Interictal high-frequency oscillations (80-500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain

Purpose: High‐frequency oscillations (HFOs) known as ripples (80–250 Hz) and fast ripples (250–500 Hz) can be recorded from macroelectrodes inserted in patients with intractable focal epilepsy. They are most likely linked to epileptogenesis and have been found in the seizure onset zone (SOZ) of human ictal and interictal recordings. HFOs occur frequently at the time of interictal spikes, but were also found independently. This study analyses the relationship between spikes and HFOs and the occurrence of HFOs in nonspiking channels. Methods: Intracerebral EEGs of 10 patients with intractable focal epilepsy were studied using macroelectrodes. Rates of HFOs within and outside spikes, the overlap between events, event durations, and the percentage of spikes carrying HFOs were calculated and compared according to anatomical localization, spiking activity, and relationship to the SOZ. Results: HFOs were found in all patients, significantly more within mesial temporal lobe structures than in neocortex. HFOs could be seen in spiking as well as nonspiking channels in all structures. Rates and durations of HFOs were significantly higher in the SOZ than outside. It was possible to establish a rate of HFOs to identify the SOZ with better sensitivity and specificity than with the rate of spikes. Discussion: HFOs occurred to a large extent independently of spikes. They are most frequent in mesial temporal structures. They are prominent in the SOZ and provide additional information on epileptogenicity independently of spikes. It was possible to identify the SOZ with a high specificity by looking at only 10 min of HFO activity.     

Interictal high frequency oscillations (HFOs) in patients with focal epilepsy and normal MRI

Objective

We aim to analysis the relationship between HFOs-generating regions and the seizure onset zone (SOZ) in epileptic patients without a visible lesion on MRI.

Methods

Intracerebral EEGs were recorded in 17 patients with intractable focal seizures and normal MRIs. The rates of interictal HFOs and spikes inside and outside the SOZ were analyzed as well as the specificity, sensitivity and accuracy of HFOs and spikes to determine the SOZ.

Results

The mean rate of spikes, ripples and fast ripples (FR) was higher in the SOZ than in the non-SOZ channels. In regard to the identification of the SOZ the sensitivity was 91% for spikes, 91% for ripples and 66% for FR, the specificity was 30% for spikes, 42% for ripples and 80% for FR, and the accuracy was 44% for spikes, 54% for ripples and 76% for FR.

Conclusions

The rates of spikes and HFOs were higher inside than outside the SOZ. However, HFOs are also more specific and accurate than spikes to delineate the SOZ.

Significance

Analysis of interictal HFOs during 5-10 min of sleep recording is a good tool to localize the SOZ in patients with epilepsy and normal MRI, and could potentially reduce the duration of chronic intracerebral EEG recordings.     

High‐frequency oscillations in idiopathic partial epilepsy of childhood

Purpose: We explored high‐frequency oscillations (HFOs) in scalp sleep electroencephalography (EEG) studies of patients with idiopathic partial epilepsy (IPE) of childhood in order to obtain a better understanding of the pathologic mechanisms underlying IPE. Methods: The subjects were 45 patients, including 32 with benign childhood epilepsy with centrotemporal spikes (BCECTS) and 13 with Panayiotopoulos syndrome (PS). A total of 136 EEG records were investigated through temporal expansion and filtering of traces and time‐frequency spectral analysis. Key Findings: HFOs with frequency of 93.8–152.3 Hz (mean 126.2 ± 13.6 Hz) in the band of ripples were detected in association with spikes in 97 records (71.3%). Time from last seizure to the EEG recording was significantly shorter in those with spike‐related HFOs than in the EEG recordings with spikes without HFOs (p = 0.006). Although time from last seizure reflects age, age at the time of recording was not significantly different between EEG studies with and without HFOs. Peak‐power values of the high‐frequency spots in time‐frequency spectra were significantly negatively correlated with time from last seizure (R² = 0.122, p < 0.001) but not with age at the time of recording. Peak frequencies of the high‐frequency spectral spots were not significantly correlated with age at the time of recording or with time from last seizure. Significance: The close relationship between the generation of spike‐related HFOs and the period of active seizure occurrence indicated that HFOs may tell us more about epileptogenicity in IPE than the spikes themselves. Because there is a spectrum of pediatric epileptic disorders extending from the benign end of BCECTS to the encephalopathic end of epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), and HFOs that have already been detected in association with CSWS were more prominent than HFOs in IPE, intense spike‐related HFOs may indicate poor prognosis.     

