Hippocampal neurons code individual episodic memories in humans.

The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode.

Quantitative EEG may predict weaning failure in ventilated patients on the neurological intensive care unit.

Neurocritical patients suffer from a substantial risk of extubation failure. The aim of this prospective study was to analyze if quantitative EEG (qEEG) monitoring is able to predict successful extubation in these patients. We analyzed EEG-monitoring for at least six hours before extubation in patients receiving mechanical ventilation (MV) on our neurological intensive care unit (NICU) between November 2017 and May 2019. Patients were divided in 2 groups: patients with successful extubation (SE) versus patients with complications after MV withdrawal (failed extubation; FE), including reintubation, need for non-invasive ventilation (NIV) or death. Bipolar six channel EEG was applied. Unselected raw EEG signal underwent automated artefact rejection and Short Time Fast Fourier Transformation. The following relative proportions of global EEG spectrum were analyzed: relative beta (RB), alpha (RA), theta (RT), delta (RD) as well as the alpha delta ratio (ADR). Coefficient of variation (CV) was calculated as a measure of fluctuations in the different power bands. Mann-Whitney U test and logistic regression were applied to analyze group differences. 52 patients were included (26 male, mean age 65 ± 17 years, diagnosis: 40% seizures/status epilepticus, 37% ischemia, 13% intracranial hemorrhage, 10% others). Successful extubation was possible in 40 patients (77%), reintubation was necessary in 6 patients (12%), 5 patients (10%) required NIV, one patient died. In contrast to FE patients, SE patients showed more stable EEG power values (lower CV) considering all EEG channels (RB: p < 0.0005; RA: p = 0.045; RT: p = 0.045) with RB as an independent predictor of weaning success in logistic regression (p = 0.004). The proportion of the EEG frequency bands (RB, RA RT, RD) of the entire EEG power spectrum was not significantly different between SE and FE patients. Higher fluctuations in qEEG frequency bands, reflecting greater fluctuation in alertness, during the hours before cessation of MV were associated with a higher rate of complications after extubation in this cohort. The stability of qEEG power values may represent a non-invasive, examiner-independent parameter to facilitate weaning assessment in neurocritical patients.

Alpha power decrease in quantitative EEG detects development of cerebral infarction after subarachnoid hemorrhage early.

OBJECTIVE: In subarachnoid hemorrhage (SAH), transcranial Doppler/color-coded-duplex sonography (TCD/TCCS) is used to detect delayed cerebral ischemia (DCI). In previous studies, quantitative electroencephalography (qEEG) also predicted imminent DCI. This study aimed to compare and analyse the ability of qEEG and TCD/TCCS to early identify patients who will develop later manifest cerebral infarction. METHODS: We analysed cohorts of two previous qEEG studies. Continuous six-channel-EEG with artefact rejection and a detrending procedure was applied. Alpha power decline of ≥ 40% for ≥ 5 hours compared to a 6-hour-baseline was defined as significant EEG event. Median reduction and duration of alpha power decrease in each channel was determined. Vasospasm was diagnosed by TCD/TCCS, identifying the maximum frequency and days of vasospasm in each territory. RESULTS: 34 patients were included (17 male, mean age 56 ± 11 years, Hunt and Hess grade: I-V, cerebral infarction: 9). Maximum frequencies in TCD/TCCS and alpha power reduction in qEEG were correlated (r = 0.43; p = 0.015). Patients with and without infarction significantly differed in qEEG parameters (maximum alpha power decrease: 78% vs 64%, p = 0.019; summed hours of alpha power decline: 236 hours vs 39 hours, p = 0.006) but showed no significant differences in TCD/TCCS parameters. CONCLUSIONS: There was a moderate correlation of TCD/TCCS frequencies and qEEG alpha power reduction but only qEEG differentiated between patients with and without cerebral infarction. SIGNIFICANCE: qEEG represents a non-invasive, continuous tool to identify patients at risk of cerebral infarction.

Quantitative EEG After Subarachnoid Hemorrhage Predicts Long-Term Functional Outcome.

