Journal Article

# High-Frequency Oscillations in Epilepsy: What Have We Learned and What Needs to be Addressed.

02 Mar 2021-Neurology (Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology)-Vol. 96, Iss: 9, pp 439-448
Abstract: For the past 2 decades, high-frequency oscillations (HFOs) have been enthusiastically studied by the epilepsy community. Emerging evidence shows that HFOs harbor great promise to delineate epileptogenic brain areas and possibly predict the likelihood of seizures. Investigations into HFOs in clinical epilepsy have advanced from small retrospective studies relying on visual identification and correlation analysis to larger prospective assessments using automatic detection and prediction strategies. Although most studies have yielded promising results, some have revealed significant obstacles to clinical application of HFOs, thus raising debate about the reliability and practicality of HFOs as clinical biomarkers. In this review, we give an overview of the current state of HFO research and pinpoint the conceptual and methodological issues that have hampered HFO translation. We highlight recent insights gained from long-term data, high-density recordings, and multicenter collaborations and discuss the open questions that need to be addressed in future research.

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Open accessJournal Article
Abstract: The analysis of biomedical signals for clinical studies and therapeutic applications can benefit from embedded devices that can process these signals locally and in real-time An example is the analysis of intracranial EEG (iEEG) from epilepsy patients for the detection of High Frequency Oscillations (HFO), which are a biomarker for epileptogenic brain tissue Mixed-signal neuromorphic circuits offer the possibility of building compact and low-power neural network processing systems that can analyze data on-line in real-time Here we present a neuromorphic system that combines a neural recording headstage with a spiking neural network (SNN) processing core on the same die for processing iEEG, and show how it can reliably detect HFO, thereby achieving state-of-the-art accuracy, sensitivity, and specificity This is a first feasibility study towards identifying relevant features in iEEG in real-time using mixed-signal neuromorphic computing technologies

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11 Citations

Open accessJournal Article
Abstract: In this work, we present a neuromorphic system that combines for the first time a neural recording headstage with a signal-to-spike conversion circuit and a multi-core spiking neural network (SNN) architecture on the same die for recording, processing, and detecting High Frequency Oscillations (HFO), which are biomarkers for the epileptogenic zone. The device was fabricated using a standard 0.18$\mu$m CMOS technology node and has a total area of 99mm$^{2}$. We demonstrate its application to HFO detection in the iEEG recorded from 9 patients with temporal lobe epilepsy who subsequently underwent epilepsy surgery. The total average power consumption of the chip during the detection task was 614.3$\mu$W. We show how the neuromorphic system can reliably detect HFOs: the system predicts postsurgical seizure outcome with state-of-the-art accuracy, specificity and sensitivity (78%, 100%, and 33% respectively). This is the first feasibility study towards identifying relevant features in intracranial human data in real-time, on-chip, using event-based processors and spiking neural networks. By providing "neuromorphic intelligence" to neural recording circuits the approach proposed will pave the way for the development of systems that can detect HFO areas directly in the operation room and improve the seizure outcome of epilepsy surgery.

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9 Citations

Open accessJournal Article
24 Mar 2021-Scientific Reports
Abstract: To achieve seizure freedom, epilepsy surgery requires the complete resection of the epileptogenic brain tissue. In intraoperative electrocorticography (ECoG) recordings, high frequency oscillations (HFOs) generated by epileptogenic tissue can be used to tailor the resection margin. However, automatic detection of HFOs in real-time remains an open challenge. Here we present a spiking neural network (SNN) for automatic HFO detection that is optimally suited for neuromorphic hardware implementation. We trained the SNN to detect HFO signals measured from intraoperative ECoG on-line, using an independently labeled dataset (58 min, 16 recordings). We targeted the detection of HFOs in the fast ripple frequency range (250-500 Hz) and compared the network results with the labeled HFO data. We endowed the SNN with a novel artifact rejection mechanism to suppress sharp transients and demonstrate its effectiveness on the ECoG dataset. The HFO rates (median 6.6 HFO/min in pre-resection recordings) detected by this SNN are comparable to those published in the dataset (Spearman’s $$\rho$$ = 0.81). The postsurgical seizure outcome was “predicted” with 100% (CI [63 100%]) accuracy for all 8 patients. These results provide a further step towards the construction of a real-time portable battery-operated HFO detection system that can be used during epilepsy surgery to guide the resection of the epileptogenic zone.

