Graph theory is a framework for the mathematical repre- sentation and analysis of complex systems. It has been applied to the analysis of artificial and biological networks (Watts and Strogatz, 1998). Graph theoretical analysis has recently attracted considerable attention in brain research because it provides a powerful formalism to quantitatively describe the topological organization of connectivity (Bullmore and Sporns, 2009; Guye et al., 2010; Bassett and Gazzaniga, 2011; Bullmore and Bassett, 2011; Alexander-Bloch et al., 2013). In graph theory terms, a network is a collection of nodes that are interconnected by edges. Nodes usually represent brain regions, while edges rep- resent (structural or functional) connections. A pre-requisite to connectivity analysis is the proper designation of nodes as distinct gray matter regions. Various parcellation schemes have been proposed, including approximating Brodmann areas based on imaging-derived surrogates of myelination (Glasser and Van Essen, 2011; Bock et al., 2013), sulcation-based atlases (Van Essen, 2005; Desikan et al., 2006), high-resolution parcellations (Hagmann et al., 2008; Honey et al., 2009), as well as schemes that take the imaging voxels/vertices themselves as nodes (Lohmann et al., 2010; Tomasi and Volkow, 2011). In addition, several studies have also used data-driven techniques such as indepen- dent brain components to define network nodes (Yu et al., 2011b, 2013). Nodal definitions have shown to have a large influence on graph-theoretical parameters (Tohka et al., 2012), and the definition of reliable, biological meaningful parcella- tions schemes continues to be an active area of current research (Geyer et al., 2011; Glasser and Van Essen, 2011; Van Essen et al., 2012).
We enrolled 43 consecutive right-handed patients suffering from unilateral HS and mTLE who received a presurgical evaluation at the Guangdong 999 Brain Hospital. The diagnosis and lateralization of the seizure focus to the left mTLE (n = 22) or the right mTLE (n = 21) that were determined based on a comprehensive evaluation, including a detailed history, video-EEG telemetry and neuroimaging. An increase in the T2 ﬂuid-attenuated inverted recovery signal in the hippocampus was used as the diagnostic criterion for HS, and the site of HS was concordant with the epileptogenic site in all patients. None of the pa- tients had a mass lesion (including tumor, vascular malformation or malformations of cortical development) or suffered from traumatic brain injury or any psychiatric disorders, but all patients experienced secondary generalized seizures. After MRI acquisition, all patients re- ceived anterior temporal lobectomy. Following qualitative histopatho- logical analysis, HS was detected in all patients. So far, there is no seizure recurrence in post-operation patients. Thirty-nine age-, gender- and education-matched right-handed healthy control partici- pants were recruited for this study. All controls were healthy and free of neurological or psychiatric disorders at the time of the study. The de- mographic and clinical data are presented in Table 1 .
Amobarbital Procedure (IAP), and neuropsychological testing was used to lateralize the side of seizure focus. All patient participants met the following inclusion criteria: unilateral temporallobe seizure onset through surface video/EEG recordings (i.e., a single unilateral temporallobe focus); MRI or PET evidence of temporallobe pathology confirming the presence of temporallobe atrophy, most commonly mesialtemporal sclerosis, in the epileptogenic temporallobe; concordant PET finding of hypometabolism in the temporallobe (available for most patients); Full-Scale IQ (FSIQ) of at least 75. TLE participants were excluded from the study on grounds of any of the following: medical illness with central nervous system impact other than epilepsy; head trauma; prior or current alcohol or illicit drug abuse; extratemporal or multifocal epilepsy (a likely ictal focus outside the one temporallobe); contraindications for MRI; psychiatric diagnosis other than a Depressive Disorder or hospitalization for an Axis I disorder listed in the Diagnostic and Statistical Manual of Mental Disorders, IV. Depressive Disorders were allowed given the high co- morbidity of depression and epilepsy (Tracy et al., 2007). Participants provided written informed consent. The study was approved by the Institutional Review Board for Research with Human Subjects at Thomas Jefferson University. Table 1 outlines the demographic and clinical characteristics of the participants.
