Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

BACKGROUND AND OBJECTIVES: Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS: A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS: The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION: These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Leukocyte filtration and leukocyte modulation therapy during extracorporeal cardiopulmonary resuscitation in a porcine model of prolonged cardiac arrest.

Extracorporeal cardiopulmonary resuscitation (ECPR) is emerging as a feasible and effective rescue strategy for prolonged cardiac arrest (CA). However, prolonged total body ischemia and reperfusion can cause microvascular occlusion that prevents organ reperfusion and recovery of function. One hypothesized mechanism of microvascular "no-reflow" is leukocyte adhesion and formation of neutrophil extracellular traps. In this study we tested the hypothesis that a leukocyte filter (LF) or leukocyte modulation device (L-MOD) could reduce NETosis and improve recovery of heart and brain function in a swine model of prolonged cardiac arrest treated with ECPR. Thirty-six swine (45.5 ± 2.5 kg, evenly distributed sex) underwent 8 min of untreated ventricular fibrillation CA followed by 30 min of mechanical CPR with subsequent 8 h of ECPR. Two females were later excluded from analysis due to CPR complications. Swine were randomized to standard care (Control group), LF, or L-MOD at the onset of CPR. NET formation was quantified by serum dsDNA and citrullinated histone as well as immunofluorescence staining of the heart and brain for citrullinated histone in the microvasculature. Primary outcomes included recovery of cardiac function based on cardiac resuscitability score (CRS) and recovery of neurologic function based on the somatosensory evoked potential (SSEP) N20 cortical response. In this model of prolonged CA treated with ECPR we observed significant increases in serum biomarkers of NETosis and immunohistochemical evidence of microvascular NET formation in the heart and brain that were not reduced by LF or L-MOD therapy. Correspondingly, there were no significant differences in CRS and SSEP recovery between Control, LF, and L-MOD groups 8 h after ECPR onset (CRS = 3.1 ± 2.7, 3.7 ± 2.6, and 2.6 ± 2.6 respectively; p = 0.606; and SSEP = 27.9 ± 13.0%, 36.7 ± 10.5%, and 31.2 ± 9.8% respectively, p = 0.194). In this model of prolonged CA treated with ECPR, the use of LF or L-MOD therapy during ECPR did not reduce microvascular NETosis or improve recovery of myocardial or brain function. The causal relationship between microvascular NETosis, no-reflow, and recovery of organ function after prolonged cardiac arrest treated with ECPR requires further investigation.

Spike ripples localize the epileptogenic zone best: an international intracranial study.

We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone compared with other leading interictal biomarkers in a multicentre, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centres who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection [International League Against Epilepsy Class 1 outcome (ILAE 1)] and those with persistent seizures (ILAE 2-6) across sites and recording types. We also evaluated available interictal biomarkers: spike, spike-gamma, wideband high frequency oscillation (HFO, 80-500 Hz), ripple (80-250 Hz) and fast ripple (250-500 Hz) rates using previously validated automated detectors. The proportion of resected events was computed and compared across subject outcomes and biomarkers. Overall, 109 subjects were included. Most spike ripples were removed in subjects with ILAE 1 outcome (P < 0.001), and this was qualitatively observed across all sites and for depth and subdural electrodes (P < 0.001 and P < 0.001, respectively). Among ILAE 1 subjects, the mean spike ripple rate was higher in the resected volume (0.66/min) than in the non-removed tissue (0.08/min, P < 0.001). A higher proportion of spike ripples were removed in subjects with ILAE 1 outcomes compared with ILAE 2-6 outcomes (P = 0.06). Among ILAE 1 subjects, the proportion of spike ripples removed was higher than the proportion of spikes (P < 0.001), spike-gamma (P < 0.001), wideband HFOs (P < 0.001), ripples (P = 0.009) and fast ripples (P = 0.009) removed. At the individual level, more subjects with ILAE 1 outcomes had the majority of spike ripples removed (79%, 38/48) than spikes (69%, P = 0.12), spike-gamma (69%, P = 0.12), wideband HFOs (63%, P = 0.03), ripples (45%, P = 0.01) or fast ripples (36%, P < 0.001) removed. Thus, in this large, multicentre cohort, when surgical resection was successful, the majority of spike ripples were removed. Furthermore, automatically detected spike ripples localize the epileptogenic tissue better than spikes, spike-gamma, wideband HFOs, ripples and fast ripples.

