Decrease in phase slip rates and phase cone structures during seizure evolution and epileptogenic activities derived from microgrid ECoG data.

Sudden phase changes are related to cortical phase transitions, which likely change in frequency and spatial distribution as epileptogenic activity evolves. A 100 s long section of micro-ECoG data obtained before and during a seizure was selected and analyzed. In addition, nine other short-duration epileptic events were also examined. The data was collected at 420 Hz, imported into MATLAB, downsampled to 200 Hz, and filtered in the 1-50 Hz band. The Hilbert transform was applied to compute the analytic phase, which was then unwrapped, and detrended to look for sudden phase changes. The phase slip rate (counts/s) and its acceleration (counts/s2) were computed with a stepping window of 1-s duration and with a step size of 5 ms. The analysis was performed for theta (3-7 Hz), alpha (7-12 Hz), and beta (12-30 Hz) bands. The phase slip rate on all electrodes in the theta band decreased while it increased for the alpha and beta bands during the seizure period. Similar patterns were observed for isolated epileptogenic events. Spatiotemporal contour plots of the phase slip rates were also constructed using a montage layout of 8 × 8 electrode positions. These plots exhibited dynamic and oscillatory formation of phase cone-like structures which were higher in the theta band and lower in the alpha and beta bands during the seizure period and epileptogenic events. These results indicate that the formation of phase cones might be an excellent biomarker to study the evolution of a seizure and also the cortical dynamics of isolated epileptogenic events.

Increased Phase Cone Turnover in 80-250 Hz Bands Occurs in the Epileptogenic Zone During Interictal Periods.

We found that phase cone clustering patterns in EEG ripple bands demonstrate an increased turnover rate in epileptogenic zones compared to adjacent regions. We employed 256 channel EEG data collected in four adult subjects with refractory epilepsy. The analysis was performed in the 80-150 and 150-250 Hz ranges. Ictal onsets were documented with intracranial EEG recordings. Interictal scalp recordings, free of epileptiform patterns, of 240-s duration, were selected for analysis for each subject. The data was filtered, and the instantaneous phase was extracted after the Hilbert transformation. Spatiotemporal contour plots of the unwrapped instantaneous phase with 1.0 ms intervals were constructed using a montage layout of the 256 electrode positions. Stable phase cone patterns were selected based on criteria that the sign of spatial gradient did not change for a minimum of three consecutive time samples and the frame velocity was consistent with known propagation velocities of cortical axons. These plots exhibited increased dynamical formation and dissolution of phase cones in the ictal onset zones, compared to surrounding cortical regions, in all four patients. We believe that these findings represent markers of abnormally increased cortical excitability. They are potential tools that may assist in localizing the epileptogenic zone.

Safety of slow-pulsed transcranial electrical stimulation in acute spike suppression.

We examined the effects of slow-pulsed transcranial electrical stimulation (TES) in suppressing epileptiform discharges in seven adults with refractory epilepsy. An MRI-based realistic head model was constructed for each subject and co-registered with 256-channel dense EEG (dEEG). Interictal spikes were localized, and TES targeted the cortical source of each subject's principal spike population. Targeted spikes were suppressed in five subject's (29/35 treatment days overall), and nontargeted spikes were suppressed in four subjects. Epileptiform activity did not worsen. This study suggests that this protocol, designed to induce long-term depression (LTD), is safe and effective in acute suppression of interictal epileptiform discharges.

EEG source imaging of epileptic activity at seizure onset.