PURPOSE: Delayed cerebral ischemia is a major complication after subarachnoid hemorrhage. Our previous study showed that alpha power reduction in continuous quantitative EEG predicts delayed cerebral ischemia. In this prospective cohort, we aimed to determine the prognostic value of alpha power in quantitative EEG for the long-term outcome of patients with subarachnoid hemorrhage. METHODS: Adult patients with nontraumatic subarachnoid hemorrhage were included if admitted early enough for EEG to start within 72 hours after symptom onset. Continuous six-channel EEG was applied. Unselected EEG signals underwent automated artifact rejection, power spectral analysis, and detrending. Alpha power decline of ≥40% for ≥5 hours was defined as critical EEG event based on previous findings. Six-month outcome was obtained using the modified Rankin scale. RESULTS: Twenty-two patients were included (14 male; mean age, 59 years; Hunt and Hess grade I-IV; duration of EEG monitoring, median 14 days). Poor outcome (modified Rankin scale, 2-5) was noted in 11 of 16 patients (69%) with critical EEG events. All six patients (100%) without EEG events achieved an excellent outcome (modified Rankin scale 0, 1) (P = 0.0062; sensitivity 100%, specificity 54.5%). Vasospasm detected with transcranial Doppler/Duplex sonography appeared 1.5 days after EEG events and showed weaker association with outcome (P = 0.035; sensitivity 100%, specificity 45.5%). There was no significant association between EEG events and ischemic lesions on imaging (P = 0.1). Also, no association between ischemic lesions and outcome was seen (P = 0.64). CONCLUSIONS: Stable alpha power in quantitative EEG reflects successful therapy and predicts good functional outcome after subarachnoid hemorrhage. Critical alpha power reduction indicates an increased risk of poor functional outcome.

Afterdischarges elicited by cortical electric stimulation in humans: When do they occur and what do they mean?

INTRODUCTION: Afterdischarges (ADs) are a common and unwanted byproduct of direct cortical stimulation during invasive electroencephalography (EEG) recordings. Brief pulse stimulation (BPS) can sometimes terminate ADs. This study investigated AD characteristics and their relevance for emergence of stimulation seizures. In addition, AD response to BPS was analyzed. MATERIAL AND METHODS: Invasive EEG recordings including mapping with direct cortical stimulation in patients with refractory epilepsy at the Erlangen Epilepsy Center were retrospectively reviewed. Afterdischarge defined as stimulation-induced rhythmic epileptiform discharges of more than a two-second duration were analyzed regarding incidence, localization, duration, propagation pattern, morphology, and seizure emergence. In addition, the influence of AD characteristics and stimulation settings on BPS success rate was studied. RESULTS: A number of 4261 stimulation trials in 20 patients were investigated. Afterdischarge occurred in 518 trials (14.2%) and lasted 12.4 s (standard deviation [SD]: 8.6 s) on average. We elicited ADs in the seizure onset zone (SOZ) (n = 64; 19.4%), the irritative zone (n = 105, 20.0%), and outside the irritative area (n = 222, 12.5%). Rhythmic spikes (30.5%) and spike-wave complexes (30.3%) represented predominant morphologies. Afterdischarge morphology in the SOZ and hippocampus differed from other areas with polyspikes and sequential spikes being the most common types there (p = 0.0005; p < 0.0001 respectively). Hippocampal ADs were particularly frequent (n = 50, 38.2%) and long-lasting (mean: 16.6, SD: 8.3 s). Brief pulse stimulation was applied in 18.1% of the AD trials (n = 94) and was successful in 37.4% (n = 40). Success rates were highest when BPS was delivered within 9.5 s (p = 0.0048) and in ADs of spike-wave morphology (p = 0.0004). Fifteen clinical seizures emerged from ADs (3.55%), mostly evolving from sequential spikes. Afterdischarges in patients with stimulation seizures appeared more widespread (p < 0.0001) and lasted longer (mean duration 7.0 s) than in those without (mean duration 21.0 s, p = 0.0054). CONCLUSION: Afterdischarges appear in the epileptogenic and nonepileptogenic cortex. Duration and propagation patterns can help to quantify the risk of stimulation seizures, with sequential spikes being most susceptible to seizure elucidation. The hippocampus is highly sensitive to AD release. Brief pulse stimulation is a safe and efficacious way to terminate ADs, especially when delivered quickly after AD onset.

Automated quantification of EEG spikes and spike clusters as a new read out in Theiler's virus mouse model of encephalitis-induced epilepsy.