Focal resection of fast ripples on extraoperative intracranial EEG improves seizure outcome in pediatric epilepsy

Purpose: High‐frequency oscillations (HFOs), termed ripples at 80–200 Hz and fast ripples (FRs) at >200/250 Hz, recorded by intracranial electroencephalography (EEG), may be a valuable surrogate marker for the localization of the epileptogenic zone. We evaluated the relationship of the resection of focal brain regions containing high‐rate interictal HFOs and the seizure‐onset zone (SOZ) determined by visual EEG analysis with the postsurgical seizure outcome, using extraoperative intracranial EEG monitoring in pediatric patients and automated HFO detection. Methods: We retrospectively analyzed 28 pediatric epilepsy patients who underwent extraoperative intracranial video‐EEG monitoring prior to focal resection. Utilizing the automated analysis, we identified interictal HFOs during 20 min of sleep EEG and determined the brain regions containing high‐rate HFOs. We investigated spatial relationships between regions with high‐rate HFOs and SOZs. We compared the size of these regions, the surgical resection, and the amount of the regions with high‐rate HFOs/SOZs within the resection area with seizure outcome. Key Findings: Ten patients were completely seizure‐free and 18 were not at 2 years after surgery. The brain regions with high‐rate ripples were larger than those with high‐rate FRs (p = 0.0011) with partial overlap. More complete resection of the regions with high‐rate FRs significantly correlated with a better seizure outcome (p = 0.046). More complete resection of the regions with high‐rate ripples tended to improve seizure outcome (p = 0.091); however, the resection of SOZ did not influence seizure outcome (p = 0.18). The size of surgical resection was not associated with seizure outcome (p = 0.22–0.39). Significance: The interictal high‐rate FRs are a possible surrogate marker of the epileptogenic zone. Interictal ripples are not as specific a marker of the epileptogenic zone as interictal FRs. Resection of the brain regions with high‐rate interictal FRs in addition to the SOZ may achieve a better seizure outcome.     

High-frequency oscillations recorded with surface EEG in neonates with seizures

ObjectiveNeonatal seizures are often the first symptom of perinatal brain injury. High-frequency oscillations (HFOs) are promising new biomarkers for epileptogenic tissue and can be found in intracranial and surface EEG. To date, we cannot reliably predict which neonates with seizures will develop childhood epilepsy. We questioned whether epileptic HFOs can be generated by the neonatal brain and potentially predict epilepsy.MethodsWe selected 24 surface EEGs sampled at 2048 Hz with 175 seizures from 16 neonates and visually reviewed them for HFOs. Interictal epochs were also reviewed.ResultsWe found HFOs in thirteen seizures (7%) from four neonates (25%). 5025 ictal ripples (rate 10 to 1311/min; mean frequency 135 Hz; mean duration 66 ms) and 1427 fast ripples (rate 8 to 356/min; mean frequency 298 Hz; mean duration 25 ms) were marked. Two neonates (13%) showed interictal HFOs (285 ripples and 25 fast ripples). Almost all HFOs co-occurred with sharp transients. We could not find a relationship between neonatal HFOs and outcome yet.ConclusionsNeonatal HFOs co-occur with ictal and interictal sharp transients.SignificanceThe neonatal brain can generate epileptic ripples and fast ripples, particularly during seizures, though their occurrence is not common and potential clinical value not evident yet.     

Epileptic high‐frequency oscillations in intraoperative electrocorticography: The effect of propofol

