal onset area, and lesion and the location impacts the proximity to eloque nt cortex and the need for mapping. Post-traumatic FCD Non-lesional Epileptogenic zone Cavemous angioma Low-grade tumor MTS Etiology Irritative zone Two or more lesions e.g. dual pathology, TS Technical Mesial or basal coverage Depths Ictal onset zone Epileptogenic lesion CHAPTER 9 the electroencephalogram in the investigation of epilepsy 105 Fig. 9.9 A patient with a left temporal lobe epilepsy due to a mesial temporal cavernoma (t op right \200\224 white arrow). The EEG shows a left temporal spike with a surface voltage distribution as seen in the top left \201 gure. to the modeling techniques and algorithms used. The forward problem refers to the problem o f accurate localization of a \201 eld potential at the recording scalp electrodes for a g iven dipole source. This is made dif \201 cult by the fact that there are intervening phys io- logical planes with varying tissue anisotropy (brain, cerebrospinal \202 uid, meninge s, skull) and additionally, head shapes and sizes vary from individual to individual. Conve rsely, the inverse problem refers to the problem of working backwards from the \201 eld p oten- tial recorded at the scalp electrodes to identifying its source. The source can be a \201 xed, moving, or rotating dipole source, multiple dipoles or a distributed source and different algorithms are used for different situations. Clinical validation for these tech niques is slowly building evidence for the utility of ESI ( 29 ), particularly in source lo calizing the interictal spike. Source localization of the ictal discharge is less convincin gly studied. demonstrating localization in relation to surrounding brain struc- tures. To lend con \201 dence to ESI accuracy, it is essential that two important criteria are ful \201 lled. Fir stly that the electrode positions incorporated into analysis are the subject \200\231s rath er than the soft- ware \200\231s default positions. Secondly, the MRI images should be the patient \200\231s own images rather than the default software images. Non- ful \201 lment of either of these caveats can result in inaccurate results. High-frequency recording High-frequency oscillations (HFOs) within the spectral frequen- ci es of 80 \200\223600 Hz can be recorded during invasive EEG in humans (Fig. 9.11 ). These h igh-frequency signals are thought to represent short-term neuronal synchronization of actio n potentials. In the last decade increased attention has been given to these EEG ele- ments as they are thought to be potential markers of epileptogenic brain tissue or epileptogenic networks. HFOs can be recorded from normal and pathologic brain tissue with a tendency for the faster HFOs (fast ripples 200 \200\223600 Hz) to be more likely present on path- ologi c epileptogenic areas whereas ripples in the 80 \200\223200 Hz range may be more likely fou nd in speci \201 c structures of normal cerebral cortex ( 30 \200\22332 ). Typically, EEG data is acquired using scalp electrodes in stand- ard 10 \200\22320, 10 \200 \22310 or \200\230high-density \200\231 electrode arrays. Although there is evidence that the accuracy of ESI yield is directly proportional to the number of electrodes used, the op timum is uncertain and beyond a certain number, a law of diminishing returns is likely. The epileptiform spike is then analyzed singly or in averaged form by ESI software using one o r more modeling techniques and algorithms. This is then pictorially represented on an MRI i mage, Although HFOs are generated in very small and limited regions of the cortex, both ictal and interictal HFOs can be recorded with oxford textbook of epilepsy and epileptic seizures 106 Fig. 9.10 (See also Color plate 5.) EEG source localization in the same patient shows sourc e localization of the spike to a dipole cluster (in red) in the close vicinity of the caver noma (white arrow). Fig. 9.11 Abnormal high-frequency oscillations of 250 Hz superimposed on interictal spikes seen in the hippocampal body depth electrodes of a patient with left mesial temporal lobe e pilepsy. CHAPTER 9 the electroencephalogram in the investigation of epilepsy 107 standard depth and subdural macroelectrodes during invasive video EEG recordings of patient s with focal epilepsy ( 32 , 33 ). Elevated sampling frequencies ( > 1000 Hz), opening of h igh-fre- quency \201 lters, and time stretching displays are necessary for record- ing an d visual analysis. 