High frequency oscillation network dynamics predict outcome in non-palliative epilepsy surgery.

High frequency oscillations are a promising biomarker of outcome in intractable epilepsy. Prior high frequency oscillation work focused on counting high frequency oscillations on individual channels, and it is still unclear how to translate those results into clinical care. We show that high frequency oscillations arise as network discharges that have valuable properties as predictive biomarkers. Here, we develop a tool to predict patient outcome before surgical resection is performed, based on only prospective information. In addition to determining high frequency oscillation rate on every channel, we performed a correlational analysis to evaluate the functional connectivity of high frequency oscillations in 28 patients with intracranial electrodes. We found that high frequency oscillations were often not solitary events on a single channel, but part of a local network discharge. Eigenvector and outcloseness centrality were used to rank channel importance within the connectivity network, then used to compare patient outcome by comparison with the seizure onset zone or a proportion within the proposed resected channels (critical resection percentage). Combining the knowledge of each patient's seizure onset zone resection plan along with our computed high frequency oscillation network centralities and high frequency oscillation rate, we develop a Naïve Bayes model that predicts outcome (positive predictive value: 100%) better than predicting based upon fully resecting the seizure onset zone (positive predictive value: 71%). Surgical margins had a large effect on outcomes: non-palliative patients in whom most of the seizure onset zone was resected ('definitive surgery', ≥ 80% resected) had predictable outcomes, whereas palliative surgeries (<80% resected) were not predictable. These results suggest that the addition of network properties of high frequency oscillations is more accurate in predicting patient outcome than seizure onset zone alone in patients with most of the seizure onset zone removed and offer great promise for informing clinical decisions in surgery for refractory epilepsy.

Estimation of Circular Statistics in the Presence of Measurement Bias.

Circular statistics and Rayleigh tests are important tools for analyzing cyclic events. However, current methods are not robust to significant measurement bias, especially incomplete or otherwise non-uniform sampling. One example is studying 24-cyclicity but having data not recorded uniformly over the full 24-hour cycle. Our objective is to present a robust method to estimate circular statistics and their statistical significance in the presence of incomplete or otherwise non-uniform sampling. Our method is to solve the underlying Fredholm Integral Equation for the more general problem, estimating probability distributions in the context of imperfect measurements, with our circular statistics in the presence of incomplete/non-uniform sampling being one special case. The method is based on linear parameterizations of the underlying distributions. We simulated the estimation error of our approach for several toy examples as well as for a real-world example: analyzing the 24-hour cyclicity of an electrographic biomarker of epileptic tissue controlled for states of vigilance. We also evaluated the accuracy of the Rayleigh test statistic versus the direct simulation of statistical significance. Our method shows a very low estimation error. In the real-world example, the corrected moments had a root mean square error of [Formula: see text]. In contrast, the Rayleigh test statistic overestimated the statistical significance and was thus not reliable. The presented methods thus provide a robust solution to computing circular moments even with incomplete or otherwise non-uniform sampling. Since Rayleigh test statistics cannot be used in this circumstance, direct estimation of significance is the preferable option for estimating statistical significance.

Optimization of ictal aborting stimulation using the dynamotype taxonomy.

Electrical stimulation is an increasingly popular method to terminate epileptic seizures, yet it is not always successful. A potential reason for inconsistent efficacy is that stimuli are applied empirically without considering the underlying dynamical properties of a given seizure. We use a computational model of seizure dynamics to show that different bursting classes have disparate responses to aborting stimulation. This model was previously validated in a large set of human seizures and led to a description of the Taxonomy of Seizure Dynamics and the dynamotype, which is the clinical analog of the bursting class. In the model, the stimulation is realized as an applied input, which successfully aborts the burst when it forces the system from a bursting state to a quiescent state. This transition requires bistability, which is not present in all bursters. We examine how topological and geometric differences in the bistable state affect the probability of termination as the burster progresses from onset to offset. We find that the most significant determining factors are the burster class (dynamotype) and whether the burster has a DC (baseline) shift. Bursters with a baseline shift are far more likely to be terminated due to the necessary structure of their state space. Furthermore, we observe that the probability of termination varies throughout the burster's duration, is often dependent on the phase when it was applied, and is highly correlated to dynamotype. Our model provides a method to predict the optimal method of termination for each dynamotype. These results lead to the prediction that optimization of ictal aborting stimulation should account for seizure dynamotype, the presence of a DC shift, and the timing of the stimulation.