5 Citations

Open accessJournal Article
01 Jul 2021-
Abstract: Interictal high-frequency oscillations are discussed as biomarkers for epileptogenic brain tissue that should be resected in epilepsy surgery to achieve seizure freedom. The prospective classification of tissue sampled by individual electrode contacts remains a challenge. We have developed an automated, prospective definition of clinically relevant high-frequency oscillations in intracranial EEG from Montreal and tested it in recordings from Zurich. We here validated the algorithm on intracranial EEG that was recorded in an independent epilepsy centre so that the analysis was blinded to seizure outcome. We selected consecutive patients who underwent resective epilepsy surgery in Geneva with post-surgical follow-up > 12 months. We analysed long-term recordings during sleep that we segmented into intervals of 5 min. High-frequency oscillations were defined in the ripple (80-250 Hz) and the fast ripple (250-500 Hz) frequency bands. Contacts with the highest rate of ripples co-occurring with fast ripples designated the relevant area. As a validity criterion, we calculated the test-retest reliability of the high-frequency oscillations area between the 5 min intervals (dwell time ≥50%). If the area was not fully resected and the patient suffered from recurrent seizures, this was classified as a true positive prediction. We included recordings from 16 patients (median age 32 years, range 18-53 years) with stereotactic depth electrodes and/or with subdural electrode grids (median follow-up 27 months, range 12-55 months). For each patient, we included several 5 min intervals (median 17 intervals). The relevant area had high test-retest reliability across intervals (median dwell time 95%). In two patients, the test-retest reliability was too low (dwell time < 50%) so that outcome prediction was not possible. The area was fully included in the resected volume in 2/4 patients who achieved post-operative seizure freedom (specificity 50%) and was not fully included in 9/10 patients with recurrent seizures (sensitivity 90%), leading to an accuracy of 79%. An additional exploratory analysis suggested that high-frequency oscillations were associated with interictal epileptic discharges only in channels within the relevant area and not associated in channels outside the area. We thereby validated the automated procedure to delineate the clinically relevant area in each individual patient of an independently recorded dataset and achieved the same good accuracy as in our previous studies. The reproducibility of our results across datasets is promising for a multicentre study to test the clinical application of high-frequency oscillations to guide epilepsy surgery.

Topics: Epilepsy surgery (56%), Epilepsy (50%), Ictal (50%)

Open accessJournal Article
Abstract: Rationale: High-frequency oscillations (HFOs) in intracranial EEG (iEEG) are used to delineate the epileptogenic zone during presurgical diagnostic assessment in patients with epilepsy. HFOs are historically divided into ripples (80-250 Hz), fast ripples (FR, >250 Hz), and their co-occurrence (FRandR). In a previous study, we had validated the rate of FRandRs during deep sleep to predict seizure outcome. Here, we ask whether epileptic FRandRs might be confounded by physiological FRandRs that are unrelated to epilepsy. Methods: We recorded iEEG in the medial temporal lobe MTL (hippocampus, entorhinal cortex, and amygdala) in 17 patients while they performed cognitive tasks. The three cognitive tasks addressed verbal working memory, visual working memory, and emotional processing. In our previous studies, these tasks activated the MTL. We re-analyzed the data of these studies with the automated detector that focuses on the co-occurrence of ripples and FRs (FRandR). Results: For each task, we identified those channels in which the HFO rate was modulated during the task condition compared to the control condition. However, the number of these channels did not exceed the chance level. Interestingly, even during wakefulness, the HFO rate was higher for channels within the seizure onset zone (SOZ) than for channels outside the SOZ. Conclusion: Our prospective definition of an epileptic HFO, the FRandR, is not confounded by physiological HFOs that might be elicited by our cognitive tasks. This is reassuring for the clinical use of FRandR as a biomarker of the EZ.

Topics: Epilepsy surgery (52%), , Temporal lobe (51%) ... read more

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62 results found

Open accessJournal Article
28 Feb 2019-Scientific Reports
Abstract: The vertebrate gene repertoire is characterized by “cryptic” genes whose identification has been hampered by their absence from the genomes of well-studied species. One example is the Bmp16 gene, a paralog of the developmental key genes Bmp2 and -4. We focus on the Bmp2/4/16 group of genes to study the evolutionary dynamics following gen(om)e duplications with special emphasis on the poorly studied Bmp16 gene. We reveal the presence of Bmp16 in chondrichthyans in addition to previously reported teleost fishes and reptiles. Using comprehensive, vertebrate-wide gene sampling, our phylogenetic analysis complemented with synteny analyses suggests that Bmp2, -4 and -16 are remnants of a gene quartet that originated during the two rounds of whole-genome duplication (2R-WGD) early in vertebrate evolution. We confirm that Bmp16 genes were lost independently in at least three lineages (mammals, archelosaurs and amphibians) and report that they have elevated rates of sequence evolution. This finding agrees with their more “flexible” deployment during development; while Bmp16 has limited embryonic expression domains in the cloudy catshark, it is broadly expressed in the green anole lizard. Our study illustrates the dynamics of gene family evolution by integrating insights from sequence diversification, gene repertoire changes, and shuffling of expression domains.

