Timing matters for accurate identification of the epileptogenic zone.

OBJECTIVE: Interictal biomarkers of the epileptogenic zone (EZ) and their use in machine learning models open promising avenues for improvement of epilepsy surgery evaluation. Currently, most studies restrict their analysis to short segments of intracranial EEG (iEEG). METHODS: We used 2381 hours of iEEG data from 25 patients to systematically select 5-minute segments across various interictal conditions. Then, we tested machine learning models for EZ localization using iEEG features calculated within these individual segments or across them and evaluated the performance by the area under the precision-recall curve (PRAUC). RESULTS: On average, models achieved a score of 0.421 (the result of the chance classifier was 0.062). However, the PRAUC varied significantly across the segments (0.323-0.493). Overall, NREM sleep achieved the highest scores, with the best results of 0.493 in N2. When using data from all segments, the model performed significantly better than single segments, except NREM sleep segments. CONCLUSIONS: The model based on a short segment of iEEG recording can achieve similar results as a model based on prolonged recordings. The analyzed segment should, however, be carefully and systematically selected, preferably from NREM sleep. SIGNIFICANCE: Random selection of short iEEG segments may give rise to inaccurate localization of the EZ.

Interictal invasive very high-frequency oscillations in resting awake state and sleep.

Interictal very high-frequency oscillations (VHFOs, 500-2000 Hz) in a resting awake state seem to be, according to a precedent study of our team, a more specific predictor of a good outcome of the epilepsy surgery compared to traditional interictal high-frequency oscillations (HFOs, 80-500 Hz). In this study, we retested this hypothesis on a larger cohort of patients. In addition, we also collected patients' sleep data and hypothesized that the occurrence of VHFOs in sleep will be greater than in resting state. We recorded interictal invasive electroencephalographic (iEEG) oscillations in 104 patients with drug-resistant epilepsy in a resting state and in 35 patients during sleep. 21 patients in the rest study and 11 patients in the sleep study met the inclusion criteria (interictal HFOs and VHFOs present in iEEG recordings, a surgical intervention and a postoperative follow-up of at least 1 year) for further evaluation of iEEG data. In the rest study, patients with good postoperative outcomes had significantly higher ratio of resected contacts with VHFOs compared to HFOs. In sleep, VHFOs were more abundant than in rest and the percentage of resected contacts in patients with good and poor outcomes did not considerably differ in any type of oscillations. In conclusion, (1) our results confirm, in a larger patient cohort, our previous work about VHFOs being a specific predictor of the area which needs to be resected; and (2) that more frequent sleep VHFOs do not further improve the results.

Multi-feature localization of epileptic foci from interictal, intracranial EEG.

OBJECTIVE: When considering all patients with focal drug-resistant epilepsy, as high as 40-50% of patients suffer seizure recurrence after surgery. To achieve seizure freedom without side effects, accurate localization of the epileptogenic tissue is crucial before its resection. We investigate an automated, fast, objective mapping process that uses only interictal data. METHODS: We propose a novel approach based on multiple iEEG features, which are used to train a support vector machine (SVM) model for classification of iEEG electrodes as normal or pathologic using 30 min of inter-ictal recording. RESULTS: The tissue under the iEEG electrodes, classified as epileptogenic, was removed in 17/18 excellent outcome patients and was not entirely resected in 8/10 poor outcome patients. The overall best result was achieved in a subset of 9 excellent outcome patients with the area under the receiver operating curve = 0.95. CONCLUSION: SVM models combining multiple iEEG features show better performance than algorithms using a single iEEG marker. Multiple iEEG and connectivity features in presurgical evaluation could improve epileptogenic tissue localization, which may improve surgical outcome and minimize risk of side effects. SIGNIFICANCE: In this study, promising results were achieved in localization of epileptogenic regions by SVM models that combine multiple features from 30 min of inter-ictal iEEG recordings.

Very high-frequency oscillations: Novel biomarkers of the epileptogenic zone.