13. Ebersole JS . Cortical generators and EEG voltage \201 elds . In: Ebersole JS , Pedle y TA (eds) Current practice of clincial electroencephalography ( 3rd edn), pp. 12 \200\2233 1 . Philadelphia, PA : Lippincott Williams & Wilkins , 2003 . 14. McCormick DA , Contreras D . On the cellular and network bases of epileptic seizures . Annu Rev Physiol 2001 ; 63 : 815 \200\223 46 . Interictal HFOs are seen on top of spikes or independent from traditional EEG spikes and ar e considered an independently gener- ated interictal epileptiform abnormality in invasive E EG record- ings. It has been postulated that the association of spikes with HFOs may result helpful in differentiating interictal spikes arising from epileptogenic tissue from interi ctal spikes of unclear signi \201 - cance. HFOs can also be seen as an ictal phenomenon at the EEG onset of seizures where they usually have a restricted \201 eld and are found mo re likely in electrodes involved in the seizure onset zone than in electrodes where seizure s propagate. 15. Malmivuo J , Plonsey R . Electroencephalography . In: Bioelectromagnet ism \200\223 pr inciples and applications of bioloelectric and biomagnetic \201 elds , pp. 257 \200\223 64 . New York : Oxford University Press , 1995 . 16. American Clinical Neurophysiology Society . Guideline 5: Guidelines for standard electr ode position nomenclature . J Clin Neurophysiol 2006 ; 23 ( 2 ): 107 \200\223 10 . 17. Devinsky O , Kelley K , Porter RJ , Theodore WH . Clinical and electroencephalographic features of simple partial seizures . Neurology 1988 ; 38 ( 9 ): 13 47 \200\223 52 . 18. Verma A , Radtke R . EEG of partial seizures . J Clin Neurophysiol 2006 ; 23 ( 4 ): 333 \200\223 9 . Several clinical studies support the role of interictal as well as ictal HFOs as biological markers of epileptogenic cortex. Interictal HFOs tend to be more geographically restricted to the seizure onset zone than interictal spikes are and more limited to the seizure onset zone independently of the type and extension of the brain lesion ( 34 , 35 ). Interictal H FOs are a more speci \201 c marker of ictal onset than spikes and HFOs become more abundan t in the period of time preceding a seizure and as antiepileptic medications are tapered do wn in the context of presurgical VEEG evaluation ( 33 ). The clinical utility of identifyin g the unique characteristics of pathologic HFOs resides in the fact that these may help ide ntify the epileptogenic zone which is the main objective of most invasive video EEG evaluat ion in patients with localization related epilepsy. Jacobs et al. was able to demonstrate t hat patients who have a larger proportion of HFO generating cortical areas surgically remov ed went on to have better postoperative outcome ( 36 ). 19. Salinsky M , Kanter R , Dasheiff RM . Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: An operational curve . Epilepsia 1987 ; 28 ( 4 ): 331 \200\223 4 . 20. Claassen J , Mayer SA , Kowalski RG , Emerson RG , Hirsch LJ . Detection of electrograp hic seizures with continuous EEG monitoring in critically ill patients . Neurology 2004 ; 6 2 ( 10 ): 1743 \200\223 8 . 21. Mendez OE , Brenner RP . Increasing the yield of EEG . J Clin Neurophysiol 2006 ; 23 ( 4 ): 282 \200\223 93 . 22. Klass DW , Westmoreland BF . Nonepileptogenic epileptiform electroencephalographic activity . Ann Neurol 1985 ; 18 ( 6 ): 627 \200\223 35 . 