Intracerebral infection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) replicates many features of viral encephalitis-induced epilepsy in humans, including neuroinflammation, early (insult-associated) and late (spontaneous) seizures, neurodegeneration in the hippocampus, and cognitive and behavioral alterations. Thus, this model may be ideally suited to study mechanisms involved in encephalitis-induced epilepsy as potential targets for epilepsy prevention. However, spontaneous recurrent seizures (SRS) occur too infrequently to be useful as a biomarker of epilepsy, e.g., for drug studies. This prompted us to evaluate whether epileptiform spikes or spike clusters in the cortical electroencephalogram (EEG) may be a useful surrogate of epilepsy in this model. For this purpose, we developed an algorithm that allows efficient and large-scale EEG analysis of early and late seizures, spikes, and spike clusters in the EEG. While 77% of the infected mice exhibited early seizures, late seizures were only observed in 33% of the animals. The clinical characteristics of early and late seizures did not differ except that late generalized convulsive (stage 5) seizures were significantly longer than early stage 5 seizures. Furthermore, the frequency of SRS was much lower than the frequency of early seizures. Continuous (24/7) video-EEG monitoring over several months following infection indicated that the latent period to onset of SRS was 61 (range 16-91) days. Spike and spike clusters were significantly more frequent in infected mice with late seizures than in infected mice without seizures or in mock-infected sham controls. Based on the results of this study, increases in EEG spikes and spike clusters in groups of infected mice may be used as a new readout for studies on antiepileptogenic or disease-modifying drug effects in this model, because the significant increase in average spike counts in mice with late seizures obviously indicates a proepileptogenic alteration.

Using wearable sensors for semiology-independent seizure detection - towards ambulatory monitoring of epilepsy.

Epilepsy is a disease of the central nervous system. Nearly 70% of people with epilepsy respond to a proper treatment, but for a successful therapy of epilepsy, physicians need to know if and when seizures occur. The gold standard diagnosis tool video-electroencephalography (vEEG) requires patients to stay at hospital for several days. A wearable sensor system, e.g. a wristband, serving as diagnostic tool or event monitor, would allow unobtrusive ambulatory long-term monitoring while reducing costs. Previous studies showed that seizures with motor symptoms such as generalized tonic-clonic seizures can be detected by measuring the electrodermal activity (EDA) and motion measuring acceleration (ACC). In this study, EDA and ACC from 8 patients were analyzed. In extension to previous studies, different types of seizures, including seizures without motor activity, were taken into account. A hierarchical classification approach was implemented in order to detect different types of epileptic seizures using data from wearable sensors. Using a k-nearest neighbor (kNN) classifier an overall sensitivity of 89.1% and an overall specificity of 93.1% were achieved, for seizures without motor activity the sensitivity was 97.1% and the specificity was 92.9%. The presented method is a first step towards a reliable ambulatory monitoring system for epileptic seizures with and without motor activity.

Automatic seizure detection in long-term scalp EEG using an adaptive thresholding technique: a validation study for clinical routine.

OBJECTIVE: In a previous study we proposed a robust method for automatic seizure detection in scalp EEG recordings. The goal of the current study was to validate an improved algorithm in a much larger group of patients in order to show its general applicability in clinical routine. METHODS: For the detection of seizures we developed an algorithm based on Short Time Fourier Transform, calculating the integrated power in the frequency band 2.5-12 Hz for a multi-channel seizure detection montage referenced against the average of Fz-Cz-Pz. For identification of seizures an adaptive thresholding technique was applied. Complete data sets of each patient were used for analyses for a fixed set of parameters. RESULTS: 159 patients (117 temporal-lobe epilepsies (TLE), 35 extra-temporal lobe epilepsies (ETLE), 7 other) were included with a total of 25,278 h of EEG data, 794 seizures were analyzed. The sensitivity was 87.3% and number of false detections per hour (FpH) was 0.22/h. The sensitivity for TLE patients was 89.9% and FpH=0.19/h; for ETLE patients sensitivity was 77.4% and FpH=0.25/h. CONCLUSIONS: The seizure detection algorithm provided high values for sensitivity and selectivity for unselected large EEG data sets without a priori assumptions of seizure patterns. SIGNIFICANCE: The algorithm is a valuable tool for fast and effective screening of long-term scalp EEG recordings.

Standardized computer-based organized reporting of EEG: SCORE.