An important tool in the presurgical evaluation of MTLE patients is functional neuroimaging with 18 F- fluorodeoxyglucose positron emission tomography (FDG- PET). FDG-PET measures regional cerebral glucose metabolism semi-quantitatively and visualizes the dis- tribution of altered glucose metabolism [8, 9]. FDG-PET scans reliably lateralize the seizure focus in patients with MTLE, with decreased metabolism in the epileptogenic temporallobe [10–12]. Absolute cerebral glucose metab- olism may be decreased by 10–30% as a result of AED use [13, 14]. FDG-PET may be a reliable indicator of clinical outcome after surgery as greater severity of preoperative hypometabolism in the resected temporallobe is associ- ated with significantly better postoperative seizure control [15–17]. Ipsilateral hypometabolism showed a predictive value of 86% for good outcome in a meta-analysis of 46 studies . However, interictal hypometabolism remote to the ictal onset zone is also often noted and is related to a poor surgical outcome [19, 20]. Also, a significant relation between the time of the last seizure and the degree of observed regional hypometabolism in epilepsypatients has been reported . The exact underlying mechanism for the interictal hypometabolism is not fully understood. In this regard, the hypometabolic area seen on interictal FDG-PET is typically larger than the abnormality identified on structural imaging and may extend beyond the tem- poral lobe, likely representing areas of seizure propagation . Thus, PET images of regional hypometabolism should
Schoene-Bake et al., 2009; Yogarajah et al., 2010). One possible reason is that inherent pre-existing abnormalities due to genetic factors or developmental abnormalities might exist in the whole brain in patients with MTLE (Velisek and Moshe, Epilepsia 2003; Love, Lancet Neurol 2005). However, whether there is any pathway that is specifically impaired compared with other white matter pathways in patients with MTLE remains unclear. Given that the epileptic activity arising from the focus is assumed to generate the functional deficit zone in remote cortical regions through white matter pathways as mentioned above, we would hypothesize that epileptic activity specifically impairs these pathways.
through these projections. According to a second hypothesis (hippocampal contribution hypothesis) , executive fun- ction deficits in MTLE are related to dysfunction of the hippocampus. Specifically, as the hippocampus is involved in the retrieval of information from short-term memory, in the formation of memory associations, and in learning new information, the MTLE patients’ impairments in working memory tasks as well as in other executive function tasks, such as the WCST, that rely on such processes would result from dysfunction of the hippocampus. Finally, increasing evidence  points to the implication of extratemporal functional and structural brain abnormalities—for example, damage to frontosubcortical circuits, volume loss, or metabolic changes in extratemporal regions—in the executive function disorders of TLE patients. Our study design does not allow us to precisely define the impact of these diﬀerent factors on executive function performance. Although an exploratory analysis indicated that patients with hippocampal abnormalities (MTLE-HC) scored lower than patients with amygdala abnormalities (MTLE-CA) and healthy controls in the WCST, we may not exclude the possibility that diﬀerent factors—propagation of epileptic discharges, dysfunction of mesialtemporal structures, and extratemporal brain modifications—contributed to the executive function disorders of MTLE patients in this study. Other investigation methods—for example, functional magnetic resonance imaging, voxel-based morphometry, or di ﬀusion tensor imaging—have to be employed, together with neuropsychological testing, to address this question.
Although MTLE patients have severe clinical symptoms and imaging can identify mesialtemporal sclerosis, for the majority of MTLE patients, conventional MRI sequences do not show obvious abnormalities in the remainder of the brain parenchy- ma.  Therefore, more sensitive MRI methods, such as diffusion tensor imaging, are needed to noninvasively detect and exam microstructural changes in the brain of MTLE patients.  In recent years, advanced MRI methods have been used to assess the brain structural and functional changes of epilepsypatients. [6 –8] A recent meta-analysis of DTI studies in MTLE patients revealed signiﬁcant, widespread microstructural changes across the majority of WM regions, with the most obvious de ﬁcits occurring in regions closely connected to the temporal WM, including the arcuate fasciculus, uncinate fasciculus, and inferior longitudinal fasciculus.  However, most studies
To the best of our knowledge, this is the first study elucidating the relationship between hippocampal atrophy and structural and functionalconnectivity in patients with left MTLE ⫹ HS. We ob- served that the regression model used was highly significant, even though a potential outlier of data was removed from the model estimation. Specifically, left HV positively correlated with the mean GFA of the left iCB, but it did not correlate with the left iFC. Compared with controls, the HV, SC, and iFC indices were sig- nificantly decreased on the lesion side of patients. As discussed below, the association between the HV and its connection to the PCC allowed us to explore the pathophysiology of the epileptic network in unilateral MTLE ⫹ HS.