OBJECTIVE: In the present study, we aimed to investigate depth electroencephalographic (EEG) recordings in a large cohort of patients with drug-resistant epilepsy and to focus on interictal very high-frequency oscillations (VHFOs) between 500Hz and 2kHz. We hypothesized that interictal VHFOs are more specific biomarkers for epileptogenic zone compared to traditional HFOs. METHODS: Forty patients with focal epilepsy who underwent presurgical stereo-EEG (SEEG) were included in the study. SEEG data were recorded with a sampling rate of 25kHz, and a 30-minute resting period was analyzed for each patient. Ten patients met selected criteria for analyses of correlations with surgical outcome: detection of interictal ripples (Rs), fast ripples (FRs), and VHFOs; resective surgery; and at least 1 year of postoperative follow-up. Using power envelope computation and visual inspection of power distribution matrixes, electrode contacts with HFOs and VHFOs were detected and analyzed. RESULTS: Interictal very fast ripples (VFRs; 500-1,000Hz) were detected in 23 of 40 patients and ultrafast ripples (UFRs; 1,000-2,000Hz) in almost half of investigated subjects (n = 19). VFRs and UFRs were observed only in patients with temporal lobe epilepsy and were recorded exclusively from mesiotemporal structures. The UFRs were more spatially restricted in the brain than lower-frequency HFOs. When compared to R oscillations, significantly better outcomes were observed in patients with a higher percentage of removed contacts containing FRs, VFRs, and UFRs. INTERPRETATION: Interictal VHFOs are relatively frequent abnormal phenomena in patients with epilepsy, and appear to be more specific biomarkers for epileptogenic zone when compared to traditional HFOs. Ann Neurol 2017;82:299-310.

The Role of Anterior Nuclei of the Thalamus: A Subcortical Gate in Memory Processing: An Intracerebral Recording Study.

OBJECTIVE: To study the involvement of the anterior nuclei of the thalamus (ANT) as compared to the involvement of the hippocampus in the processes of encoding and recognition during visual and verbal memory tasks. METHODS: We studied intracerebral recordings in patients with pharmacoresistent epilepsy who underwent deep brain stimulation (DBS) of the ANT with depth electrodes implanted bilaterally in the ANT and compared the results with epilepsy surgery candidates with depth electrodes implanted bilaterally in the hippocampus. We recorded the event-related potentials (ERPs) elicited by the visual and verbal memory encoding and recognition tasks. RESULTS: P300-like potentials were recorded in the hippocampus by visual and verbal memory encoding and recognition tasks and in the ANT by the visual encoding and visual and verbal recognition tasks. No significant ERPs were recorded during the verbal encoding task in the ANT. In the visual and verbal recognition tasks, the P300-like potentials in the ANT preceded the P300-like potentials in the hippocampus. CONCLUSIONS: The ANT is a structure in the memory pathway that processes memory information before the hippocampus. We suggest that the ANT has a specific role in memory processes, especially memory recognition, and that memory disturbance should be considered in patients with ANT-DBS and in patients with ANT lesions. ANT is well positioned to serve as a subcortical gate for memory processing in cortical structures.

Subthalamic nucleus involvement in executive functions with increased cognitive load: a subthalamic nucleus and anterior cingulate cortex depth recording study.

We studied the appearance of broadband oscillatory changes (ranging 2-45 Hz) induced by a cognitive task with two levels of complexity. The event-related de/synchronizations (ERD/S) in the subthalamic nucleus (STN) and in the anterior cingulate cortex (ACC) were evaluated in an executive function test. Four epilepsy surgery candidates with intracerebral electrodes implanted in the ACC and three Parkinson's disease patients with externalized deep brain stimulation electrodes implanted in the STN participated in the study. A Flanker test (FT) with visual stimuli (arrows) was performed. Subjects reacted to four types of stimuli presented on the monitor by pushing the right or left button: congruent arrows to the right or left side (simple task) and incongruent arrows to the right or left side (more difficult complex task). We explored the activation of STN and the activation of the ACC while processing the FT. Both conditions, i.e. congruent and incongruent, induced oscillatory changes in the ACC and also STN with significantly higher activation during incongruent trial. At variance with the ACC, in the STN not only the ERD beta but also the ERD alpha activity was significantly more activated by the incongruent condition. In line with our earlier studies, the STN appears to be involved in activities linked with increased cognitive load. The specificity and complexity of task-related activation of the STN might indicate the involvement of the STN in processes controlling human behaviour, e.g. in the selection and inhibition of competing alternatives.

Endovascular brain intervention and mapping in a dog experimental model using magnetically-guided micro-catheter technology.