The electroencephalography (EEG) signal has a high complexity, and the process of extracting clinically relevant features is achieved by visual analysis of the recordings. The interobserver agreement in EEG interpretation is only moderate. This is partly due to the method of reporting the findings in free-text format. The purpose of our endeavor was to create a computer-based system for EEG assessment and reporting, where the physicians would construct the reports by choosing from predefined elements for each relevant EEG feature, as well as the clinical phenomena (for video-EEG recordings). A working group of EEG experts took part in consensus workshops in Dianalund, Denmark, in 2010 and 2011. The faculty was approved by the Commission on European Affairs of the International League Against Epilepsy (ILAE). The working group produced a consensus proposal that went through a pan-European review process, organized by the European Chapter of the International Federation of Clinical Neurophysiology. The Standardised Computer-based Organised Reporting of EEG (SCORE) software was constructed based on the terms and features of the consensus statement and it was tested in the clinical practice. The main elements of SCORE are the following: personal data of the patient, referral data, recording conditions, modulators, background activity, drowsiness and sleep, interictal findings, "episodes" (clinical or subclinical events), physiologic patterns, patterns of uncertain significance, artifacts, polygraphic channels, and diagnostic significance. The following specific aspects of the neonatal EEGs are scored: alertness, temporal organization, and spatial organization. For each EEG finding, relevant features are scored using predefined terms. Definitions are provided for all EEG terms and features. SCORE can potentially improve the quality of EEG assessment and reporting; it will help incorporate the results of computer-assisted analysis into the report, it will make possible the build-up of a multinational database, and it will help in training young neurophysiologists.

Complementary use of video-electroencephalography and magnetoencephalography in frontal lobe epilepsy.

PURPOSE: The aim of this study was to compare magnetoencephalography (MEG) and video-electroencephalography (VEEG) source localization in frontal lobe epilepsy (FLE) and determine if these methods can be complementary to each other in clinical practice. METHOD: Thirty patients with pharmaco-resistant FLE who underwent epilepsy surgery were retrospectively enrolled. Video EEG was recorded using an IT-med system using 10/20 system. Regional localization of spikes in VEEG was defined as spikes discharged from adjacent electrodes and no further propagation to a large and/or contralateral area. Magnetoencephalography was recorded for the purpose of focus assessment. Magnetoencephalography spikes were detected for dipole localization of the epileptogenic cortex and the epileptogenic area was classified as mono- or multi-focal. RESULTS: Regional spike discharges were identified in the interictal VEEG of 20 patients and in the ictal VEEG of 17 patients. Thirteen patients had regional spikes in both interictal and ictal VEEG. Mono-focal localization was identified in the MEG of 20 patients. Fourteen of these patients had regional spike discharges in VEEG. In the remaining six patients, sources localization was only identified by MEG and there were no regional spike discharges either interictal or ictal VEEG. CONCLUSION: In clinical practice, VEEG is the routine procedure in the presurgical evaluation of FLE. However, we found six cases in which VEEG failed to locate the epileptogenic area that was identified by MEG. We therefore propose that combining VEEG and MEG will optimize the noninvasive presurgical evaluation of epileptiform activities in FLE.

Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial.

To elucidate, in a pilot-study, whether noninvasive transcutaneous vagus nerve stimulation (t-VNS) is a safe and tolerable alternative treatment option in pharmacoresistant epilepsy. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, we carried out prolonged outpatient video-electroencephalography (EEG) monitoring. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The noninvasive t-VNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy.

MEG in frontal lobe epilepsies: localization and postoperative outcome.

PURPOSE: This study aimed to analyze magnetoencephalography (MEG) localizations of epileptic clusters in different cortical regions of the frontal lobe and relate these findings to postoperative outcomes associated with frontal lobe epilepsy (FLE). METHODS: Thirty-nine patients from the Epilepsy Center of Erlangen-Nuremberg University with or without lesions on their magnetic resonance imaging (MRI) scans underwent MEG measurements and operation and were then analyzed retrospectively. MEG data were obtained using systems with either 74 or 248 channels. Single dipole analysis assuming a spherical head model was performed for localization. KEY FINDINGS: Epileptic clusters were detected by MEG in 30 patients, corresponding to a sensitivity of 76.9%; there was a sensitivity of 66.7% (20 of 30) in patients with monofocal activity (70% had an Engel class 1 outcome) and 33.3% (10 of 30) in patients with multifocal activity (20% had an Engel class 1 outcome). Of the patients who had isolated clusters, the distance between the MEG localizations and the respective lesions was equal to or <3 cm in 90% (18 of 20) of patients (13 of them had an Engel class 1 outcome) and >3 cm in 10% (2 of 20) of patients (one of them had an Engel class 1 outcome). A statistical difference was found between the outcomes of patients with a single focus and with multiple foci (p < 0.05). SIGNIFICANCE: Patients with a single focus had better postoperative outcomes compared with patients with multiple foci. MEG localizations close to the lesion marked the lesion or its surrounding network as epileptogenic. Therefore, source localization can provide important information for the presurgical evaluation of patients with FLE.