23. Foldv ary N , Klem G , Hammel J , Bingaman W , Najm I , Luders H . The localizing value of ictal EEG in focal epilepsy . Neurology 2001 ; 57 ( 11 ): 2022 \200 \223 8 . 24. Labiner DM , Bagic AI , Herman ST , Fountain NB , Walczak TS , Gumnit RJ , et al . Esse ntial services, personnel, and facilities in specialized epilepsy centers \200\224 revised 2010 guidelines . Epilepsia 2010 ; 51 ( 11 ): 2322 \200\223 33 . 25. Friedman DE , Hirsch LJ . How long does it take to make an accurate diagnosis in an epilepsy monitoring unit? J Clin Neurophysiol 2009 ; 26 ( 4 ): 213 \200\223 17 . References 26. Noe KH , Drazkowski JF . Safety of long-term video-electroencephalo graphic monitoring for evaluation of epilepsy . Mayo Clin Proc 2009 ; 84 ( 6 ): 495 \200\223 500 . 1. Berger H . \234ber das elektrenkephalogramm des menschen . Arch Psychiat Nervenkr 1929 ; 87 : 527 \200\223 70 . 2. Adrian ED , Matthews BHC . The berger rhythm. Potential changes 27. Rose S , Ebersole JS . Advances in spike localization with EEG dipole from the occipital lobe in man . Brain . 1934 ; 57 : 355 \200\223 85 . modeling . Clin EEG Neurosci 2009 ; 40 ( 4 ): 281 \200\223 7 . 3. Foerster O , Altenburger H . Elektrobiologische vorgaenge an der menschlichen hirnrinde . Dtsch Z Nervenheilk 1935 ; 135 : 277 \200\223 88 . 4. Gibbs FA , Davis H . Changes in th e human electroencephalogram 28. Brazier MA . The electrical \201 elds at the surface of the head during sleep . Electroencephalogr Clin Neurophysiol 1949 ; 1 ( 2 ): 195 \200\223 204 . 29. Plummer C , Harvey AS , Cook M . EEG source localization in focal associated with loss of consciousness . Am J Physiol 1935 ; 113 : 49 \200\223 50 . 5. Jasp er HH , Carmichal L . Electrical potentials from the intact human epilepsy: Where are we now? Epilepsia 2008 ; 49 ( 2 ): 201 \200\223 18 . 30. Engel J , Jr , Bragin A , Staba R , Mody I . High-frequency oscillations: What is norma l and what is not? Epilepsia 2009 ; 50 ( 4 ): 598 \200\223 604 . 31. Gotman J . High frequ ency oscillations: The new EEG frontier? brain . Science 1935 ; 81 : 51 \200\223 3 . 6. Feindel W , Leblanc R , de Almeida AN . Epilepsy surgery: Historical highlights 1909 \200\2232009 . Epilepsia 2009 ; 50(Suppl 3) : 131 \200\223 51 . Epilepsia 2010 ; 51(Suppl 1) : 63 \200\223 5 . 7. Nair DR , Burgess R , McIntyre CC , Luders H . Chronic subdural 32. Urrestarazu E , Chander R , Dubeau F , Gotman J . Interictal high-frequency oscillation s (100 \200\223500 hz) in the intracerebral EEG of epileptic patients . Brain 2007 ; 130 (P t 9 ): 2354 \200\223 66 . electrodes in the management of epilepsy . Clin Neurophysiol 2008 ; 119 ( 1 ): 11 \200\223 28 . 8. Talairach J , Bancaud J . Stereotactic approach to epilepsy: Methodology of anatomo-func tiona-stereotactic investigations . Prog Neurol Surg 1973 ; 5 : 297 \200\223 354 . 33. Khosravani H , Mehrotra N , Rigby M , Hader WJ , Pinnegar CR , Pillay N , et al . Spatial localization and time-dependant changes of electrographic high frequenc y oscillations in human temporal lobe epilepsy . Epilepsia 2009 ; 50 ( 4 ): 605 \200\223 1 6 . 9. Goldensohn ES . Simultanous recording of EEG and clinical seizures using kinescope . Ele ctroencephalogr Clin Neurophysiol 1966 ; 21 : 623 . 10. Velis D , Plouin P , Gotman J , da Silva FL , ILAE DMC Subcommittee on 34. Jacobs J , LeVan P , Chander R , Hall J , Dubeau F , Gotman J . Interictal high-frequen cy oscillations (80 \200\223500 hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain . Epilepsia 2008 ; 49 ( 11 ): 1893 \200\223 907 . Neurophysiology . Recommendations regarding the requirements and applications for long-term recordings in epilepsy . Epilepsia 2007 ; 48 ( 2 ): 379 \200\223 84 . 35. Jacobs J , Levan P , Chatillon CE , Olivier A , Dubeau F , Gotman J . High frequency os cillations in intracranial EEGs mark epileptogenicity rather than lesion type . Brain 2009 ; 132 (Pt 4 ): 1022 \200\223 37 . 