It is not entirely understood how temporallobeepilepsy (TLE) with and without hippocampal atrophy (HA) affect cortical language distribution. We investigated TLE patients with right HA (RHA), left HA (LHA) and negative MRI (nonHA) and controls using semantic-language fMRI task and Boston naming test (BNT). Groups did not differ in frequency of atypical language lateralization (LL). LL correlated with handedness differently in each region and group. Activation patterns and ROI-to-ROI functionalconnectivity (FC) differed between LHA and controls, as well as LHA and nonHA. Seed-to-voxel FC demonstrated greater differences between patients and controls and smaller differences among patients’ groups. RHA and LHA differed from controls in BNT. BNT correlated with fMRI activation in RHA and nonHA. Hierarchically, LHA impacts naming performance, fMRI activation pattern and FC, more than RHA, and no-HA were similar to controls, except for FC. Contrary to expected, HA, did not increase the frequency of atypical LL.
Several lines of research have linked olfactory regions with the pathophysiology of focal epilepsies. Among those regions, the piriform cortex represents the major part of the primary olfactory cortex. According to these data, we raised the hypothesis that in patients with mesialtemporallobeepilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that could be more significant compared to patients with extra‐hippocampal focal epilepsy and healthy controls. This could be the consequence of a dysfunctional epileptogenic network that extends beyond the hippocampus and affects other structures, including the piriform cortex. To test this hypothesis, we evaluated the olfactory function with the Sniffin' Sticks test in 32 patients with mesialtemporallobeepilepsy associated with hippocampal sclerosis, 30 patients with extra‐hippocampal focal epilepsy, and 22 healthy con- trols. Compared to the other study groups, patients with temporallobeepilepsy due to hippocampal sclerosis showed a basal olfactory dysfunction characterized by an impairment in odor discrimination and odor identification. We also found that high seizure frequency had a strong correlation with the evaluated olfactory tasks. Our results are consistent with neuroimaging and neuropathological data that establish a link between olfactory regions and the pathophysiology of temporallobeepilepsy.
Interictal discharges, initiated by large postsynaptic depolarizations (Staley & Dudek, 2006), are used as diagnostic tools for seizure localization and chronic pre-surgical monitoring (see Curtis, Jeﬀerys, & Avoli, 2012, for review). Using a kindling model, Wadman, Lopes da Silva, and Leung (1983) showed that in addition to the after-discharges (ADs) occuring following the kindling stimulus, short transients termed spontaneous interictal spikes (SISs) may occur spontaneously between seizures. Similar transients or spikes may be found in the clinical EEG as spikes and sharp waves of certain types of epileptic patients (Niedermeyer & Lopes da Silva, 2004). Leung (1988) observed that the frequency of SISs was high during slow-wave sleep (SWS), waking immobility, face-washing and chewing while it was relatively lower during rapid-eye-movement sleep (REMS), walking and rearing. Engel and Ackermann (1980) suggested that a high SIS rate may be correlated with an increased threshold for evoking an AD and consequently, seizures. In amygdala-kindled spontaneous seizing cats, Wada, Sato, and Corcoran (1974) reported a significant increase in the SIS rate before the onset of spontaneous convulsions, while Gotman (1984) and Gotman and Marciani (1985) demonstrated in cats and humans respectively that this increase did not aﬀect the occurrence of spontaneous seizures.
Our study included subjects with ictal semiology characteristic of mesialtemporallobeepilepsy, con ﬁrmed with video EEG monitoring
and showing ictal scalp EEG changes which localized to the involved temporallobe. While scalp EEG recordings correctly predict ﬁndings of other techniques, such as intracranial electrode studies, approxi- mately 90% of the time (Risinger et al., 1989), ictal scalp EEG patterns can be misleading in a minority of cases. For instance, as noted above, in a series of 21 patients who underwent stereotactic recordings from the insula, while 19 of 21 patients showed involvement of the insula at some point during the seizure, two of these patients (~ 10%) showed ictal onset in the insula (Isnard et al., 2000). It is thus possible that nodes in the network of increased connectivity described in this study which are outside the hippocampus, including the insula, may have functioned as the ictal onset zone and not just as a region of sec- ondary propagation of the seizure. Similarly, ictal EEG semiology for complex partial seizures, while predictive of the region of origin of seizures, is also not completely speci ﬁc for seizure localization (Palmini and Gloor, 1992). In addition, it has been historically dif ﬁcult to distinguish between medial and lateral temporal onset seizures using only clinical semiology and ictal scalp EEG. While there are a number of clinical and electrographic differences between subjects with mesial and lateral onset TLE, they are not suf ﬁcient to allow de- ﬁnitive distinction in all subjects ( O'Brien et al., 1996). Indeed, this may also re ﬂect the heterogeneity noted in our group with regards to the presence of hippocampal atrophy. Yet recent studies have noted widespread connectivity differences involving the medial tem- poral region even in patients with non-lesional epilepsy (Weaver et al., 2013). However despite the possibly heterogeneous origin of sei- zures (i.e. mesial vs. lateral temporal onset) in some of our subjects, the overall ﬁndings of increased ipsilateral hemispheric connectivity and decreased local and inter-hemispheric connectivity remain as ro- bust results in our otherwise homogeneous study cohort. Further- more our group of patients is re ﬂective of the population of patients with temporallobe seizures that are routinely seen in adult epilepsy care, supporting the generalizability of our ﬁndings. Further studies to evaluate speci ﬁc subgroups of subjects with TLE will likely be help- ful to understand the interaction between resting state functional network changes and medial and lateral TLE.
