Cellular recovery after prolonged warm ischaemia of the whole body.

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.

Video quality using outpatient smartphone videos in epilepsy: Results from the OSmartViE study.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the quality of smartphone videos (SVs) of neurologic events in adult epilepsy outpatients. The use of home video recording in patients with neurological disease states is increasing. Experts interpretation of outpatient smartphone videos of seizures and neurological events has demonstrated similar diagnostic accuracy to inpatient video-electroencephalography (EEG) monitoring. METHODS: A prospective, multicenter cohort study was conducted to evaluate SV quality in patients with paroxysmal neurologic events from August 15, 2015 through August 31, 2018. Epileptic seizures (ESs), psychogenic nonepileptic attacks (PNEAs), and physiologic nonepileptic events (PhysNEEs) were confirmed by video-EEG monitoring. Experts and senior neurology residents blindly viewed cloud-based SVs without clinical information. Quality ratings with regard to technical and operator-driven metrics were provided in responses to a survey. RESULTS: Forty-four patients (31 women, age 45.1 years [r = 20-82]) were included and 530 SVs were viewed by a mean of seven experts and six residents; one video per patient was reviewed for a mean of 133.8 s (r = 9-543). In all, 30 patients had PNEAs, 11 had ESs, and three had PhysNEEs. Quality was suitable in 70.8% of SVs (375/530 total views), with 36/44 (81.8%) patient SVs rated as adequate by the majority of reviewers. Accuracy improved with the presence of convulsive features from 72.4% to 98.2% in ESs and from 71.1% to 95.7% in PNEAs. An accurate diagnosis was given by all reviewers (100%) in 11/44 SVs (all PNEAs). Audio was rated as good by 86.2% of reviewers for these SVs compared with 75.4% for the remaining SVs (p = 0.01). Lighting was better in SVs associated with high accuracy (p = 0.06), but clarity was not (p = 0.59). Poor video quality yielded unknown diagnoses in 24.2% of the SVs reviewed. Features hindering diagnosis were limited interactivity, restricted field of view and short video duration. CONCLUSIONS: Smartphone video quality is adequate for clinical interpretation in the majority of patients with paroxysmal neurologic events. Quality can be optimized by encouraging interactivity with the patient, adequate duration of the SV, and enlarged field of view during videography. Quality limitations were primarily operational though accuracy remained for SV review of ESs and PNEAs.

Beyond implantation effect? Long-term seizure reduction and freedom following intracranial monitoring without additional surgical interventions.

The term 'implantation effect' is used to describe an immediate and transient improvement in seizure frequency following an intracranial study for seizure onset localization. We conducted a retrospective analysis of 190 consecutive patients undergoing intracranial electroencephalogram (EEG) monitoring, of whom 41 had no subsequent resection/ablation/stimulation; 33 had adequate data and follow-up time available for analysis. Analysis of seizure frequency following an intracranial study showed 36% (12/33) responder rate (>50% seizure reduction) at one year, decreasing and stabilizing at 20% from year 4 onwards. In addition, we describe three patients (9%) who had long term seizure freedom of more than five years following electrode implantation alone, two of whom had thalamic depth electrodes. Electrode implantation perhaps leads to a neuromodulatory effect sufficient enough to disrupt epileptogenic networks. Rarely, this may be significant enough to even result in long term seizure freedom, as seen in our three patients.

Seizure susceptibility and infraslow modulatory activity in the intracranial electroencephalogram.

OBJECTIVE: Studies of infraslow amplitude modulations (<0.15 Hz) of band power time series suggest that these envelope correlations may form a basis for distant spatial coupling in the brain. In this study, we sought to determine how infraslow relationships are affected by antiepileptic drug (AED) taper, time of day, and seizure. METHODS: We studied intracranial electroencephalographic (icEEG) data collected from 13 medically refractory adult epilepsy patients who underwent monitoring at Yale-New Haven Hospital. We estimated the magnitude-squared coherence (MSC) at <0.15 Hz of traditional EEG frequency band power time series for all electrode contact pairs to quantify infraslow envelope correlations between them. We studied, first, hour-long background icEEG epochs before and after AED taper to understand the effect of taper. Second, we analyzed the entire record for each patient to study the effect of time of day. Finally, for each patient, we reviewed the clinical record to find all seizures that were at least 6 hours removed from other seizures and analyzed infraslow envelope MSC before and after them. RESULTS: Infraslow envelope MSC increased slightly, but significantly, after AED taper, and increased on average during the night and decreased during the day. It was also increased significantly in all frequency bands up to 3 hours preseizure and 1 hour postseizure as compared to background icEEG (61 seizures studied). These changes occurred for both daytime and nighttime seizures (28 daytime, 33 nighttime). Interestingly, there was significant spatial variability to these changes, with the seizure onset area peaking at 3 hours preseizure, then showing progressive desynchronization from 3 hours preseizure to 1 hour postseizure. SIGNIFICANCE: Infraslow envelope analysis may be used to understand long-term changes over the course of icEEG monitoring, provide unique insight into interictal electrophysiological changes related to ictogenesis, and contribute to the development of novel seizure forecasting algorithms.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

