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 Relative to EEG alone, however, MEG offers several potential advantages. For example, in co ntrast to the electrical \201 elds meas- ured by EEG, the magnetic currents that are reco rded by MEG are less distorted by the tissue layers separating the brain and oxford textbook of epilepsy and epileptic seizures 120 Fig. 10.9 (Also see Color plate 12.) A polyphasic spike-and-slow wave interictal discharge recorded by simultanous EEG-MEG. A) The 306 magnetometers and gradiometers (green traces) a nd 34 EEG electrodes (dark blue traces) demonstrate high spatial coverage in (B) the recons tructed model. C) Comparison of individual magnetometer and orthogonal gradiometer \201 e ld maps correspond to (D) a standardized low-resolution brain electromagnetic tomography (s LORETA) analysis of the distributed dipolar source orientation strength and equivalent curr ent dipole (green dipole). Reproduced with permission of Simon Vogrin. or multiple cavernomas) or lesions of undetermined signi \201 cance ( 165 ). In addition, MEG can be used as a non-invasive alternative to ECoG in the 20 \200\22360 % of patients wh o have had previously unsuc- cessful epilepsy surgery ( 168 \200\223171 ). In such patients , scalp EEG is often distorted by scalp scarring, skull defects, and CSF collections. MEG m ay therefore offer more accurate localization than scalp EEG. In addition, it is a good alt ernative to those patients who have postoperative dural adhesions which hinder the insertio n of inva- sive intracranial electrodes. Due to the need to minimize head movements during recordings, most MEG studies have predomi- nantly aimed to localize interictal events. Some authors have docu- mented ictal events as well, but obviously this is not possible in the majority of cases, due to the associated head movements. scalp surface ( 157 ). Consequently, there is less spatial blurring of these signals, and M EG may therefore more reliably localize brain activity, at a spatial resolution of 2 \200 \2233 mm (cf. 7 \200\22310 mm with EEG) ( 158 , 159 ). Furthermore, MEG is less susceptible to variation in head geometry compared to EEG, and can be better estimated using the simpl e spherical model. MEG requires 3 \200\2234 cm 2 of syn- chronized cortical activity to det ect an epileptic spike ( 160 , 161 ), whereas 6 \200\22320 cm 2 is required for scalp EEGs ( 162 , 163 ). In comparison to other functional neuroimaging techniques, MEG has excellent temporal resol ution. When MEG source locali- zation is coregistered on patients \200\231 structural MRIs (a process known as magnetic source imaging, MSI), the magnetic dipole rep- resenting an ep ileptiform discharge can be visualized on the patient \200\231s MRI scan, thus affording go od spatial resolution as well ( 164 , 165 ). In terms of the sensitivity of MEG, one large series of 455 epi- lepsy patients who were ev aluated preoperatively demonstrated an average sensitivity of 70 % ( 165 ). Among patients who underwent surgical therapy, MSI successfully localized a lesion in 89 % , sup- plied ad ditional information in 35 % , and provided information that was crucial to medical decisio n-making in 10 % ( 165 ). Some studies suggest that MEG has speci \201 c advantages for sp ike detection in extratemporal epilepsies, particularly those that lie super \201 cially o n the brain \200\231s surface (e.g. one study showed a sensitivity in MTLE MEG plays two roles in presurgical evaluation. First, it is useful in identifying the epile ptogenic focus itself. In the case of MRI- negative cases, MEG can assist in detecting the ictal source, and MEG-guided reviews of MRI have revealed subtle abnormalities not initiall y seen in around 17.5 % of cases ( 166 , 167 ). On the other extreme, MEG can be used to id entify the epileptogenic focus in patients with multiple intracerebral lesions (e.g. tubero us sclerosis