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.

Incomplete resection of the intracranial electroencephalographic seizure onset zone is not associated with postsurgical outcomes.

Delineation of seizure onset regions using intracranial electroencephalography (icEEG) is vital in the surgical workup of drug-resistant epilepsy cases. However, it is unknown whether the complete resection of these regions is necessary for seizure freedom, or whether postsurgical seizure recurrence can be attributed to the incomplete removal of seizure onset regions. To address this gap, we retrospectively analyzed icEEG recordings from 63 subjects, identifying seizure onset regions visually and algorithmically. We assessed onset region resection and correlated this with postsurgical seizure control. The majority of subjects had more than half of their onset regions resected (82.46% and 80.65% of subjects using visual and algorithmic methods, respectively). There was no association between the proportion of the seizure onset zone (SOZ) that was subsequently resected and better surgical outcomes (area under the receiver operating characteristic curve [AUC] < .7). Investigating the spatial extent of onset regions, we found no substantial evidence of an association with postsurgical seizure control (all AUC < .7). Although seizure onset regions are typically resected completely or in large part, incomplete resection is not associated with worse postsurgical outcomes. We conclude that postsurgical seizure recurrence cannot be attributed to an incomplete resection of the icEEG SOZ alone. Other network mechanisms beyond icEEG seizure onset likely contribute.

Brain gray matter changes in children at risk for sudden unexpected death in epilepsy.

BACKGROUND: Potential failing adult brain sites, stratified by risk, mediating Sudden Unexpected Death in Epilepsy (SUDEP) have been described, but are unknown in children. METHODS: We examined regional brain volumes using T1-weighted MRI images in 21 children with epilepsy at high SUDEP risk and 62 healthy children, together with SUDEP risk scores, calculated from focal seizure frequency. Gray matter tissue type was partitioned, maps normalized, smoothed, and compared between groups (SPM12; ANCOVA; covariates, age, sex, and BMI). Partial correlations between regional volumes and seizure frequency were examined (SPM12, covariates, age, sex, and BMI); 67% were at high risk for SUDEP. RESULTS: The cerebellar cortex, hippocampus, amygdala, putamen, cingulate, thalamus, and para-hippocampal gyrus showed increased gray matter volumes in epilepsy, and decreased volumes in the posterior thalamus, lingual gyrus, and temporal cortices. The cingulate, insula, and putamen showed significant positive relationships with focal seizure frequency indices using whole-brain voxel-by-voxel partial correlations. Tissue volume changes in selected sites differed in direction from adults; particularly, cerebellar sites, key for hypotensive recovery, increased rather than adult declines. CONCLUSION: The volume increases may represent expansion by inflammatory or other processes that, with sustained repetitive seizure discharge, lead to tissue volume declines described earlier in adults. IMPACT: Children with epilepsy, who are at risk for Sudden Unexplained Death, show changes in brain volume that often differ in direction of change from adults at risk for SUDEP. Sites of volume change play significant roles in mediating breathing and blood pressure, and include areas that serve recovery from prolonged apnea and marked loss of blood pressure. The extent of volume changes correlated with focal seizure frequency. Although the underlying processes contributing to regional volume changes remain speculative, regions of tissue swelling in pediatric brain areas may represent transitory conditions that later lead to tissue loss in the adult condition.

Orienting to fear under transient focal disruption of the human amygdala.