OBJECTIVE: To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. METHODS: All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. RESULTS: There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SIGNIFICANCE: The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

50 Hz hippocampal stimulation in refractory epilepsy: Higher level of basal glutamate predicts greater release of glutamate.

OBJECTIVE: The effect of electrical stimulation on brain glutamate release in humans is unknown. Glutamate is elevated at baseline in the epileptogenic hippocampus of patients with refractory epilepsy, and increases during spontaneous seizures. We examined the effect of 50 Hz stimulation on glutamate release and its relationship to interictal levels in the hippocampus of patients with epilepsy. In addition, we measured basal and stimulated glutamate levels in a subset of these patients where stimulation elicited a seizure. METHODS: Subjects (n = 10) were patients with medically refractory epilepsy who were undergoing intracranial electroencephalography (EEG) evaluation in an epilepsy monitoring unit. Electrical stimulation (50 Hz) was delivered through implanted hippocampal electrodes (n = 11), and microdialysate samples were collected every 2 min. Basal glutamate, changes in glutamate efflux with stimulation, and the relationships between peak stimulation-associated glutamate concentrations, basal zero-flow levels, and stimulated seizures were examined. RESULTS: Stimulation of epileptic hippocampi in patients with refractory epilepsy caused increases in glutamate efflux (p = 0.005, n = 10), and 4 of ten patients experienced brief stimulated seizures. Stimulation-induced increases in glutamate were not observed during the evoked seizures, but rather were related to the elevation in interictal basal glutamate (R(2) = 0.81, p = 0.001). The evoked-seizure group had lower basal glutamate levels than the no-seizure group (p = 0.04), with no stimulation-induced change in glutamate efflux (p = 0.47, n = 4). Conversely, increased glutamate was observed following stimulation in the no-seizure group (p = 0.005, n = 7). Subjects with an atrophic hippocampus had higher basal glutamate levels (p = 0.03, n = 7) and higher stimulation-induced glutamate efflux. SIGNIFICANCE: Electrical stimulation of the epileptic hippocampus either increased extracellular glutamate efflux or induced seizures. The magnitude of stimulated glutamate increase was related to elevation in basal interictal glutamate, suggesting a common mechanism, possibly impaired glutamate metabolism. Divergent mechanisms may exist for seizure induction and increased glutamate in patients with epilepsy. These data highlight the potential risk of 50 Hz stimulation in patients with epilepsy.

The spatial and signal characteristics of physiologic high frequency oscillations.

OBJECTIVES: To study the incidence, spatial distribution, and signal characteristics of high frequency oscillations (HFOs) outside the epileptic network. METHODS: We included patients who underwent invasive evaluations at Yale Comprehensive Epilepsy Center from 2012 to 2013, had all major lobes sampled, and had localizable seizure onsets. Segments of non-rapid eye movement (NREM) sleep prior to the first seizure were analyzed. We implemented a semiautomated process to analyze oscillations with peak frequencies >80 Hz (ripples 80-250 Hz; fast ripples 250-500 Hz). A contact location was considered epileptic if it exhibited epileptiform discharges during the intracranial evaluation or was involved ictally within 5 s of seizure onset; otherwise it was considered nonepileptic. RESULTS: We analyzed recordings from 1,209 electrode contacts in seven patients. The nonepileptic contacts constituted 79.1% of the total number of contacts. Ripples constituted 99% of total detections. Eighty-two percent of all HFOs were seen in 45.2% of the nonepileptic contacts (82.1%, 47%, 34.6%, and 34% of the occipital, parietal, frontal, and temporal nonepileptic contacts, respectively). The following sublobes exhibited physiologic HFOs in all patients: Perirolandic, basal temporal, and occipital subregions. The ripples from nonepileptic sites had longer duration, higher amplitude, and lower peak frequency than ripples from epileptic sites. A high HFO rate (>1/min) was seen in 110 nonepileptic contacts, of which 68.2% were occipital. Fast ripples were less common, seen in nonepileptic parietooccipital regions only in two patients and in the epileptic mesial temporal structures. CONCLUSIONS: There is consistent occurrence of physiologic HFOs over vast areas of the neocortex outside the epileptic network. HFOs from nonepileptic regions were seen in the occipital lobes and in the perirolandic region in all patients. Although duration of ripples and peak frequency of HFOs are the most effective measures in distinguishing pathologic from physiologic events, there was significant overlap between the two groups.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

7T MR spectroscopic imaging in the localization of surgical epilepsy.