Surgical resection of the seizure onset zone (SOZ) requires that this region of the cortex is accurately localized. The onset of a seizure may be marked by transient discharges, but it also may be accompanied by oscillatory, sinusoidal electrographic activity, such as the EEG theta rhythm. However, because of the superposition of the seizure signal with other electrical signals, including noise artifacts and non-seizure brain activity, noninvasive Electrical Source Imaging (ESI) of the ictal EEG activity at seizure onset remains a challenging task for surgical planning. In the present study, we localize the SOZ from oscillatory features of the EEG at the ictal onset using 256-channel high density electroencephalography (HD-EEG), exact sensor positions, and individual electrical head models constructed from the patient's T1 magnetic resonance image (MRI). Epileptic activities at the seizure onset were characterized with joint time-frequency analysis and source estimated by standardized low resolution electromagnetic tomography (sLORETA) inverse method. The consistency of this localization was examined across multiple seizures for individual patients. For validation, results were compared to three clinical criteria: (1) epileptogenic lesions, (2) seizure onset observed in intracranial EEG, and (3) successful surgical outcomes. In this set of 84 seizures, the onsets of 56 seizures could be localized. For the lateralization measure, the results from HD-EEG with interictal spikes (8/10) and with ictal onset (10/10) were more accurate than international 10-20 EEG for interictal spikes (5/10) and ictal onset (5/10). ESI from HD-EEG with ictal onset (9/10) had greater concordance to the clinical criteria than HD-EEG with interictal spikes (6/10). Noninvasive ESI of oscillatory features at ictal onset using 256-channel HD-EEG and high-resolution individual head models can make a useful contribution to the clinical localization of the SOZ in presurgical planning.

Oscillatory Patterns of Phase Cone Formations near to Epileptic Spikes Derived from 256-Channel Scalp EEG Data.

Our objective was to determine if there are any distinguishable phase cone clustering patterns present near to epileptic spikes. These phase cones arise from episodic phase shifts due to the coordinated activity of cortical neurons at or near to state transitions and can be extracted from the high-density scalp EEG recordings. The phase cone clustering activities in the low gamma band (30-50 Hz) and in the ripple band (80-150 Hz) were extracted from the analytic phase after taking Hilbert transform of the 256-channel high density (dEEG) data of adult patients. We used three subjects in this study. Spatiotemporal contour plots of the unwrapped analytic phase with 1.0 ms intervals were constructed using a montage layout of 256 electrode positions. Stable phase cone patterns were selected based on the criteria that the sign of the spatial gradient did not change for at least three consecutive time samples and the frame velocity was within the range of propagation velocities of cortical axons. These plots exhibited dynamical formation of phase cones which were higher in the seizure area as compared with the nearby surrounding brain areas. Spatiotemporal oscillatory patterns were also visible during ±5 sec period from the location of the spike. These results suggest that the phase cone activity might be useful for noninvasive localization of epileptic sites and also for examining the cortical neurodynamics near to epileptic spikes.

A double-blind, randomised, placebo-controlled study of roxithromycin and doxycycline combination, roxithromycin alone, or matching placebo for 12 weeks in adults with frequent exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Azithromycin prophylaxis has been shown to reduce COPD exacerbations but there is poor evidence for other antibiotics. We compared exacerbation rates in COPD patients with a history of frequent exacerbations (at least three moderate or severe COPD exacerbations in the past two years) during a 12-week treatment course and over a subsequent 48-week follow up period. RESULTS: 292 patients were randomised to one of three treatments for 12 weeks: roxithromycin 300 mg daily and doxycycline 100 mg daily (n = 101); roxithromycin 300 mg daily (n = 97); or matching placebos (n = 94). There were no differences in the annualised moderate and severe exacerbation rates after treatment with roxithromycin/doxycycline (2.83 (95 % CI 2.37-3.40)) or roxithromycin only (2.69 (2.26-3.21)) compared to placebo (2.5 (2.08-3.03)) (p = 0.352 and p = 0.5832 respectively). Furthermore, there were no differences in the annualised exacerbation rates during 12-week treatment with roxithromycin/doxycycline (1.64 (95 % CI 1.17-2.30)), roxithromycin only (1.75 (1.24-2.41)) or placebo (2.23 (1.68-3.03)) (p = 0.1709 and p = 0.2545 respectively). There were also no significant differences between groups for spirometry or quality of life scores over either the 12-week treatment or 48-week post-treatment periods. Both active treatments were associated with nausea but otherwise adverse events were comparable among treatment groups. CONCLUSIONS: Twelve-weeks of prophylaxis with roxithromycin/doxycycline combination or roxithromycin alone did not reduce COPD exacerbations in patients with history of frequent exacerbations. These findings do not support the use of these antibiotics to prevent exacerbations in COPD patients.

Spatiotemporal phase clusters and phase synchronization patterns derived from high density EEG and ECoG recordings.