Responding to threat is under strong survival pressure, promoting the evolution of systems highly optimized for the task. Though the amygdala is implicated in 'detecting' threat, its role in the action that immediately follows-'orienting'-remains unclear. Critical to mounting a targeted response, such early action requires speed, accuracy, and resilience optimally achieved through conserved, parsimonious, dedicated systems, insured against neural loss by a parallelized functional organization. These characteristics tend to conceal the underlying substrate not only from correlative methods but also from focal disruption over time scales long enough for compensatory adaptation to take place. In a study of six patients with intracranial electrodes temporarily implanted for the clinical evaluation of focal epilepsy, we investigated gaze orienting to fear during focal, transient, unilateral direct electrical disruption of the amygdala. We showed that the amygdala is necessary for rapid gaze shifts towards faces presented in the contralateral hemifield regardless of their emotional expression, establishing its functional lateralization. Behaviourally dissociating the location of presented fear from the direction of the response, we implicated the amygdala not only in detecting contralateral faces, but also in automatically orienting specifically towards fearful ones. This salience-specific role was demonstrated within a drift-diffusion model of action to manifest as an orientation bias towards the location of potential threat. Pixel-wise analysis of target facial morphology revealed scleral exposure as its primary driver, and induced gamma oscillations-obtained from intracranial local field potentials-as its time-locked electrophysiological correlate. The amygdala is here reconceptualized as a functionally lateralized instrument of early action, reconciling previous conflicting accounts confined to detection, and revealing a neural organisation analogous to the superior colliculus, with which it is phylogenetically kin. Greater clarity on its role has the potential to guide therapeutic resection, still frequently complicated by impairments of cognition and behaviour related to threat, and inform novel focal stimulation techniques for the management of neuropsychiatric conditions.

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.

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.

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.

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.

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.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy.

Personalized medicine requires that treatments adapt to not only the patient but also changing factors within each individual. Although epilepsy is a dynamic disorder characterized by pathological fluctuations in brain state, surprisingly little is known about whether and how seizures vary in the same patient. We quantitatively compared within-patient seizure network evolutions using intracranial electroencephalographic (iEEG) recordings of over 500 seizures from 31 patients with focal epilepsy (mean 16.5 seizures per patient). In all patients, we found variability in seizure paths through the space of possible network dynamics. Seizures with similar pathways tended to occur closer together in time, and a simple model suggested that seizure pathways change on circadian and/or slower timescales in the majority of patients. These temporal relationships occurred independent of whether the patient underwent antiepileptic medication reduction. Our results suggest that various modulatory processes, operating at different timescales, shape within-patient seizure evolutions, leading to variable seizure pathways that may require tailored treatment approaches.

Safety of intracranial electroencephalography during functional electromagnetic resonance imaging in humans at 1.5 tesla using a head transmit RF coil: Histopathological and heat-shock immunohistochemistry observations.

OBJECTIVES: Simultaneous intracranial EEG and functional MRI (icEEG-fMRI) recordings in humans, whereby EEG is recorded from electrodes implanted inside the cranium during fMRI scanning, were made possible following safety studies on test phantoms and our specification of a rigorous data acquisition protocol. In parallel with this work, other investigations in our laboratory revealed the damage caused by the EEG electrode implantation procedure at the cellular level. The purpose of this report is to further explore the safety of performing MRI, including simultaneous icEEG-fMRI data acquisitions, in the presence of implanted intra-cranial EEG electrodes, by presenting some histopathological and heat-shock immunopositive labeling observations in surgical tissue samples from patients who underwent the scanning procedure. METHODS: We performed histopathology and heat shock protein expression analyses on surgical tissue samples from nine patients who had been implanted with icEEG electrodes. Three patients underwent icEEG-fMRI and structural MRI (sMRI); three underwent sMRI only, all at similar time points after icEEG implantation; and three who did not undergo functional or sMRI with icEEG electrodes. RESULTS: The histopathological findings from the three patients who underwent icEEG-fMRI were similar to those who did not, in that they showed no evidence of additional damage in the vicinity of the electrodes, compared to cases who had no MRI with implanted icEEG electrodes. This finding was similar to our observations in patients who only underwent sMRI with implanted icEEG electrodes. CONCLUSION: This work provides unique evidence on the safety of functional MRI in the presence of implanted EEG electrodes. In the cases studied, icEEG-fMRI performed in accordance with our protocol based on low-SAR (≤0.1 W/kg) sequences at 1.5T using a head-transmit RF coil, did not result in measurable additional damage to the brain tissue in the vicinity of implanted electrodes. Furthermore, while one cannot generalize the results of this study beyond the specific electrode implantation and scanning conditions described herein, we submit that our approach is a useful framework for the post-hoc safety assessment of MR scanning with brain implants.

