**2.2 Diffusion weighted imaging (DWI)**

One of the more commonly encountered techniques in MRI is DWI. DWI was initially introduced in clinical practice for the early detection of stroke as it is very sensitive to areas affected by ischemia [19]. Animal studies on status epilepticus have highlighted initial restricted diffusion due to cytotoxic edema and, after several days, to normalization or facilitated diffusion [20–23]. Diffusion imaging may, therefore, provide an opportunity to directly image the areas involved in seizure generation and possibly spread. Overall, the correlation between the presumed epileptogenic zone and the diffusion changes is quite variable. In focal epilepsies, peri-ictal isolated low ADC values without overt hyperintensity on DWI have been reported. Peri-ictal cytotoxic edema with foci of hyperintensity on DWI with decreased ADC values have also been reported [24–26]. Correlations seem closer in patients with longer seizures (or status) and short duration between seizure end and scan [24, 27]. In contrast, interictal neuronal loss and increased extracellular space have been reflected in increased ADC values. Other disorders related to epilepsy that may show DWI abnormalities include cortical and subcortical abnormalities in status epilepticus, antiseizure medications and transient lesions of splenium of corpus callosum related to seizures [28–30]. A significant increase in ADC has been reported in epileptogenic tubers in patients with tuberous sclerosis.

#### **2.3 Diffusion tensor imaging (DTI) and tractography**

Diffusion tensor imaging (DTI) allows measurement of water diffusion in order to provide information on microstructural changes and connections between different regions of the brain. Animal models have revealed myelin as the main barrier to water diffusion [31–34]. This allows interrogation of white matter architecture and morphological reconstruction of major tracts in vivo. This method is still quite crude, however, and cannot resolve distinct fibers that cross within a voxel. White matter tractography is generally done in two different ways, either with a method known as "deterministic" tractography or with a "probabilistic" method. Using deterministic methods, points are placed, and the tract grows in both directions along the dominant diffusion direction. The probabilistic method probe fiber orientation distributions at each voxel and is computationally more intensive but can more reliably reconstruct crossing fibers.

The objective of epilepsy surgery in pharmacoresistant focal epilepsies is complete resection or at least disconnection of the epileptogenic zone while preserving eloquent cortex [2, 35]. Exploring white matter changes in epilepsy can help us to understand epileptogenicity, they may also be a surrogate marker for cognitive difficulties and can inform clinicians about risks of epilepsy surgery procedures. Once successfully implemented into neuronavigation systems this information may also be used intraoperatively to tailor resections [36]. Extratemporal surgeries will also benefit from visualizing crucial connections and tracts such as the pyramidal tract. Implementation of DTI-based tractography has already been shown to benefit patients undergoing brain tumor surgeries and resections of vascular malformations [36–40] and will certainly be increasingly used in epilepsy surgery.

#### **2.4 fMRI**

The simultaneous recording of electroencephalogram (EEG) and functional MRI (fMRI) was first demonstrated in patients with epilepsy in the early 1990s and has since become an important research tool in epilepsy and beyond [41]. EEG-fMRI has been primarily used as a localization technique. In addition it can be combined with other more advanced modeling methodologies to study the networks connectivity. Together, both technologies may allow for novel insights in understanding the ictalonset zone, irritative zone, and functional deficit zone (the connectome).

#### **2.5 Ultra-high-field 7T MRI**

The first 7T MRI scanner was FDA approved for clinical diagnostic use in October 2017. 7T MRI is currently available for use in few centers. Improved image resolution and contrast at 7T, especially with the MP2RAGE sequence [42] opens new possibilities for visualization of internal details of hippocampal subfields [43]. Although the clinical yield of 7T visual analysis on 3T-negative cases was still unclear in TLE, studies utilizing quantitative approaches have suggested promising results [44, 45]. 7T MRI can lead to better detection of FCD in ETLE, even in some cases with negative 3T MRI [46–52]. The availability of higher magnetic field strength does not preclude the combined use of advanced image postprocessing to optimize diagnostic yields.

#### **2.6 MRI postprocessing techniques**

Several commercial packages enable the quantification of MRI structural features and are currently used in routine clinical practice. FDA-approved software packages include NeuroQuant (Cortechs Labs, San Diego, CA), BrainReader (BrainReader, Denmark), and icobrain (icometrix, Leuven, Belgium). These softwares typically generate a report that details the volume and percentile of each parcellated cortical regions, with comparison to normative databases. In epilepsy, NeuroQuant has been shown to lateralize hippocampal atrophy in TLE patients with accuracy rates that could exceed those achieved with visual inspection of clinical MR imaging studies [53].

Incorporating postprocessing techniques into routine care requires the use of high-quality MRI acquisition with 3D volumetric sequences for optimal results. It also requires specialized expertise in computational anatomy and seamless communication within the multidisciplinary epilepsy team. These techniques can provide unapparelled power in the ability to detect significant epileptogenic brain lesions in surgical candidates. Discovering a previously undetected lesion can drastically change the presurgical planning and surgical outcome. In fact, the lack of a visible lesion has consistently been shown to predict surgical failure [54, 55], and MRI-positive surgical candidates are two times more likely to become seizure free after epilepsy surgery than MRI-negative patients [56].