Increasing challenges to trial recruitment and conduct over time.

OBJECTIVE: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time. METHODS: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability. RESULTS: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20). SIGNIFICANCE: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

The BEST Conceivable Way to Talk About Epilepsy Biomarkers.

The search for valid biomarkers to aid in epilepsy diagnosis and management is a major goal of the Epilepsy Research Benchmarks. Many papers and grants answer this call by searching for new biomarkers from a wide range of disciplines. However, the academic use of the word "biomarker" is often imprecise. Without proper definition, such work is not well-prepared to progress to the next step of translating these biomarkers into clinical use. In 2016, the Food and Drug Administration and National Institutes of Health collaborated to develop the BEST (Biomarkers, EndpointS, and other Tools) Resource as a guide to adopt formal definitions that aid in pushing successful biomarkers toward regulatory approval. Using the vignette of high-frequency oscillations, which have been proposed as a potential biomarker of several potential aspects of epilepsy, we demonstrate how improper use of the term "biomarker," and lack of a clear context of use, can lead to confusion and difficulty obtaining regulatory approval. Similar conditions are likely in many areas of biomarker research. This Resource should be adopted by all researchers developing epilepsy biomarkers. Adopting the BEST guidelines will improve reproducibility, guide research objectives toward translation, and better target the Epilepsy Benchmarks.

Therapeutic Effect of Argatroban During Cardiopulmonary Resuscitation and Streptokinase During Extracorporeal Cardiopulmonary Resuscitation in a Porcine Model of Prolonged Cardiac Arrest.

Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA. DESIGN: Randomized interventional trial. SETTING: University laboratory. SUBJECTS: Swine. INTERVENTIONS: In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. MEASUREMENTS AND MAIN RESULTS: Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0-6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. CONCLUSIONS: In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.

Passive and active markers of cortical excitability in epilepsy.

Electroencephalography (EEG) has been the primary diagnostic tool in clinical epilepsy for nearly a century. Its review is performed using qualitative clinical methods that have changed little over time. However, the intersection of higher resolution digital EEG and analytical tools developed in the past decade invites a re-exploration of relevant methodology. In addition to the established spatial and temporal markers of spikes and high-frequency oscillations, novel markers involving advanced postprocessing and active probing of the interictal EEG are gaining ground. This review provides an overview of the EEG-based passive and active markers of cortical excitability in epilepsy and of the techniques developed to facilitate their identification. Several different emerging tools are discussed in the context of specific EEG applications and the barriers we must overcome to translate these tools into clinical practice.

Seizure forecasting: Where do we stand?

A lot of mileage has been made recently on the long and winding road toward seizure forecasting. Here we briefly review some selected milestones passed along the way, which were discussed at the International Conference for Technology and Analysis of Seizures-ICTALS 2022-convened at the University of Bern, Switzerland. Major impetus was gained recently from wearable and implantable devices that record not only electroencephalography, but also data on motor behavior, acoustic signals, and various signals of the autonomic nervous system. This multimodal monitoring can be performed for ultralong timescales covering months or years. Accordingly, features and metrics extracted from these data now assess seizure dynamics with a greater degree of completeness. Most prominently, this has allowed the confirmation of the long-suspected cyclical nature of interictal epileptiform activity, seizure risk, and seizures. The timescales cover daily, multi-day, and yearly cycles. Progress has also been fueled by approaches originating from the interdisciplinary field of network science. Considering epilepsy as a large-scale network disorder yielded novel perspectives on the pre-ictal dynamics of the evolving epileptic brain. In addition to discrete predictions that a seizure will take place in a specified prediction horizon, the community broadened the scope to probabilistic forecasts of a seizure risk evolving continuously in time. This shift of gears triggered the incorporation of additional metrics to quantify the performance of forecasting algorithms, which should be compared to the chance performance of constrained stochastic null models. An imminent task of utmost importance is to find optimal ways to communicate the output of seizure-forecasting algorithms to patients, caretakers, and clinicians, so that they can have socioeconomic impact and improve patients' well-being.