Comparative Effectiveness of Stereotactic Electroencephalography Versus Subdural Grids in Epilepsy Surgery.

OBJECTIVE: The aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy. METHODS: The Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit). RESULTS: Ten study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR = 2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE). INTERPRETATION: In comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939.

Serotonin receptor expression in hippocampus and temporal cortex of temporal lobe epilepsy patients by postictal generalized electroencephalographic suppression duration.

OBJECTIVE: Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. METHODS: Analyses included 36 cases (age = 14-64 years, age at epilepsy onset = 0-51 years, epilepsy duration = 2-53 years, PGES duration = 0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n = 16) and temporal cortex (n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. RESULTS: In hippocampus, 5HT2A protein by Western blot positively correlated with PGES duration (p = .0024, R2  = .52), but 5HT1A did not (p = .87, R2  = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippocampal CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated (p = .043, R2  = .26) and HTR4 positively correlated (p = .049, R2  = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p = .040, Pearson correlation r = .52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling. SIGNIFICANCE: Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.

Spectral fingerprints or spectral tilt? Evidence for distinct oscillatory signatures of memory formation.

Decreases in low-frequency power (2-30 Hz) alongside high-frequency power increases (>40 Hz) have been demonstrated to predict successful memory formation. Parsimoniously, this change in the frequency spectrum can be explained by one factor, a change in the tilt of the power spectrum (from steep to flat) indicating engaged brain regions. A competing view is that the change in the power spectrum contains several distinct brain oscillatory fingerprints, each serving different computations. Here, we contrast these two theories in a parallel magnetoencephalography (MEG)-intracranial electroencephalography (iEEG) study in which healthy participants and epilepsy patients, respectively, studied either familiar verbal material or unfamiliar faces. We investigated whether modulations in specific frequency bands can be dissociated in time and space and by experimental manipulation. Both MEG and iEEG data show that decreases in alpha/beta power specifically predicted the encoding of words but not faces, whereas increases in gamma power and decreases in theta power predicted memory formation irrespective of material. Critically, these different oscillatory signatures of memory encoding were evident in different brain regions. Moreover, high-frequency gamma power increases occurred significantly earlier compared to low-frequency theta power decreases. These results show that simple "spectral tilt" cannot explain common oscillatory changes and demonstrate that brain oscillations in different frequency bands serve different functions for memory encoding.

Theta power and theta-gamma coupling support long-term spatial memory retrieval.

Hippocampal theta oscillations have been implicated in spatial memory function in both rodents and humans. What is less clear is how hippocampal theta interacts with higher frequency oscillations to support long-term memory. Here we asked 10 presurgical epilepsy patients undergoing intracranial EEG recording to perform a long-term spatial memory task in desktop virtual reality and found that increased theta power in two discrete bands ("low" 2-5 Hz and "high" 6-11 Hz) during cued retrieval was associated with improved task performance. Similarly, increased coupling between "low" theta phase and gamma amplitude during the same period was associated with improved task performance. Finally, low and high gamma amplitude appeared to peak at different phases of the theta cycle; providing a novel connection between human hippocampal function and rodent data. These results help to elucidate the role of theta oscillations and theta-gamma phase-amplitude coupling in human long-term memory.

Visual field defects in temporal lobe epilepsy surgery.