High density scalp EEG and subdural ECoG recordings provide an opportunity to map the electrical activity of the cortex with high spatial resolution. The spatial power spectral densities conform to a power law distribution with some nonlinear variations. The spatiotemporal patterns of phase derived from these data sets have unique features, such as, amplitude and phase modulation waves and also exhibited formation of spatial phase cluster patterns. These unique features represent different cognitive states and are different between normal and diseased states. Reported results show that the rate of formation of phase cluster patterns derived from the seizure-free interictal EEG data are higher in epileptogenic zones as compared with nearby normal areas of the brain.

Auditory click stimuli evoke event-related potentials in the visual cortex.

The objective of this study was to determine whether unimodal auditory stimuli evoke event-related potentials (ERPs) in brain areas normally designated as the visual cortex (VC). The topographical distribution of ERPs evoked by auditory click stimuli was measured from (a) electroencephalographic electrodes on the scalp of six neurologically normal adult human participants and (b) intracranial electrodes implanted on the cortex of one epileptic adult human participant. In all participants, unimodal click stimuli evoked ERPs over both the auditory cortex (AC) and the VC. Relative amplitudes of ERPs at different scalp electrodes did not support the idea that the ERPs over VC were volume-conducted versions of those over AC, and intracranial records confirmed the origin of some click-evoked ERPs in both V1 and other regions of VC. We conclude that unimodal auditory stimuli can evoke ERPs in VC. This finding adds to the earlier evidence for the effect of visual stimuli on AC by providing new evidence for bidirectional functional connectivity in the audio-visual network of the human brain. The implication is that not only do visual stimuli affect hearing; auditory stimuli also affect visual perception.

Methods for examining electrophysiological coherence in epileptic networks.

Epilepsy may reflect a focal abnormality of cerebral tissue, but the generation of seizures typically involves propagation of abnormal activity through cerebral networks. We examined epileptiform discharges (spikes) with dense array electroencephalography (dEEG) in five patients to search for the possible engagement of pathological networks. Source analysis was conducted with individual electrical head models for each patient, including sensor position measurement for registration with MRI with geodesic photogrammetry; tissue segmentation and skull conductivity modeling with an atlas skull warped to each patient's MRI; cortical surface extraction and tessellation into 1 cm(2) equivalent dipole patches; inverse source estimation with either minimum norm or cortical surface Laplacian constraints; and spectral coherence computed among equivalent dipoles aggregated within Brodmann areas with 1 Hz resolution from 1 to 70 Hz. These analyses revealed characteristic source coherence patterns in each patient during the pre-spike, spike, and post-spike intervals. For one patient with both spikes and seizure onset localized to a single temporal lobe, we observed a cluster of apparently abnormal coherences over the involved temporal lobe. For the other patients, there were apparently characteristic coherence patterns associated with the discharges, and in some cases these appeared to reflect abnormal temporal lobe synchronization, but the coherence patterns for these patients were not easily related to an unequivocal epileptogenic zone. In contrast, simple localization of the site of onset of the spike discharge, and/or the site of onset of the seizure, with non-invasive 256 dEEG was useful in predicting the characteristic site of seizure onset for those cases that were verified by intracranial EEG and/or by surgical outcome.

Stochastic Behavior of Phase Synchronization Index and Cross-Frequency Couplings in Epileptogenic Zones during Interictal Periods Measured with Scalp dEEG.

The stochastic behavior of the phase synchronization index (SI) and cross-frequency couplings on different days during a hospital stay of three epileptic patients was studied for non-invasive localization of the epileptogenic areas from high density, 256-channel, scalp EEG (dEEG) recordings. The study was performed with short-duration (0-180 s), seizure-free, epileptiform-free, and spike-free interictal dEEG data on different days of three subjects. The seizure areas were localized with subdural recordings with an 8 × 8 macro-electrode grid array and strip electrodes. The study was performed in theta (3-7 Hz), alpha (7-12 Hz), beta (12-30 Hz), and low gamma (30-50 Hz) bands. A detrended fluctuation analysis was used to find the long range temporal correlations in the SI that reveals the stochastic behavior of the SI in a given time period. The phase synchronization was computed after taking Hilbert transform of the EEG data. Contour plots were constructed with 20 s time-frames using a montage of the layout of 256 electrode positions. It was found that the stochastic behavior of the SI was higher in epileptogenic areas and in nearby areas on different days for each subject. The low gamma band was found to be the best to localize the epileptic sites. Also, a stable higher pattern of SI emerged after 60-120 s in the epileptogenic areas. The cross-frequency couplings of SI in theta-gamma, beta-gamma, and alpha-gamma bands were decreased and spatial patterns were fragmented in epileptogenic areas. Combinations of an increase in the stochastic behavior of the SI and decrease in cross-frequency couplings are potential markers to assist in localizing epileptogenic areas. These findings suggest that it is possible to localize the epileptogenic areas non-invasively from a short-duration (∼180 s), seizure-free and spike-free interictal scalp dEEG recordings.

