Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

OBJECTIVE: Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. METHODS: Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. RESULTS: We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. SIGNIFICANCE: Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Identifying epileptogenic abnormality by decomposing intracranial EEG and MEG power spectra.

BACKGROUND: Accurate identification of abnormal electroencephalographic (EEG) activity is pivotal for diagnosing and treating epilepsy. Recent studies indicate that decomposing brain activity into periodic (oscillatory) and aperiodic (trend across all frequencies) components can illuminate the drivers of spectral activity changes. NEW METHODS: We analysed intracranial EEG (iEEG) data from 234 subjects, creating a normative map. This map was compared to a cohort of 63 patients with refractory focal epilepsy under consideration for neurosurgery. The normative map was computed using three approaches: (i) relative complete band power, (ii) relative band power with the aperiodic component removed, and (iii) the aperiodic exponent. Abnormalities were calculated for each approach in the patient cohort. We evaluated the spatial profiles, assessed their ability to localize abnormalities, and replicated the findings using magnetoencephalography (MEG). RESULTS: Normative maps of relative complete band power and relative periodic band power exhibited similar spatial profiles, while the aperiodic normative map revealed higher exponent values in the temporal lobe. Abnormalities estimated through complete band power effectively distinguished between good and bad outcome patients. Combining periodic and aperiodic abnormalities enhanced performance, like the complete band power approach. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Sparing cerebral tissue with abnormalities in both periodic and aperiodic activity may result in poor surgical outcomes. Both periodic and aperiodic components do not carry sufficient information in isolation. The relative complete band power solution proved to be the most reliable method for this purpose. Future studies could investigate how cerebral location or pathology influences periodic or aperiodic abnormalities.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Epileptogenic networks in extra temporal lobe epilepsy.

Extra temporal lobe epilepsy (eTLE) may involve heterogenous widespread cerebral networks. We investigated the structural network of an eTLE cohort, at the postulated epileptogenic zone later surgically removed, as a network node: the resection zone (RZ). We hypothesized patients with an abnormal connection to/from the RZ to have proportionally increased abnormalities based on topological proximity to the RZ, in addition to poorer post-operative seizure outcome. Structural and diffusion MRI were collected for 22 eTLE patients pre- and post-surgery, and for 29 healthy controls. The structural connectivity of the RZ prior to surgery, measured via generalized fractional anisotropy (gFA), was compared with healthy controls. Abnormal connections were identified as those with substantially reduced gFA (z < -1.96). For patients with one or more abnormal connections to/from the RZ, connections with closer topological distance to the RZ had higher proportion of abnormalities. The minority of the seizure-free patients (3/11) had one or more abnormal connections, while most non-seizure-free patients (8/11) had abnormal connections to the RZ. Our data suggest that eTLE patients with one or more abnormal structural connections to/from the RZ had more proportional abnormal connections based on topological distance to the RZ and associated with reduced chance of seizure freedom post-surgery.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group. Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset (ηρ2max=0.05) and longer epilepsy duration (ηρ2max=0.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellum subregions into neurobiological models of epilepsy.

Interictal magnetoencephalography abnormalities to guide intracranial electrode implantation and predict surgical outcome.

Intracranial EEG is the gold standard technique for epileptogenic zone localization but requires a preconceived hypothesis of the location of the epileptogenic tissue. This placement is guided by qualitative interpretations of seizure semiology, MRI, EEG and other imaging modalities, such as magnetoencephalography. Quantitative abnormality mapping using magnetoencephalography has recently been shown to have potential clinical value. We hypothesized that if quantifiable magnetoencephalography abnormalities were sampled by intracranial EEG, then patients' post-resection seizure outcome may be better. Thirty-two individuals with refractory neocortical epilepsy underwent magnetoencephalography and subsequent intracranial EEG recordings as part of presurgical evaluation. Eyes-closed resting-state interictal magnetoencephalography band power abnormality maps were derived from 70 healthy controls as a normative baseline. Magnetoencephalography abnormality maps were compared to intracranial EEG electrode implantation, with the spatial overlap of intracranial EEG electrode placement and cerebral magnetoencephalography abnormalities recorded. Finally, we assessed if the implantation of electrodes in abnormal tissue and subsequent resection of the strongest abnormalities determined by magnetoencephalography and intracranial EEG corresponded to surgical success. We used the area under the receiver operating characteristic curve as a measure of effect size. Intracranial electrodes were implanted in brain tissue with the most abnormal magnetoencephalography findings-in individuals that were seizure-free postoperatively (T = 3.9, P = 0.001) but not in those who did not become seizure-free. The overlap between magnetoencephalography abnormalities and electrode placement distinguished surgical outcome groups moderately well (area under the receiver operating characteristic curve = 0.68). In isolation, the resection of the strongest abnormalities as defined by magnetoencephalography and intracranial EEG separated surgical outcome groups well, area under the receiver operating characteristic curve = 0.71 and area under the receiver operating characteristic curve = 0.74, respectively. A model incorporating all three features separated surgical outcome groups best (area under the receiver operating characteristic curve = 0.80). Intracranial EEG is a key tool to delineate the epileptogenic zone and help render individuals seizure-free postoperatively. We showed that data-driven abnormality maps derived from resting-state magnetoencephalography recordings demonstrate clinical value and may help guide electrode placement in individuals with neocortical epilepsy. Additionally, our predictive model of postoperative seizure freedom, which leverages both magnetoencephalography and intracranial EEG recordings, could aid patient counselling of expected outcome.