Clinical MRI morphological analysis of functional seizures compared to seizure-naïve and psychiatric controls.

PURPOSE: Functional seizures (FS), also known as psychogenic nonepileptic seizures (PNES), are physical manifestations of acute or chronic psychological distress. Functional and structural neuroimaging have identified objective signs of this disorder. We evaluated whether magnetic resonance imaging (MRI) morphometry differed between patients with FS and clinically relevant comparison populations. METHODS: Quality-screened clinical-grade MRIs were acquired from 666 patients from 2006 to 2020. Morphometric features were quantified with FreeSurfer v6. Mixed-effects linear regression compared the volume, thickness, and surface area within 201 regions-of-interest for 90 patients with FS, compared to seizure-naïve patients with depression (n = 243), anxiety (n = 68), and obsessive-compulsive disorder (OCD, n = 41), respectively, and to other seizure-naïve controls with similar quality MRIs, accounting for the influence of multiple confounds including depression and anxiety based on chart review. These comparison populations were obtained through review of clinical records plus research studies obtained on similar scanners. RESULTS: After Bonferroni-Holm correction, patients with FS compared with seizure-naïve controls exhibited thinner bilateral superior temporal cortex (left 0.053 mm, p = 0.014; right 0.071 mm, p = 0.00006), thicker left lateral occipital cortex (0.052 mm, p = 0.0035), and greater left cerebellar white-matter volume (1085 mm3, p = 0.0065). These findings were not accounted for by lower MRI quality in patients with FS. CONCLUSIONS: These results reinforce prior indications of structural neuroimaging correlates of FS and, in particular, distinguish brain morphology in FS from that in depression, anxiety, and OCD. Future work may entail comparisons with other psychiatric disorders including bipolar and schizophrenia, as well as exploration of brain structural heterogeneity within FS.

Protocol for multicentre comparison of interictal high-frequency oscillations as a predictor of seizure freedom.

In drug-resistant focal epilepsy, interictal high-frequency oscillations (HFOs) recorded from intracranial EEG (iEEG) may provide clinical information for delineating epileptogenic brain tissue. The iEEG electrode contacts that contain HFO are hypothesized to delineate the epileptogenic zone; their resection should then lead to postsurgical seizure freedom. We test whether our prospective definition of clinically relevant HFO is in agreement with postsurgical seizure outcome. The algorithm is fully automated and is equally applied to all data sets. The aim is to assess the reliability of the proposed detector and analysis approach. We use an automated data-independent prospective definition of clinically relevant HFO that has been validated in data from two independent epilepsy centres. In this study, we combine retrospectively collected data sets from nine independent epilepsy centres. The analysis is blinded to clinical outcome. We use iEEG recordings during NREM sleep with a minimum of 12 epochs of 5 min of NREM sleep. We automatically detect HFO in the ripple (80-250 Hz) and in the fast ripple (250-500 Hz) band. There is no manual rejection of events in this fully automated algorithm. The type of HFO that we consider clinically relevant is defined as the simultaneous occurrence of a fast ripple and a ripple. We calculate the temporal consistency of each patient's HFO rates over several data epochs within and between nights. Patients with temporal consistency <50% are excluded from further analysis. We determine whether all electrode contacts with high HFO rate are included in the resection volume and whether seizure freedom (ILAE 1) was achieved at ≥2 years follow-up. Applying a previously validated algorithm to a large cohort from several independent epilepsy centres may advance the clinical relevance and the generalizability of HFO analysis as essential next step for use of HFO in clinical practice.

Visual cortex responds to sound onset and offset during passive listening.