Purpose: Epileptic high‐frequency oscillations (HFOs; 80–500 Hz) may be used to guide neurosurgeons during epilepsy surgery to identify epileptogenic tissue. We studied the effect of the anesthetic agent propofol on the occurrence of HFOs in intraoperative electrocorticography (ECoG). Methods: We selected patients who were undergoing surgery for temporal lobe epilepsy with a standardized electrode grid placement. Intraoperative ECoG was recorded at 2,048 Hz following cessation of propofol. The number and distribution of interictal spikes, ripples (R [80–250 Hz]), and fast ripples (FRs; 250–500 Hz) were analyzed. The amount of events on mesiotemporal channels and lateral neocortical channels were compared between patients with a suspected mesiotemporal and lateral epileptogenic area (Student’s t‐test), and HFOs were compared with the irritative zone, using correlation between amounts of events per channel, to provide evidence for the epileptic nature of the HFOs. Next, the amount of events within the first minute and the last minute were compared to each other and the change in events over the entire epochs was analyzed using correlation analyses of 10 epochs during the emergence periods (Spearman rank test). We studied whether the duration of HFOs changed over time. The change in events within presumed epileptogenic area was compared to the change outside this area (Student’s t‐test). Periods of burst suppression and continuous background activity were compared between and within patients (t‐test). Key Findings: Twelve patients were included: five with suspected mesiotemporal epileptogenic area and three with suspected lateral epileptogenic area (and four were “other”). Spikes, ripples, and FRs were related to the suspected epileptogenic areas, and HFO zones were related to the irritative zones. Ripples and FRs increased during emergence from propofol anesthesia (mean number of ripples from first minute–last minute: 61.5–73.0, R = 0.46, p < 0.01; FRs: 3.1–5.7, R = 0.30, p < 0.01) and spikes remained unchanged (80.1–79.9, R = ?0.05, p = 0.59). There was a decrease in number of channels with spikes (R = ?0.18, p = 0.05), but no change in ripples (R = ?0.13, p = 0.16) or FRs (R = 0.11, p = 0.45). There was no change in the durations of HFOs. The amount of HFOs in the presumed epileptogenic areas did not change more than the amount outside the presumed epileptogenic area, whereas spikes paradoxically decreased more within the suspected epileptogenic area. Six patients showing burst‐suppression had lower rates of ripples than six other patients with continuous background activity (p = 0.02). No significant difference was found between burst suppression and continuous background activity in four patients, but there was a trend toward showing more ripples during continuous background activity (p = 0.16). Significance: Propofol, known for its antiepileptic effects, reduces the number of epileptic HFOs, but has no effect on spikes. This enforces the hypothesis that, in epilepsy, HFOs mirror the disease activity and HFOs might be useful for monitoring antiepileptic drug treatment. It is feasible to record HFOs during surgery, but propofol infusion should be interrupted for some minutes to improve detection.     

Hippocampal high frequency oscillations in unilateral and bilateral mesial temporal lobe epilepsy

ObjectiveThe main aim of this study was to investigate the potential differences in terms of interictal high frequency oscillations (HFOs) between both hippocampi in unilateral (U-MTLE) and bilateral mesial temporal lobe epilepsy (B-MTLE).MethodsSixteen patients with MTLE underwent bilateral hippocampal depth electrode implantation as part of epilepsy surgery evaluation. Interictal HFOs were detected automatically. The analyses entail comparisons of the rates and spatial distributions of ripples and fast ripples (FR) in hippocampi and amygdalae, with respect to the eventual finding of hippocampal sclerosis (HS).ResultsIn U-MTLE, higher ripple and FR rates were found in the hippocampi ipsilateral to the seizure onset than in the contralateral hippocampi. Non-epileptic hippocampi in U-MTLE were distinguished by significantly lower ripple rate than in the remaining analyzed hippocampi. There were not differences between the hippocampi in B-MTLE. In the hippocampi with proven HS, higher FR rates were observed in the ventral than in the dorsal parts.ConclusionsNon-epileptic hippocampi in U-MTLE demonstrated significantly lower ripple rates than those epileptic in U-MTLE and B-MTLE.SignificanceLow interictal HFO occurrence might be considered as a marker of the non-epileptic hippocampi in MTLE.     