Complementary structural and functional abnormalities to localise epileptogenic tissue.

BACKGROUND: When investigating suitability for epilepsy surgery, people with drug-refractory focal epilepsy may have intracranial EEG (iEEG) electrodes implanted to localise seizure onset. Diffusion-weighted magnetic resonance imaging (dMRI) may be acquired to identify key white matter tracts for surgical avoidance. Here, we investigate whether structural connectivity abnormalities, inferred from dMRI, may be used in conjunction with functional iEEG abnormalities to aid localisation of the epileptogenic zone (EZ), improving surgical outcomes in epilepsy. METHODS: We retrospectively investigated data from 43 patients (42% female) with epilepsy who had surgery following iEEG. Twenty-five patients (58%) were free from disabling seizures (ILAE 1 or 2) at one year. Interictal iEEG functional, and dMRI structural connectivity abnormalities were quantified by comparison to a normative map and healthy controls. We explored whether the resection of maximal abnormalities related to improved surgical outcomes, in both modalities individually and concurrently. Additionally, we suggest how connectivity abnormalities may inform the placement of iEEG electrodes pre-surgically using a patient case study. FINDINGS: Seizure freedom was 15 times more likely in patients with resection of maximal connectivity and iEEG abnormalities (p = 0.008). Both modalities separately distinguished patient surgical outcome groups and when used simultaneously, a decision tree correctly separated 36 of 43 (84%) patients. INTERPRETATION: Our results suggest that both connectivity and iEEG abnormalities may localise epileptogenic tissue, and that these two modalities may provide complementary information in pre-surgical evaluations. FUNDING: This research was funded by UKRI, CDT in Cloud Computing for Big Data, NIH, MRC, Wellcome Trust and Epilepsy Research UK.

Normative brain mapping using scalp EEG and potential clinical application.

A normative electrographic activity map could be a powerful resource to understand normal brain function and identify abnormal activity. Here, we present a normative brain map using scalp EEG in terms of relative band power. In this exploratory study we investigate its temporal stability, its similarity to other imaging modalities, and explore a potential clinical application. We constructed scalp EEG normative maps of brain dynamics from 17 healthy controls using source-localised resting-state scalp recordings. We then correlated these maps with those acquired from MEG and intracranial EEG to investigate their similarity. Lastly, we use the normative maps to lateralise abnormal regions in epilepsy. Spatial patterns of band powers were broadly consistent with previous literature and stable across recordings. Scalp EEG normative maps were most similar to other modalities in the alpha band, and relatively similar across most bands. Towards a clinical application in epilepsy, we found abnormal temporal regions ipsilateral to the epileptogenic hemisphere. Scalp EEG relative band power normative maps are spatially stable across time, in keeping with MEG and intracranial EEG results. Normative mapping is feasible and may be potentially clinically useful in epilepsy. Future studies with larger sample sizes and high-density EEG are now required for validation.

Intracranial EEG Structure-Function Coupling and Seizure Outcomes After Epilepsy Surgery.