Noninvasive localization of epileptic sites from stable phase synchronization patterns on different days derived from short duration interictal scalp dEEG.

The stochastic behavior of the phase synchronization index (SI) on different days during a hospital stay of epileptic patients was studied for noninvasive localization of the epileptogenic areas from high density (256 channel) scalp EEG recordings. The study was performed on three subjects with interictal EEG data on different days. The seizure areas were localized with subdural recordings with an 8 × 8 grid electrode array. The study was performed in low gamma (30-50 Hz) band with short duration (0-180 s), seizure-free and spike-free scalp EEG data. A detrended fluctuation analysis was used to find the averaged stochastic fluctuations in the SI. The phase synchronization was computed after taking Hilbert transform of the EEG data. Contour plots were constructed with 20 s time-frames using a montage of the layout of 256 electrode positions. It was found that the stochastic behavior of the SI was higher in epileptogenic areas on different days for each subject. Also, a stable higher pattern of SI emerged after 60-100 s in the epileptogenic areas. These findings suggest that it is possible to localize the epileptogenic areas from the short duration (60-100 s), seizure-free and spike-free high density scalp EEG recordings.

Epilepsy surgery after treatment of pediatric malignant brain tumors.

Epilepsy surgery is common in the face of benign brain tumors, but rarely for patients with a history of malignant brain tumors. Seizures are a common sequelae in survivors of malignant pediatric brain tumors. Medical management alone may not adequately treat epilepsy, including in this group. We report four cases of patients who previously underwent gross total resection, radiation therapy, and chemotherapy for successful treatment of malignant brain neoplasia, yet suffered from medically intractable seizures. All underwent surgery for treatment of epilepsy with extension of the original resection. Despite the aggressive primary treatment of the neoplasm, and the potential for diffuse cerebral insults, all benefited from focal surgical resection. Aggressive surgical management of intractable epilepsy can be considered in survivors of malignant brain tumors.

Late-onset temporal lobe epilepsy in a patient with juvenile myoclonic epilepsy.

We report a patient with longstanding, severe juvenile myoclonic epilepsy who subsequently developed features of temporal lobe epilepsy, which gradually became clinically dominant. Over the years, there was an electrographic evolution from the typical generalised epileptiform patterns, characteristic of juvenile myoclonic epilepsy, to the novel appearance of interictal temporal spikes immediately preceding bisynchronous discharges, and subsequently to temporal intermittent rhythmic delta activity and temporal lobe-onset seizures. In this rare case of coexistent primary generalised epilepsy and focal epilepsy, the epileptic networks of the two forms of epilepsy appear to overlap.

Noninvasive epileptic seizure localization from stochastic behavior of short duration interictal high density scalp EEG data.

The stochastic behavior of the phase synchronization index (SI) in different EEG bands was examined for noninvasive localization of the epileptogenic areas from the short duration (30-60 s), seizure-free and spike-free high density (256 channel) scalp EEG data. We also examined the cross-frequency and cross-electrode coupling in different EEG bands. EEG data of four subjects was used. The seizure areas were localized with subdural recordings with an 8×8 grid electrode array. It was found that the stochastic behavior of the SI in low gamma band (30-50 Hz) was higher in epileptogenic areas. The beta (12-30 Hz) band also showed similar tendencies. The stochastic behavior in theta (3-7 Hz) band was depressed in the seizure area while it was widespread in large areas over the scalp in the alpha (7-12 Hz) band. The stochastic behavior of the cross-frequency and cross-electrode couplings in theta-gamma, alpha-gamma and beta-gamma bands were decreased in the seizure areas for all four subjects. These findings suggest that it is possible to localize the epileptogenic areas from the short duration seizure-free and spike-free high density scalp EEG data.