Sounds enhance our ability to detect, localize, and respond to co-occurring visual targets. Research suggests that sounds improve visual processing by resetting the phase of ongoing oscillations in visual cortex. However, it remains unclear what information is relayed from the auditory system to visual areas and if sounds modulate visual activity even in the absence of visual stimuli (e.g., during passive listening). Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three forms of auditory information during a passive listening task: auditory onset responses, auditory offset responses, and rhythmic entrainment to sounds. Because some auditory neurons respond to both sound onsets and offsets, visual timing and duration processing may benefit from each. In addition, if auditory entrainment information is relayed to visual cortex, it could support the processing of complex stimulus dynamics that are aligned between auditory and visual stimuli. Results demonstrate that in visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to sound modulation frequencies. These findings suggest that activity in visual cortex (as measured with iEEG in response to auditory stimuli) may not be affected by temporally fine-grained auditory stimulus dynamics during passive listening (though it remains possible that this signal may be observable with simultaneous auditory-visual stimuli). Moreover, auditory responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by auditory discontinuities.NEW & NOTEWORTHY Using intracranial electroencephalography (iEEG) in humans during a passive listening task, we demonstrate that sounds modulate activity in visual cortex at both the onset and offset of sounds, which likely supports visual timing and duration processing. However, more complex auditory rate information did not affect visual activity. These findings are based on one of the largest multisensory iEEG studies to date and reveal the type of information transmitted between auditory and visual regions.

Interictal high frequency background activity as a biomarker of epileptogenic tissue.

High frequency oscillations (HFOs) are very brief events that are a well-established biomarker of the epileptogenic zone (EZ) but are rare and comprise only a tiny fraction of the total recorded EEG. We hypothesize that the interictal high frequency 'background' data, which has received little attention but represents the majority of the EEG record, also may contain additional, novel information for identifying the EZ. We analysed intracranial EEG (30-500 Hz frequency range) acquired from 24 patients who underwent resective surgery. We computed 38 quantitative features based on all usable, interictal data (63-307 h per subject), excluding all detected HFOs. We assessed association between each feature and the seizure onset zone (SOZ) and resected volume (RV) using logistic regression. A pathology score per channel was also created via principle component analysis and logistic regression, using hold-out-one-patient cross-validation to avoid in-sample training. Association of the pathology score with the SOZ and RV was quantified using an asymmetry measure. Many features were associated with the SOZ: 23/38 features had odds ratios >1.3 or <0.7 and 17/38 had odds ratios different than zero with high significance (P < 0.001/39, logistic regression with Bonferroni Correction). The pathology score, the rate of HFOs, and their channel-wise product were each strongly associated with the SOZ [median asymmetry ≥0.44, good surgery outcome patients; median asymmetry ≥0.40, patients with other outcomes; 95% confidence interval (CI) > 0.27 in both cases]. The pathology score and the channel-wise product also had higher asymmetry with respect to the SOZ than the HFO rate alone (median difference in asymmetry ≥0.18, 95% CI >0.05). These results support that the high frequency background data contains useful information for determining the EZ, distinct and complementary to information from detected HFOs. The concordance between the high frequency activity pathology score and the rate of HFOs appears to be a better biomarker of epileptic tissue than either measure alone.

Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex.

Speech perception is a central component of social communication. Although principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues. Visual speech modulates activity in cortical areas subserving auditory speech perception including the superior temporal gyrus (STG). However, it is unknown whether visual modulation of auditory processing is a unitary phenomenon or, rather, consists of multiple functionally distinct processes. To explore this question, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes in 21 patients with epilepsy. We found that visual speech modulated auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differed across frequency bands. In the theta band, visual speech suppressed the auditory response from before auditory speech onset to after auditory speech onset (-93 to 500 ms) most strongly in the posterior STG. In the beta band, suppression was seen in the anterior STG from -311 to -195 ms before auditory speech onset and in the middle STG from -195 to 235 ms after speech onset. In high gamma, visual speech enhanced the auditory response from -45 to 24 ms only in the posterior STG. We interpret the visual-induced changes prior to speech onset as reflecting crossmodal prediction of speech signals. In contrast, modulations after sound onset may reflect a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception.

The accuracy of quantitative EEG biomarker algorithms depends upon seizure onset dynamics.