11. Cooper R , Winter AL , Crow HJ , Walter WG . Comparison of subcortical, cortical and sc alp activity using chronically indwelling electrodes in man . Electroencephalogr Clin Neuro physiol 1965 ; 18 : 217 \200\223 28 . 12. Tao JX , Ray A , Hawes-Ebersole S , Ebersole JS . Intracranial EEG 36. Jacobs J , Zijlmans M , Zelmann R , Chatillon CE , Hall J , Olivier A , et al . High-fr equency electroencephalographic oscillations correlate with outcome of epilepsy surgery . A nn Neurol 2010 ; 67 ( 2 ): 209 \200\223 20 . substrates of scalp EEG interictal spikes . Epilepsia 2005 ; 46 ( 5 ): 669 \200\223 76 . This page intentionally left blank CHAPTER 10 Neuroimaging in the Investigation of Epilepsy Trevor T.-J. Chong and Mark Cook Introduction Modern clinical neurology has at its disposal a myriad of neuroim- aging techn iques to study the brains of patients in vivo . The raison d \200\231etre for neuroimaging in clinical epilepsy is to localize an epilep- togenic focus (Table 10.1 ) with the ultimat e goal of resecting it, while minimizing the extent to which normal brain tissue is excised . Typically, the work-up of a patient with epilepsy will initially include long-term video electroencephalography (EEG), as well as structural and functional neuroimaging. If the sum of these data converges upon a single ictal focus, then surgical treatment might be undert aken with the aid of electrocorticography (ECoG). patients with newly diagnosed epilepsy ( 5 ) or a \201 rst seizure ( 6 ), but rises to 65 \200\22383 % in patient groups with intractable temporal lobe epilepsy (TLE) who are being considered for surgery ( 7 \200\2239 ). It is worth noting that, despite its superior spat ial resolution, MRI can still miss more subtle structural lesions, such as small areas of c or- tical dysplasia ( 10 ). Standard scanning protocols can be insuf \201 cient to detect the majority of lesions in p atients with refractory epilepsy ( 11 ), so imaging protocols should be tailored to the cli nical scenario ( 12 ). A screening protocol for epilepsy should include at least axial T1- and T2-weighted images, proton density sequences, and \202 uid attenuated inversion recov ery (FLAIR) sequences (Fig. 10.1 ). T1-weighted images provide good de \201 nition of the normal anat- omy and gray \200\223white matter differentiation; T2-weighted images allow be tter visualization of focal pathology; and FLAIR sequences provide high lesion contrast in areas close to cerebrospinal In this review, we provide a brief overview of the current imag- ing modalities available t o the modern epileptologist. Due to space constraints, this review does not aim to be compr ehensive; rather, our overarching goal is to summarize the current status of the available neuroimaging techniques, with an emphasis on their clin- ical application and limitations i n evaluating patients with epilepsy. We conclude with a general discussion on the relative utility of each modality individually and when applied together. Table 10.1 Description of zones and lesions of the cortex of patients with epilepsy Zone De \201 nition Structural imaging Magnetic resonance imaging In patients who present acutely with a \201 rst-episode seizure, com- puted tomography (CT) is an ef \201 cient \201 rst-line inves tigation which can exclude many acute neurological problems requiring urgent intervention, such as an intracerebral hemorrhage or abscess. CT has a number of advantages, including lo w cost, accessibility, ef \201 - ciency and ease of use, but its sensitivity in unselected patients with epilepsy is less than 30 % ( 3 ). Today, due to its greater spatial reso- lu tion, magnetic resonance imaging (MRI) has overtaken CT as the mainstay of imaging in patie nts who are not acutely unwell. In fact, the International League Against Epilepsy (ILAE) h as long stated that \200\230Everybody with epilepsy should have, in the ideal situ- ation, a high-quality MRI \200\231 ( 4 ). Irritative zone Region of cortex that generates interictal