PURPOSE: With the success that surgical approaches can provide for localization-related epilepsy, accurate seizure localization remains important. Although magnetic resonance (MR) spectroscopy has had success in earlier studies in medial temporal lobe epilepsy, there have been fewer studies evaluating its use in a broader range of localization-related epilepsy. With improvements in signal-to-noise with ultra-high field MR, we report on the use of high resolution 7T MR spectroscopic imaging (MRSI) in 25 surgically treated patients studied over a 3.5-year period. METHODS: Patients were included in this analysis if the region of MRSI study included the surgical resection region. Concordance between region of MRSI abnormalities and of surgical resection was classified into three groups (complete, partial, or no agreement) and outcome was dichotomized by International League Against Epilepsy (ILAE) I-III and IV-VI groups. MRSI was performed with repetition time/echo time 1.5 s/40 msec in two-dimensional (2D) or three-dimensional (3D) encoding for robust detection of singlets N-acetyl aspartate (NAA), creatine (Cr), and choline with abnormalities in NAA/Cr determined with correction for tissue content of gray matter. KEY FINDINGS: The concordance between MRSI-determined abnormality and surgical resection region was significantly related to outcome: Outcome was better if the resected tissue was metabolically abnormal. All 14 patients with complete resection of the region with the most severe metabolic abnormality had good outcome, including five requiring intracranial electroencephalography (EEG) analysis, whereas only 3/11 without complete resection of the most severe metabolic abnormality had good outcome (p < 0.001). SIGNIFICANCE: This is consistent with the seizure-onset zone being characterized by metabolic dysfunction and suggests that high resolution MRSI can help define these regions for the purposes of outcome prediction.

Artificial neural network trained on smartphone behavior can trace epileptiform activity in epilepsy.

A range of abnormal electrical activity patterns termed epileptiform discharges can occur in the brains of persons with epilepsy. These epileptiform discharges can be monitored and recorded with implanted devices that deliver therapeutic neurostimulation. These continuous recordings provide an opportunity to study the behavioral correlates of epileptiform discharges as the patients go about their daily lives. Here, we captured the smartphone touchscreen interactions in eight patients in conjunction with electrographic recordings (accumulating 35,714 h) and by using an artificial neural network model addressed if the behavior reflected the epileptiform discharges. The personalized model outputs based on smartphone behavioral inputs corresponded well with the observed electrographic data (R: 0.2-0.6, median 0.4). The realistic reconstructions of epileptiform activity based on smartphone use demonstrate how day-to-day digital behavior may be converted to personalized markers of disease activity in epilepsy.

A prospective study of loss of consciousness in epilepsy using virtual reality driving simulation and other video games.

Patients with epilepsy are at risk of traffic accidents when they have seizures while driving. However, driving is an essential part of normal daily life in many communities, and depriving patients of driving privileges can have profound consequences for their economic and social well-being. In the current study, we collected ictal performance data from a driving simulator and two other video games in patients undergoing continuous video/EEG monitoring. We captured 22 seizures in 13 patients and found that driving impairment during seizures differed in terms of both magnitude and character, depending on the seizure type. Our study documents the feasibility of a prospective study of driving and other behaviors during seizures through the use of computer-based tasks. This methodology may be applied to further describe differential driving impairment in specific types of seizures and to gain data on anatomical networks disrupted in seizures that impair consciousness and driving safety.

Assessment of the Predictive Value of Outpatient Smartphone Videos for Diagnosis of Epileptic Seizures.