Extrahippocampal high‐frequency oscillations during epileptogenesis

The current study aimed to investigate the spatial and temporal patterns of high‐frequency oscillations (HFOs) in the intra‐/extrahippocampal areas during epileptogenesis. Local field potentials were bilaterally recorded from hippocampus (CA1), thalamus, motor cortex, and prefrontal cortex in 13 rats before and after intrahippocampal kainic acid (KA) lesions. HFOs in the ripple (100‐200 Hz) and fast ripple (250‐500 Hz) ranges were detected and their rates were computed during different time periods (1‐5 weeks) after KA‐induced status epilepticus (SE). Recurrent spontaneous seizures were observed in 7 rats after SE, and the other 6 rats did not develop epilepsy. During the latent period, the rate of hippocampal HFOs increased at the ipsilateral site of the KA lesion in both groups, and the HFO rate was significantly higher in the animals that later developed epilepsy. Animals that later developed epilepsy also demonstrated widespread appearance of HFOs, in both the ripple and the fast ripple range, whereas animals that did not develop epilepsy only exhibited changes in the ipsilateral intrahippocampal HFO rate. This study demonstrates an association between an increased rate of widespread HFOs and the later development of epilepsy, suggesting the formation of large‐scale distributed pathological networks during epileptogenesis.     

Neurosteroids differentially modulate fast and slow interictal discharges in the hippocampal CA3 area

Two types of spontaneous interictal discharge, identified as fast and slow events, can be recorded from the hippocampal CA3 area in rat brain slices during application of 4‐aminopyridine (4AP) (50 μm ). Here, we addressed how neurosteroids modulate the occurrence of these interictal events and of the associated high‐frequency oscillations (HFOs) (ripples, 80–200 Hz; fast ripples, 250–500 Hz). Under control conditions (i.e. during 4AP application), ripples and fast ripples were detected in 12.3 and 17.5% of fast events, respectively; in contrast, the majority of slow events (> 98%) did not co‐occur with HFOs. Application of 0.1, 1 or 5 μm allotetrahydrodeoxycorticosterone (THDOC) to 4AP‐treated slices caused a dose‐dependent decrease in the duration of the fast events and an increase in the occurrence of ripples, but not fast ripples; in contrast, the duration of slow events increased. THDOC potentiated the slow events that were recorded during pharmacological blockade of glutamatergic transmission, but had no effect on interictal discharges occurring during GABA_A receptor antagonism. These results demonstrate that potentiation of GABA_A receptor‐mediated signaling by THDOC differentially affects slow and fast interictal discharges; these differences may provide insights into how hyperexcitable activity is influenced by neurosteroids.     

Continuous high-frequency activity in mesial temporal lobe structures

Purpose: Many recent studies have reported the importance of high‐frequency oscillations (HFOs) in the intracerebral electroencephalography (EEG) of patients with epilepsy. These HFOs have been defined as events that stand out from the background. We have noticed that this background often consists itself of high‐frequency rhythmic activity. The purpose of this study is to perform a first evaluation of the characteristics of high‐frequency continuous or semicontinuous background activity. Methods: Because the continuous high‐frequency pattern was noted mainly in mesial temporal structures, we reviewed the EEG studies from these structures in 24 unselected patients with electrodes implanted in these regions. Sections of background away from interictal spikes were marked visually during periods of slow‐wave sleep and wakefulness. They were then high‐passed filtered at 80 Hz and categorized as having high‐frequency rhythmic activity in one of three patterns: continuous/semicontinuous, irregular, sporadic. Wavelet entropy, which measures the degree of rhythmicity of a signal, was calculated for the marked background sections. Key Findings: Ninety‐six bipolar channels were analyzed. The continuous/semicontinuous pattern was found frequently (29/96 channels during wake and 34/96 during sleep). The different patterns were consistent between sleep and wakefulness. The continuous/semicontinuous pattern was found significantly more often in the hippocampus than in the parahippocampal gyrus and was rarely found in the amygdala. The types of pattern were not influenced by whether a channel was within the seizure‐onset zone, or whether it was a lesional channel. The continuous/semicontinuous pattern was associated with a higher frequency of spikes and with high rates of ripples and fast ripples. Significance: It appears that high‐frequency activity (above 80 Hz) does not appear only in the form of brief paroxysmal events but also in the form of continuous rhythmic activity or very long bursts. In this study limited to mesial temporal structures, we found a clear anatomic preference for the hippocampus. Although associated with spikes and with distinct HFOs, this pattern was not clearly associated with the seizure‐onset zone. Future studies will need to evaluate systematically the presence of this pattern, as it may have a pathophysiologic significance and it will also have an important influence on the very definition of HFOs.     