BACKGROUND AND OBJECTIVES: Surgery is an effective treatment for drug-resistant epilepsy, which modifies the brain's structure and networks to regulate seizure activity. Our objective was to examine the relationship between brain structure and function to determine the extent to which this relationship affects the success of the surgery in controlling seizures. We hypothesized that a stronger association between brain structure and function would lead to improved seizure control after surgery. METHODS: We constructed functional and structural brain networks in patients with drug-resistant focal epilepsy by using presurgery functional data from intracranial EEG (iEEG) recordings, presurgery and postsurgery structural data from T1-weighted MRI, and presurgery diffusion-weighted MRI. We quantified the relationship (coupling) between structural and functional connectivity by using the Spearman rank correlation and analyzed this structure-function coupling at 2 spatial scales: (1) global iEEG network level and (2) individual iEEG electrode contacts using virtual surgeries. We retrospectively predicted postoperative seizure freedom by incorporating the structure-function connectivity coupling metrics and routine clinical variables into a cross-validated predictive model. RESULTS: We conducted a retrospective analysis on data from 39 patients who met our inclusion criteria. Brain areas implanted with iEEG electrodes had stronger structure-function coupling in seizure-free patients compared with those with seizure recurrence (p = 0.002, d = 0.76, area under the receiver operating characteristic curve [AUC] = 0.78 [95% CI 0.62-0.93]). Virtual surgeries on brain areas that resulted in stronger structure-function coupling of the remaining network were associated with seizure-free outcomes (p = 0.007, d = 0.96, AUC = 0.73 [95% CI 0.58-0.89]). The combination of global and local structure-function coupling measures accurately predicted seizure outcomes with a cross-validated AUC of 0.81 (95% CI 0.67-0.94). These measures were complementary to other clinical variables and, when included for prediction, resulted in a cross-validated AUC of 0.91 (95% CI 0.82-1.0), accuracy of 92%, sensitivity of 93%, and specificity of 91%. DISCUSSION: Our study showed that the strength of structure-function connectivity coupling may play a crucial role in determining the success of epilepsy surgery. By quantitatively incorporating structure-function coupling measures and standard-of-care clinical variables into presurgical evaluations, we may be able to better localize epileptogenic tissue and select patients for epilepsy surgery. CLASSIFICATION OF EVIDENCE: This is a Class IV retrospective case series showing that structure-function mapping may help determine the outcome from surgical resection for treatment-resistant focal epilepsy.

Effects of anterior temporal lobe resection on cortical morphology.

Neuroimaging can capture brain restructuring after anterior temporal lobe resection (ATLR), a surgical procedure to treat drug-resistant temporal lobe epilepsy (TLE). Here, we examine the effects of this surgery on brain morphology measured in recently-proposed independent variables. We studied 101 individuals with TLE (55 left, 46 right onset) who underwent ATLR. For each individual we considered one pre-surgical MRI and one follow-up MRI 2-13 months after surgery. We used a surface-based method to locally compute traditional morphological variables, and the independent measures K, I, and S, where K measures white matter tension, I captures isometric scaling, and S contains the remaining information about cortical shape. A normative model trained on data from 924 healthy controls was used to debias the data and account for healthy ageing effects occurring during scans. A SurfStat random field theory clustering approach assessed changes across the cortex caused by ATLR. Compared to preoperative data, surgery had marked effects on all morphological measures. Ipsilateral effects were located in the orbitofrontal and inferior frontal gyri, the pre- and postcentral gyri and supramarginal gyrus, and the lateral occipital gyrus and lingual cortex. Contralateral effects were in the lateral occipital gyrus, and inferior frontal gyrus and frontal pole. The restructuring following ATLR is reflected in widespread morphological changes, mainly in regions near the resection, but also remotely in regions that are structurally connected to the anterior temporal lobe. The causes could include mechanical effects, Wallerian degeneration, or compensatory plasticity. The study of independent measures revealed additional effects compared to traditional measures.

The impact of temporal lobe epilepsy surgery on picture naming and its relationship to network metric change.