Importance: Misdiagnosis of epilepsy is common. Video electroencephalogram provides a definitive diagnosis but is impractical for many patients referred for evaluation of epilepsy. Objective: To evaluate the accuracy of outpatient smartphone videos in epilepsy. Design, Setting, and Participants: This prospective, masked, diagnostic accuracy study (the OSmartViE study) took place between August 31, 2015, and August 31, 2018, at 8 academic epilepsy centers in the United States and included a convenience sample of 44 nonconsecutive outpatients who volunteered a smartphone video during evaluation and subsequently underwent video electroencephalogram monitoring. Three epileptologists uploaded videos for physicians from the 8 epilepsy centers to review. Main Outcomes and Measures: Measures of performance (accuracy, sensitivity, specificity, positive predictive value, and negative predictive value) for smartphone video-based diagnosis by experts and trainees (the index test) were compared with those for history and physical examination and video electroencephalogram monitoring (the reference standard). Results: Forty-four eligible epilepsy clinic outpatients (31 women [70.5%]; mean [range] age, 45.1 [20-82] years) submitted smartphone videos (530 total physician reviews). Final video electroencephalogram diagnoses included 11 epileptic seizures, 30 psychogenic nonepileptic attacks, and 3 physiologic nonepileptic events. Expert interpretation of a smartphone video was accurate in predicting a video electroencephalogram monitoring diagnosis of epileptic seizures 89.1% (95% CI, 84.2%-92.9%) of the time, with a specificity of 93.3% (95% CI, 88.3%-96.6%). Resident responses were less accurate for all metrics involving epileptic seizures and psychogenic nonepileptic attacks, despite greater confidence. Motor signs during events increased accuracy. One-fourth of the smartphone videos were correctly diagnosed by 100% of the reviewing physicians, composed solely of psychogenic attacks. When histories and physical examination results were combined with smartphone videos, correct diagnoses rose from 78.6% to 95.2%. The odds of receiving a correct diagnosis were 5.45 times greater using smartphone video alongside patient history and physical examination results than with history and physical examination alone (95% CI, 1.01-54.3; P = .02). Conclusions and Relevance: Outpatient smartphone video review by experts has predictive and additive value for diagnosing epileptic seizures. Smartphone videos may reliably aid psychogenic nonepileptic attacks diagnosis for some people.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Spatial distribution of intracranially recorded spikes in medial and lateral temporal epilepsies.

PURPOSE: Although seizures and interictal spikes are not always colocalized, there may be valuable localizing information in the spatial distribution of spikes. To test this hypothesis, we studied the spatial distribution of intracranially recorded interictal spikes in patients with medial temporal (MT) and lateral temporal (LT) neocortical seizure onset. METHODS: A total of 21 patients (MT n = 12, LT n = 9) who completed intracranial monitoring were selected for this study. Two 4-h intracranial electroencephalography (icEEG) epochs were analyzed, one during wake and one during sleep, both at least 6 h removed from seizures. Spikes detected automatically in medial temporal structures [hippocampal formation (H) and entorhinal cortex (EC)], and in five cortical areas (occipital, frontal, parietal, lateral temporal, and inferior temporal) were tabulated. RESULTS: Interictal spikes occurred broadly over medial temporal structures and cortical areas in MT and LT patients. The patients differed with a greater number of spikes in medial temporal structures in the MT group (p < 0.05 for H and p < 0.001 for EC) and a greater number of spikes in parietal (p < 0.01) and frontal (p < 0.001) areas in the LT group. There were sleep-related increases in spike rates in inferomedial temporal structures in both groups. The two groups could be separated with a classifier based on medial temporal and parietal and frontal spikes (p < 0.0001). DISCUSSION: MT and LT patients have different spatial distributions of interictal spikes and can be distinguished by the relative spike rates in medial temporal and extratemporal areas during sleep and wake.

Interictal spikes on intracranial recording: behavior, physiology, and implications.

PURPOSE: The physiological, pathological, and clinical meaning of interictal spikes (IISs) remains controversial. We systematically analyzed the frequency, occurrence, and distribution of IISs recorded from multiple intracranial electrodes in 34 refractory epileptic patients with respect to seizures and antiepileptic drug (AED) changes. METHODS: Continuous spike counts from all recorded contacts of all implanted electrodes, and also separately for the subset of contacts involved at seizure onset, were tabulated for every hour of every day of recording, and expressed as spikes per hour in six preselected, 24-h intervals (defined to exclude seizures): (1) on medications; (2) prepreseizure; (3) preseizure; (4) postseizure; (5) off meds; and (6) resumed meds. Mean spike rates were analyzed for differences between designated 24-h intervals. RESULTS: Spike rate in all recorded contacts consistently and significantly decreased after AED withdrawal, despite variability in initial spike rate, diurnal occurrence, seizure character/number/localization of onset, and type(s) of AED continued or withdrawn (p < 0.0001). A significant increase in spike rate was noted in the 24 h after seizures of medial temporal origin, in the medial temporal lobe contacts; neocortical onset seizures did not show any increase. CONCLUSIONS: These observations confirm and extend previous reports, suggesting a general effect of AED withdrawal, and a more specific effect of medial temporal lobe seizures, on IIS rate. AED mechanisms and efficacy might be demonstrated by quantifying IIS with changes in AEDs. Furthermore, variability in IIS rate after seizures distinguishes localization of seizure onset in medial temporal versus neocortical locations.