Spontaneous and evoked high-frequency oscillations in the tetanus toxin model of epilepsy

Purpose: High‐frequency oscillations (HFOs) are an emerging biomarker for epileptic tissue. Yet the mechanism by which HFOs are produced is unknown, and their rarity makes them difficult to study. Our objective was to examine the occurrence of HFOs in relation to action potentials (APs) and the effect of microstimulation in the tetanus toxin (TT) model of epilepsy, a nonlesional model with a short latency to spontaneous seizures. Methods: Rats were injected with TT into dorsal hippocampus and implanted with a 16‐channel (8 × 2) multielectrode array, one row each in CA3 and CA1. After onset of spontaneous seizures (3–9 days), recordings were begun of APs and local field potentials, analyzed for the occurrence of interictal spikes and HFOs. Recordings were made during microstimulation of each electrode using customized, open‐source software. Results: Population bursts of APs during interictal spikes were phase‐locked with HFOs, which were observable almost exclusively with high‐amplitude interictal spikes. Furthermore, HFOs could reliably be produced by microstimulation of the hippocampus, providing evidence that these oscillations can be controlled temporally by external means. Discussion: We show for the first time the occurrence of HFOs in the TT epilepsy model, an attractive preparation for their experimental investigation and, importantly, one with a different etiology than that of status models, providing further evidence of the generality of HFOs. The ability to provoke HFOs with microstimulation may prove useful for better understanding of HFOs by directly evoking them in the lab, and designing high‐throughput techniques for presurgical localization of the epileptic focus.     

High frequency oscillations relate to cognitive improvement after epilepsy surgery in children

ObjectiveTo investigate how high frequency oscillations (HFOs; ripples 80–250 Hz, fast ripples (FRs) 250–500 Hz) and spikes in intra-operative electrocorticography (ioECoG) relate to cognitive outcome after epilepsy surgery in children.MethodsWe retrospectively included 20 children who were seizure free after epilepsy surgery using ioECoG and determined their intelligence quotients (IQ) pre- and two years postoperatively. We analyzed whether the number of HFOs and spikes in pre- and postresection ioECoGs, and their change in the non-resected areas relate to cognitive improvement (with ≥ 5 IQ points increase considered to be clinically relevant (=IQ+ group) and < 5 IQ points as irrelevant (=IQ− group)).ResultsThe IQ+ group showed significantly more FRs in the resected tissue (p = 0.01) and less FRs in the postresection ioECoG (p = 0.045) compared to the IQ− group. Postresection decrease of ripples on spikes was correlated with postoperative cognitive improvement (correlation coefficient = −0.62 with p = 0.01).ConclusionsPostoperative cognitive improvement was related to reduction of pathological HFOs signified by removing FR generating areas with subsequently less residual FRs, and decrease of ripples on spikes in the resection edge of the non-resected area.SignificanceHFOs recorded in ioECoG could play a role as biomarkers in the prediction and understanding of cognitive outcome after epilepsy surgery.     

Scalp‐recorded high‐frequency oscillations in childhood sleep‐induced electrical status epilepticus

Because high‐frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow‐wave sleep through temporal expansion of the EEG traces with a low‐cut frequency filter at 70 Hz as well as through time‐frequency power spectral analysis. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high‐frequency peak with the greatest power in each patient’s spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.     

Value of electrical stimulation and high frequency oscillations (80–500 Hz) in identifying epileptogenic areas during intracranial EEG recordings

Purpose: Electrical stimulation (ES) is used during intracranial electroencephalography (EEG) investigations to delineate epileptogenic areas and seizure‐onset zones (SOZs) by provoking afterdischarges (ADs) or patients’ typical seizure. High frequency oscillations (HFOs—ripples, 80–250 Hz; fast ripples, 250–500 Hz) are linked to seizure onset. This study investigates whether interictal HFOs are more frequent in areas with a low threshold to provoke ADs or seizures. Methods: Intracranial EEG studies were filtered at 500 Hz and sampled at 2,000 Hz. HFOs were visually identified. Twenty patients underwent ES, with gradually increasing currents. Results were interpreted as agreeing or disagreeing with the intracranial study (clinical‐EEG seizure onset defined the SOZ). Current thresholds provoking an AD or seizure were correlated with the rate of HFOs of each channel. Results: ES provoked a seizure in 12 and ADs in 19 patients. Sixteen patients showed an ES response inside the SOZ, and 10 had additional areas with ADs. The response was more specific for mesiotemporal than for neocortical channels. HFO rates were negatively correlated with thresholds for ES responses; especially in neocortical regions; areas with low threshold and high HFO rate were colocalized even outside the SOZ. Discussion: Areas showing epileptic HFOs colocalize with those reacting to ES. HFOs may represent a pathologic correlate of regions showing an ES response; both phenomena suggest a more widespread epileptogenicity.     