Topics: Gene duplication (56%), Gene (53%), Synteny (53%) ... read more

987 Citations

Open accessJournal Article
01 May 2010-Epilepsia
Abstract: SUMMARY Purpose: To estimate the burden of lifetime epilepsy (LTE) and active epilepsy (AE) and examine the influence of study characteristics on prevalence estimates. Methods: We searched online databases and identified articles using prespecified criteria. Random-effects metaanalyses were used to estimate the median prevalence in developed countries and in urban and rural settings in developing countries. The impact of study characteristics on prevalence estimates was determined using metaregression models. Results: The median LTE prevalence for developed countries was 5.8 per 1,000 (5th–95th percentile range 2.7– 12.4) compared to 15.4 per 1,000 (4.8–49.6) for rural and 10.3 (2.8–37.7) for urban studies in developing countries. The median prevalence of AE was 4.9 per 1,000 (2.3–10.3) for developed countries and 12.7 per 1,000 (3.5–45.5) and 5.9 (3.4–10.2) in rural and urban studies in developing countries. The estimates of burden for LTE and AE in developed countries were 6.8 million (5th–95th percentile range 3.2–14.7) and 5.7 million (2.7–12.2), respectively. In developing countries these were 45 (14–145) million LTE and 17 (10–133) million AE in rural areas and 17 (5–61) million LTE and 10 (5–17) million AE in urban areas. Studies involving all ages or only adults showed higher estimates than pediatric studies. Higher prevalence estimates were also associated with rural location and small study size. Conclusions: This study estimates the global burden of epilepsy and the proportions with AE, which may benefit from treatment. There are systematic differences in reported prevalence estimates, which are only partially

938 Citations

Open accessJournal Article
Anatol Bragin1, Jerome Engel1, Charles L. Wilson1, Itzhak Fried1  +1 moreInstitutions (1)
01 Feb 1999-Epilepsia
Abstract: 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 Buzsaki 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.

Topics: Epilepsy (58%), Entorhinal cortex (56%), Hippocampus (55%) ... read more

640 Citations

Open accessJournal Article
Abstract: Thirty percent to 40% of patients with focal epilepsy are medically intractable,1 and for some, surgical removal of epileptogenic areas is the best option to gain seizure freedom. Intracranial electroencephalographic (iEEG) investigations are indicated for patients in whom noninvasive methods fail to identify a single focal seizure generator.2 iEEG is used to define the seizure onset zone (SOZ).3 Removal of the SOZ alone, however, does not always predict the surgical benefit.4,5 It is uncertain whether the outcome can be improved by removing areas of interictal spiking, often more widespread than the SOZ.6,7 Intracranial studies also have limitations, as their results depend on electrode location and type of implantation (intracortical vs subdural). For instance, iEEG electrodes only record neuronal activity in their direct vicinity and are blind for other areas,8 making it hard to judge whether the activity at seizure onset really represents the seizure generator or is the result of propagation from else-where. Thus the actual focus and its extent may be missed, leading to unsuccessful surgery. Microelectrode-recorded high-frequency oscillations (HFOs), ripples (80 –250Hz), and fast ripples (FRs, 250 –500Hz), were found predominantly in epileptogenic tissue.9 –11 They can also be recorded with macroelectrodes during clinical iEEG investigation.12,13 HFOs were more specific in indicating the SOZ than spikes.14 Additionally, they were linked to the SOZ independently of the underlying lesion and were infrequent in lesional areas outside the SOZ.15 Evidence therefore suggests that HFOs are good markers of epileptic tissue and may help to identify epileptogenic areas. We hypothesize that removing areas generating HFOs results in good surgical outcome. The correlation between removal of HFO-generating areas and seizure outcome was compared to that coming from spikes and to the current gold standard, removing the SOZ.

Topics: Ictal (54%), Epilepsy surgery (52%)

532 Citations

Open accessJournal Article
Greg Worrell1, Andrew B. Gardner1, S. Matt Stead1, Sanqing Hu1  +5 moreInstitutions (1)
01 Apr 2008-Brain
Abstract: Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80-250 Hz) and fast ripple (250-1000 Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC - 9000 Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 +/- 49.3 Hz versus 116.3 +/- 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.