served decreases in mean blood flow or metabolism could be due to mesialtemporal atrophy. However, in one case (patient 7), a clear asymmetry in per- fusion (asymmetry index 5 2 12.88) was identified despite normal structural MR imaging (hippocam- pal volume asymmetry index 5 0.51). This finding suggests dissociation between structure and func- tion. Additional evidence supporting structure- function dissociation can be found in the data re- garding patients 1 and 6 in this series, which indicate that the functional parameters, MR perfu- sion asymmetry index and PET asymmetry index, lateralized to the right and the structural parameter, MR volumetric asymmetry index, lateralized to the left. Patient 6 continued to have seizures, but pa- tient 1 was seizure-free after surgery. We also note that lateralization using functional tests (perfusion MR imaging and 18 FDG-PET) correlated more
To investigate the eﬀect of heterozygous and homozygous (double hit) events, genes carrying ≥2 mutations in het- erozygous and homozygous conﬁgurations were summa- rized. At least 1 hit inherited from each unaﬀected parent is required to ﬁt the sporadic nature of the recruited samples. Rare variants at MAF ≤ 1% (in the 1000 Genomes Project Phase III, ExAC, and dbSNP137 databases) were considered in the analysis. We considered the following scenarios of genes carrying double hit variants, which are rare/absent in the population: (1) candidate genes suggested by functional databases (Phenolyzer and SynaptomeDB) and with ad- justed p values <0.05; (2) both contributing variants are nonsense and not found among phased controls (Genome of the Netherlands project suggested double knockout by Loss- of-Function variants are very rare) 22 ; and/or (3) genes with de novo variants carried by the patients with MTLE-HS. Details of each approach are described in Supplemental materials, links.lww.com/NXG/A55. The recurrences in the subsequent gene list were further investigated for their rel- evance to MTLE-HS.
Patients with MTLE-HS were identified from a large clinical database developed by the EpiPGX consortium, a European multicentre research project on epilepsy pharmacogenetics (www.epipgx.eu). This database contains phenotypic information collected from medical records on over 12000 patients with a confirmed diagnosis of epilepsy, with detailed information on more than 40000 AED trials. Data collection was approved by the Institutional Review Boards of the participating centres and all patients provided written informed consent for use of their clinical data.