Pitfalls of high-pass filtering for detecting epileptic oscillations: A technical note on “false” ripples

ObjectivesTo analyze interictal High frequency oscillations (HFOs) as observed in the medial temporal lobe of epileptic patients and animals (ripples, 80–200 Hz and fast ripples, 250–600 Hz). To show that the identification of interictal HFOs raises some methodological issues, as the filtering of sharp transients (e.g., epileptic spikes or artefacts) or signals with harmonics can result in “false” ripples. To illustrate and quantify the occurrence of false ripples on filtered EEG traces.MethodsWe have performed high-pass filtering on both simulated and real data. We have also used two alternate methods: time-frequency analysis and matching pursuit.ResultsTwo types of events were shown to produce oscillations after filtering that could be confounded with actual oscillatory activity: sharp transients and harmonics of non-sinusoidal signals.ConclusionsHigh-pass filtering of EEG traces for detection of oscillatory activity should be performed with great care. Filtered traces should be compared to original traces for verification of presence of transients. Additional techniques such as time-frequency transforms or sparse decompositions are highly beneficial.SignificanceOur study draws the attention on an issue of great importance in the marking of HFOs on EEG traces. We illustrate complementary methods that can help both researchers and clinicians.     

High‐frequency oscillations: The state of clinical research

Modern electroencephalographic (EEG) technology contributed to the appreciation that the EEG signal outside the classical Berger frequency band contains important information. In epilepsy, research of the past decade focused particularly on interictal high‐frequency oscillations (HFOs) > 80 Hz. The first large application of HFOs was in the context of epilepsy surgery. This is now followed by other applications such as assessment of epilepsy severity and monitoring of antiepileptic therapy. This article reviews the evidence on the clinical use of HFOs in epilepsy with an emphasis on the latest developments. It highlights the growing literature on the association between HFOs and postsurgical seizure outcome. A recent meta‐analysis confirmed a higher resection ratio for HFOs in seizure‐free versus non–seizure‐free patients. Residual HFOs in the postoperative electrocorticogram were shown to predict epilepsy surgery outcome better than preoperative HFO rates. The review further discusses the different attempts to separate physiological from epileptic HFOs, as this might increase the specificity of HFOs. As an example, analysis of sleep microstructure demonstrated a different coupling between HFOs inside and outside the epileptogenic zone. Moreover, there is increasing evidence that HFOs are useful to measure disease activity and assess treatment response using noninvasive EEG and magnetoencephalography. This approach is particularly promising in children, because they show high scalp HFO rates. HFO rates in West syndrome decrease after adrenocorticotropic hormone treatment. Presence of HFOs at the time of rolandic spikes correlates with seizure frequency. The time‐consuming visual assessment of HFOs, which prevented their clinical application in the past, is now overcome by validated computer‐assisted algorithms. HFO research has considerably advanced over the past decade, and use of noninvasive methods will make HFOs accessible to large numbers of patients. Prospective multicenter trials are awaited to gather information over long recording periods in large patient samples.     

Hippocampal and Entorhinal Cortex High-Frequency Oscillations (100–500 Hz) in Human Epileptic Brain and in Kainic Acid-Treated Rats with Chronic Seizures