PURPOSE OF REVIEW: Surgery can provide a robust long-standing seizure remission in drug-refractory mesial temporal lobe epilepsy (MTLE). Despite this, a significant proportion of postoperative patients are ineligible to gain a driving licence due to the size of the subsequent visual field defect (VFD). The amygdala and hippocampus are intimately related to several important white fibre association tracts and damage to the optic radiation results in a contralateral superior quadrantanopia. For this reason, several different modifications to established surgical approaches and novel techniques have recently been applied to mitigate or prevent damage to the optic radiation. There is still no consensus on which operative technique results in optimal outcomes regarding seizure remission, neuropsychological sequelae and VFD rates. We explore contemporary surgical approaches to the mesial temporal lobe and describe the intraoperative use of tractography and iMRI in preventing VFDs. RECENT FINDINGS: Established approaches for the surgical treatment of MTLE include standardized approaches in the form of anterior temporal lobectomies, selective approaches and various modifications thereof. Recent advancements in microsurgical techniques have seen numerous modifications to these approaches to spare the optic radiation as well as the introduction of minimally invasive alternatives such as laser interstitial thermal therapy (LITT) and stereotactic radiosurgery (SRS). The intraoperative use of optic radiation tractography through overlays in the operative microscope and interventional MRI suites to correct for brain shift have been shown to reduce VFDs. SUMMARY: VFDs following the surgical treatment of drug-refractory MTLE can have a significant impact on the quality of life. Each of the surgical techniques carries a risk to the visual pathways but the use of minimally invasive techniques as well as surgical adjuncts may reduce or prevent acquired VFDs.

Timing of syncope in ictal asystole as a guide when considering pacemaker implantation.

INTRODUCTION: In patients with ictal asystole (IA) both cardioinhibition and vasodepression may contribute to syncopal loss of consciousness. We investigated the temporal relationship between onset of asystole and development of syncope in IA, to estimate the frequency with which pacemaker therapy, by preventing severe bradycardia, may diminish syncope risk. METHODS: In this retrospective cohort study, we searched video-EEG databases for individuals with focal seizures and IA (asystole ≥ 3 s preceded by heart rate deceleration) and assessed the durations of asystole and syncope and their temporal relationship. Syncope was evaluated using both video observations (loss of muscle tone) and EEG (generalized slowing/flattening). We assumed that asystole starting ≤3 s before syncope onset, or after syncope began, could not have been the dominant cause. RESULTS: We identified 38 seizures with IA from 29 individuals (17 males; median age: 41 years). Syncope occurred in 22/38 seizures with IA and was more frequent in those with longer IA duration (median duration: 20 [range: 5-32] vs. 5 [range: 3-9] s; p < .001) and those with the patient seated vs. supine (79% vs. 46%; p = .049). IA onset always preceded syncope. In 20/22 seizures (91%), IA preceded syncope by >3 s. Thus, in only two instances was vasodepression rather than cardioinhibition the dominant presumptive syncope triggering mechanism. CONCLUSIONS: In IA, cardioinhibition played an important role in most seizure-induced syncopal events, thereby favoring the potential utility of pacemaker implantation in patients with difficult to suppress IA.

Metabolic lesion-deficit mapping of human cognition.

In theory the most powerful technique for functional localization in cognitive neuroscience, lesion-deficit mapping is in practice distorted by unmodelled network disconnections and strong 'parasitic' dependencies between collaterally damaged ischaemic areas. High-dimensional multivariate modelling can overcome these defects, but only at the cost of commonly impracticable data scales. Here we develop lesion-deficit mapping with metabolic lesions-discrete areas of hypometabolism typically seen on interictal 18F-fluorodeoxyglucose PET imaging in patients with focal epilepsy-that inherently capture disconnection effects, and whose structural dependence patterns are sufficiently benign to allow the derivation of robust functional anatomical maps with modest data. In this cross-sectional study of 159 patients with widely distributed focal cortical impairments, we derive lesion-deficit maps of a broad range of psychological subdomains underlying affect and cognition. We demonstrate the potential clinical utility of the approach in guiding therapeutic resection for focal epilepsy or other neurosurgical indications by applying high-dimensional modelling to predict out-of-sample verbal IQ and depression from cortical metabolism alone.

Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs.

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.