BACKGROUND: Anterior temporal lobe resection (ATLR) is a successful treatment for medically-refractory temporal lobe epilepsy (TLE). In the language-dominant hemisphere, 30%- 50% of individuals experience a naming decline which can impact upon daily life. Measures of structural networks are associated with language performance pre-operatively. It is unclear if analysis of network measures may predict post-operative decline. METHODS: White matter fibre tractography was performed on preoperative diffusion MRI of 44 left lateralised and left resection individuals with TLE to reconstruct the preoperative structural network. Resection masks, drawn on co-registered pre- and post-operative T1-weighted MRI scans, were used as exclusion regions on pre-operative tractography to estimate the post-operative network. Changes in graph theory metrics, cortical strength, betweenness centrality, and clustering coefficient were generated by comparing the estimated pre- and post-operative networks. These were thresholded based on the presence of the connection in each patient, ranging from 75% to 100% in steps of 5%. The average graph theory metric across thresholds was taken. We incorporated leave-one-out cross-validation with smoothly clipped absolute deviation (SCAD) least absolute shrinkage and selection operator (LASSO) feature selection and a support vector classifier to assess graph theory metrics on picture naming decline. Picture naming was assessed via the Graded Naming Test preoperatively and at 3 and 12 months post-operatively and the outcome was classified using the reliable change index (RCI) to identify clinically significant decline. The best feature combination and model was selected using the area under the curve (AUC). The sensitivity, specificity and F1-score were also reported. Permutation testing was performed to assess the machine learning model and selected regions difference significance. RESULTS: A combination of clinical and graph theory metrics were able to classify outcome of picture naming at 3 months with an AUC of 0.84. At 12 months, change in strength to cortical regions was best able to correctly classify outcome with an AUC of 0.86. Longitudinal analysis revealed that betweenness centrality was the best metric to identify patients who declined at 3 months, who will then continue to experience decline from 3 to 12 months. Both models were significantly higher AUC values than a random classifier. CONCLUSION: Our results suggest that inferred changes of network integrity were able to correctly classify picture naming decline after ATLR. These measures may be used to prospectively to identify patients who are at risk of picture naming decline after surgery and could potentially be utilised to assist tailoring the resection in order to prevent this decline.

Temporal stability of intracranial electroencephalographic abnormality maps for localizing epileptogenic tissue.

OBJECTIVE: Identifying abnormalities on interictal intracranial electroencephalogram (iEEG), by comparing patient data to a normative map, has shown promise for the localization of epileptogenic tissue and prediction of outcome. The approach typically uses short interictal segments of approximately 1 min. However, the temporal stability of findings has not been established. METHODS: Here, we generated a normative map of iEEG in nonpathological brain tissue from 249 patients. We computed regional band power abnormalities in a separate cohort of 39 patients for the duration of their monitoring period (.92-8.62 days of iEEG data, mean = 4.58 days per patient, >4800 hours recording). To assess the localizing value of band power abnormality, we computed D RS -a measure of how different the surgically resected and spared tissue was in terms of band power abnormalities-over time. RESULTS: In each patient, the D RS value was relatively consistent over time. The median D RS of the entire recording period separated seizure-free (International League Against Epilepsy [ILAE] = 1) and not-seizure-free (ILAE > 1) patients well (area under the curve [AUC] = .69). This effect was similar interictally (AUC = .69) and peri-ictally (AUC = .71). SIGNIFICANCE: Our results suggest that band power abnormality D_RS, as a predictor of outcomes from epilepsy surgery, is a relatively robust metric over time. These findings add further support for abnormality mapping of neurophysiology data during presurgical evaluation.

Identifying epileptogenic abnormalities through spatial clustering of MEG interictal band power.

Successful epilepsy surgery depends on localizing and resecting cerebral abnormalities and networks that generate seizures. Abnormalities, however, may be widely distributed across multiple discontiguous areas. We propose spatially constrained clusters as candidate areas for further investigation and potential resection. We quantified the spatial overlap between the abnormality cluster and subsequent resection, hypothesizing a greater overlap in seizure-free patients. Thirty-four individuals with refractory focal epilepsy underwent pre-surgical resting-state interictal magnetoencephalography (MEG) recording. Fourteen individuals were totally seizure-free (ILAE 1) after surgery and 20 continued to have some seizures post-operatively (ILAE 2+). Band power abnormality maps were derived using controls as a baseline. Patient abnormalities were spatially clustered using the k-means algorithm. The tissue within the cluster containing the most abnormal region was compared with the resection volume using the dice score. The proposed abnormality cluster overlapped with the resection in 71% of ILAE 1 patients. Conversely, an overlap only occurred in 15% of ILAE 2+ patients. This effect discriminated outcome groups well (AUC = 0.82). Our novel approach identifies clusters of spatially similar tissue with high abnormality. This is clinically valuable, providing (a) a data-driven framework to validate current hypotheses of the epileptogenic zone localization or (b) to guide further investigation.