Summary: Purpose: Properties of oscillations with frequencies >100 Hz were studied in kainic acid (KA)-treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy. Methods: Prolonged in vivo wideband recordings of electrical activity were made in hippocampus and entorhinal cortex (EC) of (a) normal rats, (b) kindled rats, (c) rats having chronic recurrent spontaneous seizures after intrahippocampal KA injections, and (d) patients with epilepsy undergoing depth electrode evaluation in preparation for surgical treatment. Results: Intermittent oscillatory activity ranging from 100 to 200 Hz in frequency and 50–150 ms in duration was recorded in CA1 and EC of all three animal groups, and in epileptic human hippocampus and EC. This activity had the same characteristics in all groups, resembled previously observed “ripples” described by Buzsáki et al., and appeared to represent field potentials of inhibitory postsynaptic potentials (IPSPs) on principal cells. Unexpectedly, higher frequency intermittent oscillatory activity ranging from 200 to 500 Hz and 10–100 ms in duration was encountered only in KA-treated rats and patients with epilepsy. These oscillations, termed fast ripples (FRs), were found only adjacent to the epileptogenic lesion in hippocampus, EC, and dentate gyrus, and appeared to represent field potential population spikes. Their local origin was indicated by correspondence with the negative phase of burst discharges of putative pyramidal cells. Conclusions: The persistence of normal-appearing ripples in epileptic brain support the view that inhibitory processes are preserved. FRs appear to be field potentials reflecting hypersynchronous bursting of excitatory neurons and provide an opportunity to study the role of this pathophysiologic phenomenon in epilepsy and seizure initiation. Furthermore, if FR activity is unique to brain areas capable of generating spontaneous seizures, its identification could be a powerful functional indicator of the epileptic region in patients evaluated for surgical treatment.     

Increased high-frequency oscillations precede in vitro low-Mg seizures

PURPOSE: High-frequency oscillations (HFOs) in the range of > or = 80 Hz have been recorded in neocortical and hippocampal brain structures in vitro and in vivo and have been associated with physiologic and epileptiform neuronal population activity. Frequencies in the fast-ripple range (> 200 Hz) are believed to be exclusive to epileptiform activity and have been recorded in vitro, in vivo, and in epilepsy patients. Although the presence of HFOs is well characterized, their temporal evolution in the context of transition to seizure activity is not well understood. METHODS: With an in vitro low-magnesium model of spontaneous seizures, we obtained extracellular field recordings (hippocampal regions CA1 and CA3) of interictal, preictal, and ictal activity. Recordings were subjected to power-frequency analysis, in time, by using a local multiscale Fourier transform. The power spectrum was computed continuously and was quantified for each epileptiform discharge into four frequency ranges spanning subripple, ripple, and two fast-ripple frequency bands. RESULTS: A statistically significant increasing trend was observed in the subripple (0-100 Hz), ripple (100-200 Hz), and fast-ripple 1 (200-300 Hz) frequency bands during the epoch corresponding to the transition to seizure (preictal to ictal). CONCLUSIONS: Temporal patterns of HFOs during epileptiform activity are indicative of dynamic changes in network behavior, and their characterization may offer insights into pathophysiologic processes underlying seizure initiation.     

How to establish causality in epilepsy surgery

Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill’s criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80 Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management.     

Prospective observational study: Fast ripple localization delineates the epileptogenic zone

ObjectiveTo investigate spatial correlation between interictal HFOs and neuroimaging abnormalities, and to determine if complete removal of prospectively identified interictal HFOs correlates with post-surgical seizure-freedom.MethodsInterictal fast ripples (FRs: 250–500 Hz) in 19 consecutive children with pharmacoresistant focal epilepsy who underwent extra-operative electrocorticography (ECoG) recording were prospectively analyzed. The interictal FRs were sampled at 2000 Hz and were visually identified during 10 min of slow wave sleep. Interictal FRs, MRI and FDG-PET were delineated on patient-specific reconstructed three-dimensional brain MRI.ResultsInterictal FRs were observed in all patients except one. Thirteen out of 18 patients (72%) exhibited FRs beyond the extent of neuroimaging abnormalities. Fifteen of 19 children underwent resective surgery, and survival analysis with log-rank test demonstrated that complete resection of cortical sites showing interictal FRs correlated with longer post-operative seizure-freedom (p < 0.01). Complete resection of seizure onset zones (SOZ) also correlated with longer post-operative seizure-freedom (p = 0.01), yet complete resection of neuroimaging abnormalities did not (p = 0.43).ConclusionsProspective visual analysis of interictal FRs was feasible, and it seemed to accurately localize epileptogenic zones.SignificanceTopological extent of epileptogenic region may exceed what is discernible by multimodal neuroimaging.