AIM: Despite the substantial progress that has been achieved in interventional cardiology and cardiac electrophysiology, endovascular intervention for the diagnosis and treatment of central nervous system (CNS) disorders such as stroke, epilepsy and CNS malignancy is still limited, particularly due to highly tortuous nature of the cerebral arterial and venous system. Existing interventional devices and techniques enable only limited and complicated access especially into intra-cerebral vessels. The aim of this study was to develop a micro-catheter magnetically-guided technology specifically designed for endovascular intervention and mapping in deep CNS vascular structures. METHODS: Mapping of electrical brain activity was performed via the venous system on an animal dog model with the support of the NIOBE II system. RESULTS: A novel micro-catheter specially designed for endovascular interventions in the CNS, with the support of the NIOBE II technology, was able to reach safely deep intra-cerebral venous structures and map the electrical activity there. Such structures are not currently accessible using standard catheters. CONCLUSION: This is the first study demonstrating successful use of a new micro-catheter in combination with NIOBE II technology for endovascular intervention in the brain.

Ictal and peri-ictal oscillations in the human basal ganglia in temporal lobe epilepsy.

Preictal, ictal, and postictal oscillations in the basal ganglia were analyzed. Five persons with temporal lobe epilepsy who were candidates for surgery had diagonal depth electrodes implanted in the basal ganglia: four of them in the putamen, and one in the pallidum and caudate. Time-frequency and power spectral analyses were used to analyze the EEG. Significant frequency components of 2-10 Hz were consistently observed in the basal ganglia. The frequency of this component slowed during seizures. There was a significant ictal increase in power spectral density in all frequency ranges. The changes in the basal ganglia were consistent while seizure activity spread over the cortex, and partially persisted after the clinical seizure ended. They were inconsistent in the period after seizure onset. Seizures originating in the mesiotemporal structures can affect physiological rhythms in the basal ganglia. The basal ganglia did not generate epileptiform EEG activity. An inhibitory role for the basal ganglia during temporal lobe seizures is suggested.

Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome.

BACKGROUND: Patients with congenital long QT syndrome (LQTS) type 2 (LQT2) may develop arrhythmias during emotional stress, acoustic stimuli, or sleep. Women with LQT2 are more susceptible to fatal arrhythmias than are men. OBJECTIVE: The purpose of this study was to examine the effects of sleep on RR and QT intervals in patients with LQT1, in those with LQT2, and in controls and to test the hypothesis that there is a gene-specific effect of sleep on the QT interval in LQT2 that may be especially evident in women with LQT2. METHODS: Thirty-four subjects with genotyped LQTS and 18 healthy controls were studied. Among the 34 subjects with LQTS, 16 (10 women, age 32 +/- 3 years) had LQT1 and 18 (11 women, age 38 +/- 3 years) had LQT2. Subjects underwent standard polysomnography including ECG recordings. RR, QT, and QTc (Bazett and Fridericia formulas) were measured over recordings obtained during stable conditions during wakefulness, during stage 2 and stages 3-4 of non-rapid eye movement (NREM), and during rapid eye movement (REM) sleep. RESULTS: LQT2 women showed a marked RR decrease and marked QT and QTc increase from NREM to REM sleep, changes that were not observed in either women or men with LQT1 or in men with LQT2. CONCLUSION: Pronounced cardiac activation during REM and substantial QTc prolongation is noted in a sex- and gene-specific fashion among women with LQT2. REM-related changes in cardiac activation and ventricular repolarization may be implicated in sleep-related malignant arrhythmias in women with the LQT2 genotype.

Interictal high-frequency oscillations indicate seizure onset zone in patients with focal cortical dysplasia.

Interictal high-frequency oscillations (HFO) were recently identified in recordings from depth macroelectrodes in epileptic patients. StereoEEG (SEEG) recordings were analyzed in four patients with medically intractable partial seizures due to focal cortical dysplasia type IIA. Characteristics of HFO within seizure onset zone (SOZ), irritative zone, and remote brain areas were investigated. Whilst the rate of occurrence for ripples (80-200 Hz) was significantly higher in recordings from within than outside the SOZ, the rate of fast ripples (200-450 Hz) was less reliable index of SOZ. Interestingly, the mean powers across subjects were significantly higher within than outside the SOZ in both ripple and fast ripple frequency ranges. Our study demonstrates a capacity of interictal HFO to detect the SOZ in focal cortical dysplasias.

Heightened acute circulatory responses to smoking in women.