A possible physiological basis for the discontinuity of consciousness.

A comparison is made between the frequency of local minima in the analytic power (AP) of intracranial EEG (ECoG) from waking and unconscious human subjects and the frequency of putative frames of consciousness reported in earlier psychological literature. In ECoG from unconscious subjects, the frequency of deep minima in AP is found to be a linear function of bandwidth. In contrast, in ECoG from conscious subjects, the bandwidth/minima-frequency curve saturates or plateaus at minima frequencies similar to the frequencies of previously reported frames of consciousness. This result is consistent with the hypothesis that local minima in AP may act as the shutter in a cinematographic model of consciousness. The fact that artificially generated samples of black noise with power spectra similar to ECoG data give similar results in the analyses above suggests that the discontinuous nature of consciousness is not due to some specifically biological factor, but is simply a consequence of the physical properties of the 1/f (aka power law) oscillations that are widely found in nature.

Behavioral states may be associated with distinct spatial patterns in electrocorticogram.

To determine if behavioral states are associated with unique spatial electrocorticographic (ECoG) patterns, we obtained recordings with a microgrid electrode array applied to the cortical surface of a human subject. The array was constructed with the intent of extracting maximal spatial information by optimizing interelectrode distances. A 34-year-old patient with intractable epilepsy underwent intracranial ECoG monitoring after standard methods failed to reveal localization of seizures. During the 8-day period of invasive recording, in addition to standard clinical electrodes a square 1 × 1 cm microgrid array with 64 electrodes (1.25 mm separation) was placed on the right inferior temporal gyrus. Careful review of video recordings identified four extended naturalistic behaviors: reading, conversing on the telephone, looking at photographs, and face-to-face interactions. ECoG activity recorded with the microgrid that corresponded to these behaviors was collected and ECoG spatial patterns were analyzed. During periods of ECoG selected for analysis, no electrographic seizures or epileptiform patterns were present. Moments of maximal spatial variance are shown to cluster by behavior. Comparisons between conditions using a permutation test reveal significantly different spatial patterns for each behavior. We conclude that ECoG recordings obtained on the cortical surface with optimal high spatial frequency resolution reveal distinct local spatial patterns that reflect different behavioral states, and we predict that similar patterns will be found in many if not most cortical areas on which a microgrid is placed.

Comparing noninvasive dense array and intracranial electroencephalography for localization of seizures.

OBJECTIVE: To compare the localization of the seizure onset zone estimated from ictal recordings with high spatial resolution, 256-channel scalp dense array electroencephalographic video long-term monitoring (LTM) with the aid of source analysis with that obtained from subsequent intracranial ictal recordings. METHODS: Ten patients with medically refractory epilepsy, all surgical candidates, underwent intracranial LTM after standard noninvasive evaluation failed to provide adequate localizing information regarding ictal origins. Before invasive studies, all patients underwent dense array electroencephalographic LTM in which habitual clinical seizures were recorded for each patient. Source analysis was applied to ictal onsets. Intracranial electrode placement followed conventional guidelines, although the neurosurgeon was aware of the dense array electroencephalographic results. Patients ranged in age from 10 to 49 years (mean age, 24 y); 7 were male. Identified risk factors included closed head injury in 1 patient and childhood meningitis in another. No focal neurological signs were found in any patient. Magnetic resonance imaging findings were normal in 6 patients; 1 patient had cerebellar hypoplasia, 1 had right frontoparietal dysplasia, 1 had bilateral nonspecific white matter abnormalities, and 1 had bilateral cavernous angiomas. RESULTS: Ictal onsets, based on invasive recordings, were in the mesiotemporal lobe (3 patients), lateroparietal (2 patients), mesioparietal (1 patient), laterofrontal (1 patient), superolateral frontocentral (1 patient), frontopolar (1 patient), and posteroinferior temporo-occipital neocortex (1 patient). Dense array electroencephalography localized ictal onsets to the same region as intracranial monitoring in 8 of 10 cases; invasive studies disclosed an additional ictal focus in 2 of these patients. Surgical resections were based only on intracranial electroencephalographic findings. CONCLUSION: Dense array electroencephalography has the potential to assist in the noninvasive localization of epileptic seizures and to guide the placement of invasive electrodes for localizing seizure onset.