Complementary structural and functional abnormalities to localise epileptogenic tissue.

Background: When investigating suitability for epilepsy surgery, people with drug-refractory focal epilepsy may have intracranial EEG (iEEG) electrodes implanted to localise seizure onset. Diffusion-weighted magnetic resonance imaging (dMRI) may be acquired to identify key white matter tracts for surgical avoidance. Here, we investigate whether structural connectivity abnormalities, inferred from dMRI, may be used in conjunction with functional iEEG abnormalities to aid localisation of the epileptogenic zone (EZ), improving surgical outcomes in epilepsy. Methods: We retrospectively investigated data from 43 patients with epilepsy who had surgery following iEEG. Twenty-five patients (58%) were free from disabling seizures (ILAE 1 or 2) at one year. Interictal iEEG functional, and dMRI structural connectivity abnormalities were quantified by comparison to a normative map and healthy controls. We explored whether the resection of maximal abnormalities related to improved surgical outcomes, in both modalities individually and concurrently. Additionally, we suggest how connectivity abnormalities may inform the placement of iEEG electrodes pre-surgically using a patient case study. Findings: Seizure freedom was 15 times more likely in patients with resection of maximal connectivity and iEEG abnormalities (p=0.008). Both modalities separately distinguished patient surgical outcome groups and when used simultaneously, a decision tree correctly separated 36 of 43 (84%) patients. Interpretation: Our results suggest that both connectivity and iEEG abnormalities may localise epileptogenic tissue, and that these two modalities may provide complementary information in pre-surgical evaluations. Funding: This research was funded by UKRI, CDT in Cloud Computing for Big Data, NIH, MRC, Wellcome Trust and Epilepsy Research UK.

Normative brain mapping using scalp EEG and potential clinical application.

A normative electrographic activity map could be a powerful resource to understand normal brain function and identify abnormal activity. Here, we present a normative brain map using scalp EEG in terms of relative band power. In this exploratory study we investigate its temporal stability, its similarity to other imaging modalities, and explore a potential clinical application. We constructed scalp EEG normative maps of brain dynamics from 17 healthy controls using source-localised resting-state scalp recordings. We then correlated these maps with those acquired from MEG and intracranial EEG to investigate their similarity. Lastly, we use the normative maps to lateralise abnormal regions in epilepsy. Spatial patterns of band powers were broadly consistent with previous literature and stable across recordings. Scalp EEG normative maps were most similar to other modalities in the alpha band, and relatively similar across most bands. Towards a clinical application in epilepsy, we found abnormal temporal regions ipsilateral to the epileptogenic hemisphere. Scalp EEG relative band power normative maps are spatially stable across time, in keeping with MEG and intracranial EEG results. Normative mapping is feasible and may be potentially clinically useful in epilepsy. Future studies with larger sample sizes and high-density EEG are now required for validation.

Interictal MEG abnormalities to guide intracranial electrode implantation and predict surgical outcome.

Intracranial EEG (iEEG) is the gold standard technique for epileptogenic zone (EZ) localisation, but requires a preconceived hypothesis of the location of the epileptogenic tissue. This placement is guided by qualitative interpretations of seizure semiology, MRI, EEG and other imaging modalities, such as magnetoencephalography (MEG). Quantitative abnormality mapping using MEG has recently been shown to have potential clinical value. We hypothesised that if quantifiable MEG abnormalities were sampled by iEEG, then patients' post-resection seizure outcome may be better. Thirty-two individuals with refractory neocortical epilepsy underwent MEG and subsequent iEEG recordings as part of pre-surgical evaluation. Eyes-closed resting-state interictal MEG band power abnormality maps were derived from 70 healthy controls as a normative baseline. MEG abnormality maps were compared to iEEG electrode implantation, with the spatial overlap of iEEG electrode placement and cerebral MEG abnormalities recorded. Finally, we assessed if the implantation of electrodes in abnormal tissue, and subsequent resection of the strongest abnormalities determined by MEG and iEEG corresponded to surgical success. Intracranial electrodes were implanted in brain tissue with the most abnormal MEG findings - in individuals that were seizure-free post-operatively (T=3.9, p=0.003), but not in those who did not become seizure free. The overlap between MEG abnormalities and electrode placement distinguished surgical outcome groups moderately well (AUC=0.68). In isolation, the resection of the strongest abnormalities as defined by MEG and iEEG separated surgical outcome groups well, AUC=0.71, AUC=0.74 respectively. A model incorporating all three features separated surgical outcome groups best (AUC=0.80). Intracranial EEG is a key tool to delineate the EZ and help render individuals seizure-free post-operatively. We showed that data-driven abnormality maps derived from resting-state MEG recordings demonstrate clinical value and may help guide electrode placement in individuals with neocortical epilepsy. Additionally, our predictive model of post-operative seizure-freedom, which leverages both MEG and iEEG recordings, could aid patient counselling of expected outcome.