epileptiform discharge on EEG or MEG Seizure onset/ pacemaker zone Region of cortex from which the clinical seizures originate Ictal symptomatic zone Region of cortex that generates the initial seizure symptomatology Functional de \201 cit zone Region of cortex that, in the interictal period, is functioning abnormally, as indicated by neuropsychological examination, neuropsychological testing and functional imaging or non-e pileptiform EEG or MEG abnormalities. Epileptogenic lesion Structural lesion causally related to the epilepsy Epileptogenic zone Region of cortex that is indispensable for seizure generation. By de \201 nition, complete removal is both necessary and suf \201 cient for seizure free dom The diagnostic yield of MRI depends on several factors; for example, the patient population , the pathological substrate, the quality of the scanner, the imaging protocols, and the ex perience of the interpreting physician. With regards to the patient population, the yield f or identifying putative lesions is around 12.7 \200\22314 % in Eloquent cortex Region of cortex that is indispensable for de \201 ned cortical functions Adapted from L ders and Awad ( 1 , 2 ). oxford textbook of epilepsy and epileptic seizures 110 Fig. 10.1 Structural MRI of a patient with left temporal lobe epilepsy secondary to hippoca mpal sclerosis. A) Coronal FLAIR and (B) T2-weighted images showing increased signal and lo ss of internal structure of the left hippocampus (arrows). From Deblaere K, Achten E. Struc tural magnetic resonance imaging in epilepsy. European Radiology 2008; 18:119 \200\22329. One of the problems that this \201 eld will face in the future will be how to differentia te the epileptogenic potential of more subtle lesions detected with more advanced imaging t echniques. This will necessitate garnering converging evidence using other forms of imaging , as will be discussed in later sections. \202 uid (CSF). These sequences should be acquired in at least two orthog onal planes cov ering the whole brain, with the minimum achievable slice thickness. In particular, the acqu isition of T2-weighted or FLAIR images in the coronal plane perpendicular to the long axis of the hippocampus is critical to adequately visual- ize mesial temporal structures. Usuall y the administration of gadolinium is unnecessary in an initial scan, unless indicated in t he clinical history (e.g. a suspicion of a mass lesion or vascular lesion) ( 13 ). Voxel-based morphometry The principal shortcoming of attempting to quantify more subtle str uctural abnormalities on individual MRIs is that a volume of interest must \201 rst be de \201 ned (e.g. the hippocampus), and manual volumetry typically requires approximately 30 minutes of interac- tive time. In the research domain, voxel-based morphometry (VBM) is an MRI analysis technique which attempts to objectively and automatically identify morphologi cal abnormalities across a group of patients with epilepsy. Typically in VBM, T1-weighted v olumetric MRI scans are acquired for individual patients, and these images subsequently und ergo spatial normalization, tissue segmentation, and spatial smoothing in order to warp pat ients \200\231 brains to a standard space (Fig. 10.2 ). Statistical tests are then performe d across all voxels in the image to identify volume differ- ences between the patient group and a reference population. The advantage of this approach is that it can detect regional changes in tissue volume or density objectively and automatically, without needing to speci fy a priori which brain areas to examine ( 22 , 23 ). In addition to the aforementioned sequences, an optimized epi- lepsy protocol should also c omprise a high-resolution (ideally slice thickness <1.5 mm), three-dimensional, T1-weighted , gradient echo volume acquisition ( 14 , 15 ). This can be accomplished with a magnetizati on-prepared rapid acquisition with gradient echo (MPRAGE) sequence, or spoiled