OBJECTIVE: To compare the performance of different ictal quantitative biomarkers of the seizure onset zone (SOZ) across many seizures in a cohort of consecutive patients with a variety of seizure onset patterns. METHODS: The Epileptogenicity Index (EI, a measure of fast activity) and Slow Polarizing Shift index (SPS, a measure of infraslow activity) were calculated for 212 seizures (22 patients). After stratification by onset pattern, median index values inside and outside the SOZ were compared in aggregate and for each of the onset patterns. Receiver Operating Characteristic (ROC) curves were constructed to compare the performance of each index. RESULTS: Median values of EI (0.056 vs 0.0087), SPS (0.27 vs 0.19), and CI (0.21 vs 0.12) were significantly higher for contacts inside the SOZ, all p < 0.0001. Analysis of AUC showed variable performance of these indices across seizure types, although AUC for EI and SPS was generally greatest for seizures with fast activity at onset. CONCLUSIONS: All indices were significantly higher for contacts inside the SOZ; however, the performance of these indices varied depending on the pattern of seizure onset. SIGNIFICANCE: These findings suggest that future studies of quantitative biomarkers of the SOZ should account for seizure onset pattern.

A minority of patients with functional seizures have abnormalities on neuroimaging.

OBJECTIVE: Functional seizures often are managed incorrectly as a diagnosis of exclusion. However, a significant minority of patients with functional seizures may have abnormalities on neuroimaging that typically are associated with epilepsy, leading to diagnostic confusion. We evaluated the rate of epilepsy-associated findings on MRI, FDG-PET, and CT in patients with functional seizures. METHODS: We studied radiologists' reports from neuroimages at our comprehensive epilepsy center from a consecutive series of patients diagnosed with functional seizures without comorbid epilepsy from 2006 to 2019. We summarized the MRI, FDG-PET, and CT results as follows: within normal limits, incidental findings, unrelated findings, non-specific abnormalities, post-operative study, epilepsy risk factors (ERF), borderline epilepsy-associated findings (EAF), and definitive EAF. RESULTS: Of the 256 MRIs, 23% demonstrated ERF (5%), borderline EAF (8%), or definitive EAF (10%). The most common EAF was hippocampal sclerosis, with the majority of borderline EAF comprising hippocampal atrophy without T2 hyperintensity or vice versa. Of the 87 FDG-PETs, 26% demonstrated borderline EAF (17%) or definitive EAF (8%). Epilepsy-associated findings primarily included focal hypometabolism, especially of the temporal lobes, with borderline findings including subtle or questionable hypometabolism. Of the 51 CTs, only 2% had definitive EAF. SIGNIFICANCE: This large case series provides further evidence that, while uncommon, EAF are seen in patients with functional seizures. A significant portion of these abnormal findings are borderline. The moderately high rate of these abnormalities may represent framing bias from the indication of the study being "seizures," the relative subtlety of EAF, or effects of antiseizure medications.

Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.

STUDY OBJECTIVE: Outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest depend on time to therapy initiation. We hypothesize that it would be feasible to select refractory out-of-hospital cardiac arrest patients for expedited transport based on real-time estimates of the 911 call to the emergency department (ED) arrival interval, and for emergency physicians to rapidly initiate ECPR in eligible patients. METHODS: In a 2-tiered emergency medical service with an ECPR-capable primary destination hospital, adults with refractory shockable or witnessed out-of-hospital cardiac arrest were randomized 4:1 to expedited transport or standard care if the predicted 911 call to ED arrival interval was less than or equal to 30 minutes. The primary outcomes were the proportion of subjects with 911 call to ED arrival less than or equal to 30 minutes and ED arrival to ECPR flow less than or equal to 30 minutes. RESULTS: Of 151 out-of-hospital cardiac arrest 911 calls, 15 subjects (10%) were enrolled. Five of 12 subjects randomized to expedited transport had an ED arrival time of less than or equal to 30 minutes (overall mean 32.5 minutes [SD 7.1]), and 5 were eligible for and treated with ECPR. Three of 5 ECPR-treated subjects had flow initiated in less than or equal to 30 minutes of ED arrival (overall mean 32.4 minutes [SD 10.9]). No subject in either group survived with a good neurologic outcome. CONCLUSION: The Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest trial did not meet predefined feasibility outcomes for selecting out-of-hospital cardiac arrest patients for expedited transport and initiating ECPR in the ED. Additional research is needed to improve the accuracy of predicting the 911 call to ED arrival interval, optimize patient selection, and reduce the ED arrival to ECPR flow interval.