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.

Incidence and Types of Cardiac Arrhythmias in the Peri-Ictal Period in Patients Having a Generalized Convulsive Seizure.

BACKGROUND AND OBJECTIVES: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases. METHODS: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z-score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors. RESULTS: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers (p > 0.05). DISCUSSION: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Wake slow waves in focal human epilepsy impact network activity and cognition.

Slow waves of neuronal activity are a fundamental component of sleep that are proposed to have homeostatic and restorative functions. Despite this, their interaction with pathology is unclear and there is only indirect evidence of their presence during wakefulness. Using intracortical recordings from the temporal lobe of 25 patients with epilepsy, we demonstrate the existence of local wake slow waves (LoWS) with key features of sleep slow waves, including a down-state of neuronal firing. Consistent with a reduction in neuronal activity, LoWS were associated with slowed cognitive processing. However, we also found that LoWS showed signatures of a homeostatic relationship with interictal epileptiform discharges (IEDs): exhibiting progressive adaptation during the build-up of network excitability before an IED and reducing the impact of subsequent IEDs on network excitability. We therefore propose an epilepsy homeostasis hypothesis: that slow waves in epilepsy reduce aberrant activity at the price of transient cognitive impairment.

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.

Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

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.

Brain Connectivity Correlates of Breathing and Cardiac Irregularities in SUDEP: A Resting-State fMRI Study.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality among people with epilepsy. Evidence from witnessed and monitored SUDEP cases indicate seizure-induced cardiovascular and respiratory failures; yet, the underlying mechanisms remain obscure. SUDEP occurs often during the night and early morning hours, suggesting that sleep or circadian rhythm-induced changes in physiology contribute to the fatal event. Resting-state fMRI studies have found altered functional connectivity between brain structures involved in cardiorespiratory regulation in later SUDEP cases and in individuals at high-risk of SUDEP. However, those connectivity findings have not been related to changes in cardiovascular or respiratory patterns. Here, we compared fMRI patterns of brain connectivity associated with regular and irregular cardiorespiratory rhythms in SUDEP cases with those of living epilepsy patients of varying SUDEP risk, and healthy controls. We analysed resting-state fMRI data from 98 patients with epilepsy (9 who subsequently succumbed to SUDEP, 43 categorized as low SUDEP risk (no tonic-clonic seizures (TCS) in the year preceding the fMRI scan), and 46 as high SUDEP risk (>3 TCS in the year preceding the scan)) and 25 healthy controls. The global signal amplitude (GSA), defined as the moving standard deviation of the fMRI global signal, was used to identify periods with regular ('low state') and irregular ('high state') cardiorespiratory rhythms. Correlation maps were derived from seeds in twelve regions with a key role in autonomic or respiratory regulation, for the low and high states. Following principal component analysis, component weights were compared between the groups. We found widespread alterations in connectivity of precuneus/posterior cingulate cortex in epilepsy compared to controls, in the low state (regular cardiorespiratory activity). In the low state, and to a lesser degree in the high state, reduced anterior insula connectivity (mainly with anterior and posterior cingulate cortex) in epilepsy appeared, relative to healthy controls. For SUDEP cases, the insula connectivity differences were inversely related to the interval between the fMRI scan and death. The findings suggest that anterior insula connectivity measures may provide a biomarker of SUDEP risk. The neural correlates of autonomic brain structures associated with different cardiorespiratory rhythms may shed light on the mechanisms underlying terminal apnea observed in SUDEP.

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.

Hippocampal theta activity during encoding promotes subsequent associative memory in humans.

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings.

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.

A framework for focal and connectomic mapping of transiently disrupted brain function.

The distributed nature of the neural substrate, and the difficulty of establishing necessity from correlative data, combine to render the mapping of brain function a far harder task than it seems. Methods capable of combining connective anatomical information with focal disruption of function are needed to disambiguate local from global neural dependence, and critical from merely coincidental activity. Here we present a comprehensive framework for focal and connective spatial inference based on sparse disruptive data, and demonstrate its application in the context of transient direct electrical stimulation of the human medial frontal wall during the pre-surgical evaluation of patients with focal epilepsy. Our framework formalizes voxel-wise mass-univariate inference on sparsely sampled data within the statistical parametric mapping framework, encompassing the analysis of distributed maps defined by any criterion of connectivity. Applied to the medial frontal wall, this transient dysconnectome approach reveals marked discrepancies between local and distributed associations of major categories of motor and sensory behaviour, revealing differentiation by remote connectivity to which purely local analysis is blind. Our framework enables disruptive mapping of the human brain based on sparsely sampled data with minimal spatial assumptions, good statistical efficiency, flexible model formulation, and explicit comparison of local and distributed effects.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

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.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

Altered Amygdala Volumes and Microstructure in Focal Epilepsy Patients with Tonic-Clonic Seizures, Ictal and Post-Ictal Central Apnea.

Objectives: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by presence or absence of FBTCS, ictal central apnea (ICA) and post-ictal central apnea (PICA). Methods: 73 patients with only-focal seizures and 30 with FBTCS recorded during video EEG (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomical and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all epilepsy patients and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between healthy subjects, and patients with only-focal seizures or FBTCS The FBTCS group was further subdivided by presence of ICA and PICA, verified by VEEG. Results: Bilateral amygdala volumes were significantly increased in the FBTCS cohort compared to healthy controls and the focal cohort. Patients with recorded PICA had the highest increase in bilateral amygdala volume of the FBTCS cohort.Amygdala neurite density index (NDI) values were significantly decreased in both the focal and FBTCS groups relative to healthy controls, with values in the FBTCS group being the lowest of the two. The presence of PICA was associated with significantly lower NDI values vs the non-apnea FBTCS group (p=0.004). Significance: Individuals with FBTCS and PICA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

A library of quantitative markers of seizure severity.

OBJECTIVE: Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures. METHODS: We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures. RESULTS: Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum r > .3 , p < .05 ) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients. SIGNIFICANCE: We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.