gradient rec alled (SpGR). This acquisition allows viewing of multiplanar images; avoids partial volume effects in detecting malformations of cortical development; and can correct for coronal hea d rotation. In addition, a further gradient echo T2 image (T2 * ) or susceptibility weighte d image (SWI) can be acquired to detect haemosiderin deposits, small cav- ernomas, or vascu lar anomalies. More recently, a new technique in MRI acquisition has been described (the PR OPELLER sequence), which images hippocampal structures with greater spatial resolu- tion ( 16 ). New morphometric methods are also being developed to automatically measure brain stru ctures ( 17 ). Several attempts have been made to improve on the standard approach, including tensor-based morphometry, which employs more detailed warping procedures ( 24 ); cortical thickness map - ping, in which gray matter thickness is compared across the brain surface; and voxel-base d relaxometry to compare T2 signal between subjects ( 25 ). In general, VBM and its derivat ives have provided interesting data showing the widespread structural changes that occur in epilepsy. For example, one study showed that patients with mesial TLE had widespread gray matter changes which extended to the thalamus, limbic system, and cerebellum, while patient s with cryptogenic TLE had gray matter loss in the tempo- ral, frontal and orbitofrontal co rtices ( 26 ). The precise de \201 nition of \200\230a high-quality MRI, \200\231 as suggested by the IL AE ( 4 ), obviously changes with time. In fact, further techni- cal and methodological adva nces in MRI have meant that some patients with previously unremarkable imaging have been sh own to have identi \201 able lesions in newer scanners with more advanced protocols. From a technical perspective, the use of higher \201 eld strength magnets (e.g. 3 Tesla) and/o r phased array surface coils ( 18 , 19 ) has been shown to increase the yield of structural MRI. Together, these advances have led some authors to advocate that patients with previou sly unremarkable MRI scans be rescanned as more advanced equipment and methods become avail able ( 20 ). CHAPTER 10 neuroimaging in the investigation of epilepsy 111 Fig.10.2 The process of spatial pre-processing for voxel-based morphometry. A) Raw images a re normalized to stereotaxic space (B) using the 305 normal data set of Montreal Neurologic al Institute (Template). C) Gray matter is automatically segmented from normalized images u sing a combined voxel intensity and a priori knowledge approach. D) An extraction technique removes non-gray-matter voxels. E) Normalized gray matter images are smoothed with an isot ropic Gaussian kernel with full- width half-maximum of 10 mm. There is bilateral hippocampa l pathology and diminished left parahippocampal-fusiform gray/white matter differentiation is visible in all stages. Adapted from Keller S, et al. Voxel based morphometry of gray mat ter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration Journal of Neurology, Neurosurgery and Psychia try 2002; 73( 6 ):648 \200\22355. magnetic \201 eld gradients into a standard spin echo sequence, one can acquire images th at are sensitive to the diffusion properties of water. By using this phenomenon, diffusion tensor imaging (DTI) aims to measure the movement of water molecules (i.e. the overall magn itude of diffusion), expressed as mean diffusivity (MD) or an apparent diffusion coef \201 cient (ADC) ( 31 ). The tendency of water molecules to diffuse in one direction over anoth er is expressed as fractional anisotropy (FA). ADC and FA represent the two key parameters in DTI. Increases in ADC and reductions in FA are thought to relate to neuronal loss, glios is, axonal or myelin abnor- malities, abnormal connections between brain regions, and/or st ructural disorganization, which may not be visible on conven- tional MRI ( 32 ). 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.