Objective. Smoking, a major risk factor for cardiovascular morbidity and mortality, may be particularly harmful to women. Sympathetic and hemodynamic responses to cigarette smoking may be implicated in the link between smoking and acute cardiovascular events. We tested the hypothesis that acute effects of smoking on cardiovascular function are potentiated in women compared with men. Methods. We examined the effects of cigarette smoking and sham smoking on muscle sympathetic nerve activity, blood pressure and heart rate in 20 female and 20 male middle-aged healthy habitual smokers. Results. Sham smoking had no effect on muscle sympathetic nerve activity, blood pressure, or heart rate. Although cigarette smoking increased average systolic blood pressure and heart rate in both females and males, systolic blood pressure increased more in women (12+/-2 mmHg) than in men (6+/-2 mmHg; p = 0.02), as did heart rate (16+/-2 beats/min in women vs 9+/-2 beats/min in men; p = 0.002). Female smokers also had greater smoking-related increases in systolic blood pressure variability compared with males (2.2+/-0.6 vs 0.4+/-0.4 mmHg, respectively; p = 0.01) and greater decreases in RR variability (-28+/-5 vs -7+/-4 ms; p = 0.002). Despite the potentiated blood pressure increase in females, which would be expected to inhibit sympathetic activity to a greater extent in females than in males, changes in muscle sympathetic nerve activity during smoking were similar in both sexes. Conclusions. Acute pressor and tachycardic effects of smoking are potentiated in women compared with men. These findings may have important implications for understanding increased vulnerability to acute cardiovascular events in women who smoke.

Intracerebral recording of cortical activity related to self-paced voluntary movements: a Bereitschaftspotential and event-related desynchronization/synchronization. SEEG study.

To analyze the distribution of the cortical electrical activity related to self-paced voluntary movements, i.e. the movement-related readiness potentials (Bereitschaftspotential, BP) and the event-related desynchronization (ERD) and synchronization (ERS) of cortical rhythms using intracerebral recordings. EEG was recorded in 14 epilepsy surgery candidates during preoperative video-stereo-EEG monitoring. Subjects performed self-paced hand movements, with their right and left fingers in succession. EEG signals were obtained from a total of 501 contacts using depth electrodes located in primary and nonprimary cortical regions. In accordance with previous studies, BP was found consistently in the primary motor (M1) and somatosensory (S1) cortex, the supplementary motor area (SMA), and in a few recordings also in the cingulate cortex and in the dorsolateral prefrontal and premotor cortex. ERD and ERS of alpha and beta rhythms were also observed in these cortical regions. The distribution of contacts showing ERD or ERS was larger than the distribution of those showing BP. In contrast to BP, ERD and ERS frequently occurred in the lateral and mesial temporal cortex and the inferior parietal lobule. The number of contacts and cortical regions showing ERD and ERS and not BP suggests that the two electrophysiological phenomena are differently involved in the preparation and execution of simple voluntary movements. Substantial differences between BP and ERD in spatial distribution and the widespread topography of ERD/ERS in temporal and higher-order motor regions suggest that oscillatory cortical changes are coupled with cognitive processes supporting movement tasks, such as memory, time interval estimation, and attention.

Sympathetic neural responses to smoking are age dependent.

OBJECTIVE: Smoking is an important risk factor for cardiovascular disease. Sympathetic responses to cigarette smoking may be implicated in the link between smoking and cardiovascular disease. We tested the hypothesis that the sympathetic neural responses to smoking are age dependent. METHODS: We examined the effects of cigarette smoking and sham smoking on muscle sympathetic nerve activity, blood pressure and heart rate in 14 normotensive middle-aged (49 +/- 4 years) and 12 young (29 +/- 4 years) habitual smokers matched for body mass index (25 +/- 2 kg/m2 in both groups). RESULTS: Sham smoking had no significant effect on sympathetic drive, blood pressure or heart rate in either group. Cigarette smoking increased heart rate in both middle-aged subjects and young subjects. In comparison to younger subjects, middle-aged smokers showed similar smoking-related increases in systolic blood pressure (SBP) [10 +/- 3 versus 12 +/- 2 mmHg, respectively, not significant (NS)]. Smoking decreased sympathetic nerve activity by 28 +/- 12% of baseline values (P < 0.01) in young subjects. However, muscle sympathetic nerve activity did not change significantly after smoking in middle-aged subjects (5 +/- 8%, NS), despite the increased blood pressures, which would be expected to inhibit sympathetic activity. By contrast, in young subjects, the heart rate increase (22 +/- 2 bpm) was greater than that seen in middle-aged subjects (13 +/- 2 bpm, P < 0.01). CONCLUSIONS: The autonomic responses to smoking are age dependent. While blood pressure increases are similar in both groups, young subjects respond to smoking by marked increases in heart rate and suppression of central sympathetic outflow. In middle-aged subjects, the heart rate increase is less marked, but sympathetic vasoconstrictor activity is not suppressed.