50% of such patients proceeding to surgery (Lhatoo et al. 2003). Furthermore for each 50 million people a backlog exists of 5000 patients who would benefit from surgery (Lhatoo et al. 2003; Cascino 2008 ). Localisation-related seizures of temporallobe origin have been considered to most likely benefit from surgery. In a randomised, controlled intention-to-treat trial including 80 patients, the 40 patients who had temporallobeepilepsy surgery had a 58% chance of freedom form disabling seizures compared with 8% of patients who continued medical therapy (p<0.001) (Wiebe et al. 2001). The goal of epilepsy surgery is complete removal of the epileptogenic area without causing a permanent neurological deficit. Several different diagnostic techniques can be used to determine the ictal generator and epileptogenic zone. Structural and functional imaging, neurophysiological techniques and psychological testing help to identify the seizure focus and will be discussed in the paragraphs below. Even though there might be a high chance of seizure freedom, the risks and benefit of epilepsy surgery vary for each individual patient. Epilepsy surgery may be divided into two major categories: resective and functional. In adults, the most common surgical procedure for mTLE involves the medial temporallobe—either an
Resting-state fMRI provides a promising methodology for helping to elucidate the relationship between cognitive dysfunction abnormalities in MTLE and a broader, maladaptive extra-temporal brain network. Functionalconnectivity (FC) measures for resting-state fMRI highlight the temporal correlations between remote brain regions (Friston, 1994). In epilepsy, such resting state studies have begun to show functional changes in large-scale networks, compared with healthy participants. Such investigations have resulted in the description of functionalconnectivity abnormalities in the whole brain (Liao et al., 2010), and within several functional networks outside the temporallobe such as the well-known default-mode (Zhang et al., 2010), in addition to attentional (Zhang et al., 2009), and language (Waites et al., 2006) networks. To date several studies with MTLE patients have specifically explored the FC emerging from the hippocampus at rest (Bettus et al., 2009; Morgan et al., 2011; Pereira et al., 2010), and tested a relationship to memory functioning (Bettus et al., 2009). These studies, however, have mainly explored the FC between both temporal lobes, excluding extra-temporal regions. For example, Bettus et al. (2010) investigated FC between bilateral temporal regions in a left TLE patient sample. They highlighted reduced FC within the left pathologic temporallobe, while the right non- epileptic temporallobe was associated with increased FC, compared to controls. In another study, FC changes between the posterior and anterior parts of the right hippocampus were associated with a working memory quotient in a left MTLE group (Bettus et al., 2009). Although such a direct relation between neuropsychological and resting state functional
Data preprocessing was performed by using the Statistical Para- metric Mapping software package (SPM8; http://www.fil.ion. ucl.ac.uk/spm/software/spm12). For each subject, the first 10 vol- umes of scanning data were discarded to reduce magnetic satura- tion effects. The remaining 150 volumes of data were corrected by registering and reslicing for head motion. Subsequently, these volumes were normalized to standard echo-planar imaging tem- plates in Montreal Neurological Institute space. The resulting im- ages were spatially smoothed with a Gaussian filter with an 8-mm full width at half maximum kernel, detrended to remove linear trends, and temporally filtered with a Chebyshev bandpass filter (0.01– 0.08 Hz) to reduce artifacts caused by respiration or cardiac action. All fMRI volumes were registered to a Montreal Neuro- logical Institute template before further time-series extraction for ROIs. The Montreal Neurological Institute coordinates for the ROIs in this template are shown in the On-line Table. Each re- gional mean time-series was further corrected for the effects of WM, CSF, and head movement by regression on the time-series of WM, CSF signal and translations, and rotations of the head esti- mated in the course of initial movement correction by image re- alignment. The residuals of these regressions constituted the set of regional mean time-series used for functionalconnectivity analysis. 16
recent study presents functional coherence of ictal spikes followed by fast rhythmic spikes in the frontal lobes of mTLE patient with epileptic nystagmus (Kim et al., 2013).
In contrast to significant decreases in resting state connectivity, we observed significantly increased connectivity to the thalamus (DMN and SN) and precuneus (DMN and DAN). The thalamus is anatomically connected to the mesolimbic structures, namely the hippocampus, amygdala, and entorhinal cortex (Carlesimo et al., 2011; Swenson, 2006) and the associated thalamo-cortical activity has been implicated in the regulation of consciousness (Min, 2010; Zhou et al., 2011). Both the DMN and SN play a critical role in maintaining consciousness and awareness; as such, disturbances in functionalconnectivity within these networks might be associated with reductions or loss of awareness during seizures (Craig, 2009; Luo et al., 2014). We suggest that the increased connectivity to the thalamus may serve as a compensatory mechanism that counters the functional alterations within the DMN and SN in mTLE patients. The precuneus, on the other hand, is known to be involved during orienting tasks (Kelley et al., 2008, Yantis et al., 2002) and is anatomically connected to the intraparietal sulcus, an area critically involved in visual and spatial processing (Cavanna and Trimble, 2006). Other cortical and sub-cortical projections to and from the precuneus have been demonstrated, for instance to the thalami (Schmahmann and Pandya, 1990), claustrum, and brainstem (Yeterian and Pandya, 1993). This wide range of connections indicates the importance and complexity of the precuneus in regulating higher cognitive function, although its exact role and mechanism are not fully understood. Its abnormal connectivity to intraparietal sulcus in mTLE patients might, however, suggest compensatory recruitment in response to the lack of functional coherence within the DMN and DAN networks.