Thalamostriatal disconnection underpins long-term seizure freedom in frontal lobe epilepsy surgery.

Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network. To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks. Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom.

Contribution of White Matter Fiber Bundle Damage to Language Change After Surgery for Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: In medically refractory temporal lobe epilepsy (TLE), 30%-50% of patients experience substantial language decline after resection in the language-dominant hemisphere. In this study, we investigated the contribution of white matter fiber bundle damage to language change at 3 and 12 months after surgery. METHODS: We studied 127 patients who underwent TLE surgery from 2010 to 2019. Neuropsychological testing included picture naming, semantic fluency, and phonemic verbal fluency, performed preoperatively and 3 and 12 months postoperatively. Outcome was assessed using reliable change index (RCI; clinically significant decline) and change across timepoints (postoperative scores minus preoperative scores). Functional MRI was used to determine language lateralization. The arcuate fasciculus (AF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus, middle longitudinal fasciculus (MLF), and uncinate fasciculus were mapped using diffusion MRI probabilistic tractography. Resection masks, drawn comparing coregistered preoperative and postoperative T1 MRI scans, were used as exclusion regions on preoperative tractography to estimate the percentage of preoperative tracts transected in surgery. Chi-squared assessments evaluated the occurrence of RCI-determined language decline. Independent sample t tests and MM-estimator robust regressions were used to assess the impact of clinical factors and fiber transection on RCI and change outcomes, respectively. RESULTS: Language-dominant and language-nondominant resections were treated separately for picture naming because postoperative outcomes were significantly different between these groups. In language-dominant hemisphere resections, greater surgical damage to the AF and IFOF was related to RCI decline at 3 months. Damage to the inferior frontal subfasciculus of the IFOF was related to change at 3 months. In language-nondominant hemisphere resections, increased MLF resection was associated with RCI decline at 3 months, and damage to the anterior subfasciculus was related to change at 3 months. Language-dominant and language-nondominant resections were treated as 1 cohort for semantic and phonemic fluency because there were no significant differences in postoperative decline between these groups. Postoperative seizure freedom was associated with an absence of significant language decline 12 months after surgery for semantic fluency. DISCUSSION: We demonstrate a relationship between fiber transection and naming decline after temporal lobe resection. Individualized surgical planning to spare white matter fiber bundles could help to preserve language function after surgery.

Value of semiology in predicting epileptogenic zone and surgical outcome following frontal lobe epilepsy surgery.

OBJECTIVE: To evaluate the ability of semiology alone in localising the epileptogenic zone (EZ) in people with frontal lobe epilepsy (FLE) who underwent resective surgery. METHODS: We examined data on all individuals who had FLE surgery at our centre between January 01, 2011 and December 31, 2020. Descriptions of ictal semiology were obtained from video-EEG telemetry reports and presurgical multidisciplinary meeting summaries. The putative EZ was represented by the final site of resection. We assessed how well initial and combined set-of-semiologies correlated anatomically with the EZ, using a semiology visualisation tool to generate probabilistic cortical heatmaps of involvement in seizures. RESULTS: Sixty-one individuals had FLE surgery over the study period. Twelve months following surgery, 28/61 (46%) were completely seizure-free, with a further eight experiencing only auras. Comparing the semiology database with the putative EZ, combined set-of-semiology correctly lateralised in 77% (95% CI: 69-85%), localised to the frontal lobe in 57% (95% CI: 48-67%), frontal lobe subregions in 52% (95% CI: 43-62%), and frontal gyri in 25% (95% CI: 16-33%). No difference in degree of correlation was seen comparing those with ongoing seizures 12 months after surgery to those seizure free. SIGNIFICANCE: Semiology alone was able to correctly lateralize the putative EZ in 77%, and localise to a sublobar level in approximately half of individuals who had FLE surgery. Semiology is not adequate alone and must be combined with imaging and EEG data to identify the epileptogenic zone.