Local spatial effect of 50 Hz cortical stimulation in humans.

PURPOSE: Cortical stimulation to abort seizures is under human investigation. Ideal electrode placement and stimulating parameters are unknown with poor understanding of tissue volume affected by stimulation or duration and nature of its effect on cortical activity. To help characterize this effect, we analyzed electrocorticography (ECoG) recorded adjacent to stimulated contacts during and after bipolar stimulation in patients undergoing functional cortical mapping with subdural electrodes. METHODS: We analyzed four functional mapping procedures in three patients. One row of contacts was chosen for bipolar stimulation at sequential distances. Stimulation parameters were those used for functional mapping. Pooled Teager energy (TE) and band power were calculated for: (1) baseline, (2) 5 s during stimulation, and (3) 5-15 s after the stimulus. RESULTS: Average TE increased during stimulation, falling with distance from the stimulus. Average poststimulus TE increased (284-905%) compared to baseline. Increased TE was observed: (1) up to 10 s after stimulation, (2) stimulation amplitudes of 4 mA or greater, and (3) up to 2 cm from the stimulus. There was no difference in poststimulus TE between the stimulated pair of contacts and outside the pair. Greatest increase in poststimulus signal power occurred in beta and gamma bands. CONCLUSIONS: Human cortical stimulation of 50 Hz resulted in elevated ECoG energy measurements up to 10 s poststimulation. Contacts >2 cm from stimulated electrodes did not show significant response to stimulation. Separating contacts >2 cm on the cortical surface may not result in efficacious treatment of seizure activity using common stimulation amplitudes (2-10 mA).

On the use of bipolar montages for time-series analysis of intracranial electroencephalograms.

OBJECTIVE: Bipolar montages are routinely employed for the interpretation of scalp and intracranial EEGs (icEEGs). In this manuscript we consider the assumptions that support the use of a bipolar montage and question the universal appropriateness of bipolar representation of icEEGs for the time-series analysis of these signals. Bipolar montages introduce an element of spatial processing into the observed time-series. In the case of icEEGs, we argue ambiguity may be introduced in some settings through this operation because of a lack of certifiability of local differentiability and continuity of the spatial structure of icEEGs, and their suboptimal spatial sampling. METHODS: Example icEEGs were collected from three patients being studied for possible resective epilepsy surgery. Referential and bipolar representations of these signals were subjected to different visual and time-series analysis. The time-series measures calculated were the power spectral density and magnitude squared coherence. RESULTS: Visual analysis and time-series measures revealed that the icEEG time-series was altered by the use of a bipolar montage. The changes resulted from either the introduction of unrelated information from the two referential time-series into the bipolar time-series, or from the removal or alteration of information common to the two referential time-series in the bipolar time-series. The changes could not be predicted without prior knowledge of the relationship between measurement sites that form the bipolar montage. CONCLUSIONS: In certain settings, bipolar montages alter icEEGs and can confound the time-series analysis of these signals. In such settings, bipolar montages should be used with caution in the time-series analysis of icEEGs. SIGNIFICANCE: This manuscript addresses the representation of the intracranial EEG for time-series analysis. There may be contexts where the assumptions underpinning correct application of the bipolar montage to the intracranial EEG are not satisfied.

The relationship between seizures, interictal spikes and antiepileptic drugs.

OBJECTIVE: A considerable decrease in spike rate accompanies antiepileptic drug (AED) taper during intracranial EEG (icEEG) monitoring. Since spike rate during icEEG monitoring can be influenced by surgery to place intracranial electrodes, we studied spike rate during long-term scalp EEG monitoring to further test this observation. METHODS: We analyzed spike rate, seizure occurrence and AED taper in 130 consecutive patients over an average of 8.9days (range 5-17days). RESULTS: We observed a significant relationship between time to the first seizure, spike rate, AED taper and seizure occurrence (F (3,126)=19.77, p<0.0001). A high spike rate was related to a longer time to the first seizure. Further, in a subset of 79 patients who experienced seizures on or after day 4 of monitoring, spike rate decreased initially from an on- to off-AEDs epoch (from 505.0 to 382.3 spikes per hour, p<0.00001), and increased thereafter with the occurrence of seizures. CONCLUSIONS: There is an interplay between seizures, spikes and AEDs such that spike rate decreases with AED taper and increases after seizure occurrence. SIGNIFICANCE: The direct relationship between spike rate and AEDs and between spike rate and time to the first seizure suggests that spikes are a marker of inhibition rather than excitation.