MCD is generally regarded as the most common epileptogenic substrate that can evade detection. Sometimes the only MRI finding of MCD can just be subtle blurring at the gray–white junction without hyperintensity on T2 or FLAIR. Novel quantitative image analyses can increase the yield of detecting relevant structural lesions in a sensitive, replicable, and reader-independent fashion, significantly complementing conventional visual analysis. Image reconstruction by manual means in a curvilinear plane—a plane parallel to the cortical surface and perpendicular in relation to the gyri—can show progressively deeper surfaces of the brain. This will result in a more

uniform distribution of gray matter on both hemispheres assisting in comparison of homologous regions of the cortex [57–59]. In addition to improving the detection of subtle MCDs, such surface reconstructions can also more precisely assess the location of subdural grids and depth electrodes and aid in presurgical planning.

## **2.7 Voxel-based morphometry (VBM)**

VBM is one of the most popular and most useful postprocessing algorithms to date. Large-population control averages are used as common reference [60], however, references for adults should not be used to study paediatric cohorts. This fully automated technique extracts gray matter and white matter maps from individuals to make statistical comparisons with respect to a normal database [61]. VBM is able to accentuate abnormalities in the gray-white junction [62], minimizing "false-positive" studies. When there is an a priori hypothesis based on clinical and EEG data to confine the analysis to a certain brain region, VBM can be used to aim for maximal specificity. Whereas when EEG or other functional imaging data do not point to a region of interest, it is essential to opt for maximal sensitivity.

VBM consistently reported gray matter abnormalities extending beyond the visible culprit, sometimes distant from the epileptogenic area [63–66]. These changes could be due to occult dysplastic regions undetectable by visual analysis or represent an abnormal gyration [63]. These clusters may indicate dysplastic abnormalities much more widespread across the hemispheres than the changes visible on the MRI and may explain, at least in part, why in some cases complete resection of MRI lesion does not always lead to seizure freedom. It is also conceivable that these changes may potentially become active at a later stage and cause seizure recurrence after surgery [67].

#### **2.8 MRI volumetry**

In temporal lobe epilepsy (TLE), the epileptogenic network causes variable degrees of neuronal loss and astrogliosis across hippocampal subfields, the amygdala, and the entorhinal cortex, namely mesial temporal sclerosis (MTS) [68]. In many patients, MTS can be visualized on MRI as noticeable hippocampal atrophy, increased T2-weighted signal, and loss of internal architecture. However, the visual identification of morphologic and signal characteristics of the hippocampus is highly subjective and depends heavily on the experience of the reader. Manual MRI volumetry is a commonly used quantitative technique to assess mesial temporal lobe atrophy, as it has been demonstrated to be more sensitive than visual evaluation [69]. Volumetry of the entorhinal cortex, amygdala, and temporopolar region as well as the thalamus may also assist in lateralization of the seizure focus [70]. Specifically, in patients with a normal-appearing hippocampal structure by visual inspection, volumetry of the entorhinal cortex atrophy can provide accurate lateralization of the seizure focus in 25% of cases [71]. Quantification of mesial temporal structures is strongly recommended in order to detect subtle atrophy or abnormal signal increases ipsilateral to the seizure focus and to assess objectively the integrity of the contralateral structures in preparation for epilepsy surgery. Indeed, bilateral mesial temporal lobe atrophy raises concern of markedly reduced chance of seizure freedom after surgery, and an increased risk of memory impairment.

Volumetry studies have consistently revealed gray matter reduction extending beyond the atrophic hippocampus to the adjacent parahippocampal, frontal and anterior temporal regions, suggesting a disruption of frontolimbic pathways. These widespread abnormalities have been associated with seizure frequency [72], epilepsy duration [73, 74], and cognitive dysfunction [75–78]. Patients with persistent seizures after removal of the hippocampus may also have a more widespread neocortical grey matter volume loss [79, 80].

## **2.9 Sulcal morphometry**

Sulcal and gyral abnormalities in ETLE patients are characterized by a spectrum of changes [81–83]. In some instances these sulcal morphologic signs may be the only marker for cortical dysgenesis. It was reported that 85% of small FCD lesions that elude visual inspection are found at the bottom of an abnormally deep sulcus [84]. Such preferential location can be explained by local weakness within the developing cortical mantle, co-occurrence of incomplete maturation, decreased neuronal density, and disrupted connectivity in areas surrounding the FCD [69, 85]. Automated extraction, identification, and statistical analysis of cortical sulci was tested in a small series and small FCDs not detected on routine MRI was found on histopathology, particularly in the depth of the posterosuperior and intermediate frontal sulci [86].