Network characteristics of idiopathic generalized epilepsies in combined MEG/EEG.

Seven patients with idiopathic generalized epilepsies were investigated using MEG and EEG. Spike-wave series were seen in all patients, single spikes in six. For both, source analysis showed most often involvement of frontal, perinsular and subcortical/thalamic areas. In all patients, a unilateral frontal accentuation of activity could be observed. Patients with juvenile myoclonic and myoclonic absence epilepsy presented with localizations mainly in the central and premotor regions versus prefrontal accentuation in the other absence patients. MEG/EEG source localization provides important information concerning regional network involvement in idiopathic generalized epilepsies. As a consequence for a neurophysiological concept of "generalized" epileptic seizures and syndromes, a third subgroup with regional activity in bilateral homologous regions can be differentiated next to pure focal and multifocal generalized epilepsies.

Lobar localization information in epilepsy patients: MEG--a useful tool in routine presurgical diagnosis.

Epilepsy surgery is an established therapy for pharmacoresistant focal epilepsy. This study investigated the contribution of routinely used magnetoencepahlography (MEG) in addition to long term video-EEG-monitoring in presurgical evaluation. The distribution of localization results to anatomical lobes was compared with special focus to MEG spike localization results in cases without or with ambiguous EEG findings. A total of 105 consecutive patients with intractable focal epilepsy and epilepsy surgery after investigation by video-EEG-monitoring and MEG were included. The percentages of monolobar results were analysed and compared, especially with respect to the resection lobe. Postoperative outcome was used for further validation. No spikes were recorded on MEG in 30% (32 of 105). In cases with a diagnostic finding by the respective method, MEG localized in 82% (60 of 73 patients) within one anatomical lobe. Ictal EEG localized within one lobe in 72% (66 of 92 patients), interictal EEG in 60% (59 of 98 patients). In 25 of 105 patients (24%) no clear localization within one lobe was found either in interictal or in ictal EEG. In 11 of these cases MEG localized within the resection lobe. Six patients of these became seizure free, the other five had at least 50% reduction of their seizure rate 1 year after surgery. In summary MEG is a useful tool in the routine workup for epilepsy surgery contributing information to focus hypothesis in addition to video-EEG.

Spatial relationship of source localizations in patients with focal epilepsy: Comparison of MEG and EEG with a three spherical shells and a boundary element volume conductor model.

Epilepsy surgery is an option for patients with pharmacoresistant focal epilepsies, but it requires a precise focus localization procedure. Magnetoencephalography (MEG) and electroencephalography (EEG) can be used for analysis of interictal activity. The aim of this prospective study was to compare clusters of source localization results with MEG and EEG using a three spherical shells (3SS) and a boundary element method (BEM) volume conductor model. The study was closed when 100 patients met the inclusion criteria. Simultaneous MEG and EEG were recorded during presurgical evaluation. Epileptiform signals were analyzed using an equivalent current dipole model. Centroids of source localizations from MEG, EEG, 3SS, and BEM in their respective combinations were compared. In a 3SS model, MEG source localizations were 5.6 mm inferior to those obtained by EEG, while in a BEM model MEG source localizations were 6.3 mm anterior and 4.8 mm superior. The mean scattering of source localizations between both volume conductor models was 19.5 mm for EEG and 9.6 mm for MEG. For MEG no systematic difference between BEM and 3SS source localizations was found. For EEG, source localizations with BEM were 5.9 mm posterior and 11.7 mm inferior to those determined using 3SS. No differences were found between the 46 temporal and the 54 extratemporal lobe epilepsy patients. The observed systematic differences of source localizations of epileptic spikes due to the applied source signal modality and volume conductor model should be considered in presurgical evaluation when only one source signal and volume conductor model is available.