High-frequency oscillations and epilepsy: Clinical and basic science perspectives

High-frequency oscillations (80 to 500 Hz) are being studied as biomarkers of epileptogenic areas in the brain, as well as markers to be used in epilepsy surgery. Dr. Cecilie Nome leads a discussion about clinical research on HFOs and areas of uncertainty, as well as the importance of basic research in helping to understand this phenomenon.

Publications mentioned during the episode: 

Roehri Eng N, et al. High-frequency oscillations are not better biomarkers of epileptogenic tissues than spikes. 2017. Annals of Neurology

Jacobs J, et al. Removing high-frequency oscillations: A prospective multicenter study on seizure outcome. 2018. Neurology

Zweiphenning W, et al. Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial. 2022. Lancet Neurology

Lisgaras CP et al. High-frequency oscillations (250–500 Hz) in animal models of Alzheimer's disease and two animal models of epilepsy. 2022. Epilepsia

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

[00:00:00] Dr. Cecilie Nome: So, hello everyone and welcome to this podcast episode on Sharp Waves. My name is Cecilie Nome and I will be moderating this episode. Today we are going to discuss a very interesting and also hot topic in the field of epilepsy, namely high-frequency oscillations. And for this, we have invited two experts within the field to discuss this interesting topic.

So I'm very happy to welcome Professor Maeike Zijlmans and Dr. Christos Lisgaras. It's a great pleasure to have you here. So could we do a short introduction round? Maybe Professor Zijlmans, could you start?

[00:00:42] Dr. Maeike Zijlmans: Thank you very much. So my name is Maeike Zijlmans. I'm a professor in neurology and especially epilepsy at the University Hospital in Utrecht and also in Stichting Epilepsie Instellingen Nederland, which is also called SEIN. And I will be also the director of research there.

[00:01:06] Dr. Christos Lisgaras: Thank you so much, Cecile. So I'm Christos Lisgaras. I'm a research assistant professor at NYU Langone at the Department of Psychiatry and Research Scientist at the Center for Dementia Research at the Nathan Klein Institute.

[00:01:21] Dr. Cecilie Nome: Thank you very much. So. What are high-frequency oscillations and what role does this phenomenon play in humans? 

[00:01:32] Dr. Maeike Zijlmans: So I will comment. Yeah, so high frequency oscillations are EEG phenomena. So we see them in the electrical signal of the brain. They were discovered invasively, first in animals and then in humans.

And especially with invasive electrodes and first in a micro context, which was done for research purposes. But later we also found that we can see them in a clinical invasive EEG and later on, even that they can even be visualized in the normal surface EEG. 

We're talking about high-frequency oscillations, ripples and fast ripples. Ripples are between 80 and 250 hertz, and fast ripples are between 250 and 500 hertz. And maybe there are even higher frequencies that are interesting. They can be physiological and pathological, in the sense that we can find them as part of physiological activity. They have been described previously as having an important role in for instance, memory, typical sharp wave ripples. But we also see them in the typical primary areas in the human brain, for instance, the visual cortex or the motor cortex or in language areas.

Pathologically they have been found in epilepsy, especially in areas where the cortex normally does not produce these high frequencies. So there, they seem really a sign that the tissue is abnormal there.

[00:03:06] Dr. Christos Lisgaras: So the healthy brain is capable of generating a variety of oscillations, including high-frequency oscillations, in the normal brain. As Maeike mentioned, these oscillations are thought to participate in cognitive processes, and their disruption has been associated with memory deficits in animals and also humans. For instance, one brain area that is particularly critical for memory, the hippocampus, is capable of generating ripple oscillations during sleep. And those oscillations are very important for consolidating the experience of memory. Other brain areas, such as the somatosensory cortex, can generate faster oscillations than ripples. So different brain areas can generate different frequencies of oscillations. And of course, in the epileptic brain, they can still generate, but also they generate other types of oscillations like the pathological ones that Maeike mentioned.

[00:04:10] Dr. Cecilie Nome: Thank you so much. High-frequency oscillations in healthy people, they are actually quite important then for memory and other important functions. But how do you actually detect these ripples or these high frequency oscillations? I mean, they're quite fast, right?

[00:04:29] Dr. Christos Lisgaras: So there, there are several ways to check whether a recording has HFOs. One can detect the HFOs manually or check the record and see using filter settings that allow them to see HFOs in their EEG records.

There are several features that investigators use to define HFOs. One of them is based on their frequency. We heard about ripples and fast ripples. Another feature is their duration, how long they last. The number of oscillations that you see within an HFO. As well as their amplitude. So these defining features are embedded into algorithms for automatic detection that help you identify putative HFO events. 

Then most investigators that detect those events, they do a post hoc review of those events which is often necessary to exclude events that may be due to concurrent artifacts or other sources of noise. Because most HFOs occur during sleep, most investigators like to start looking for HFOs during sleep and especially during periods that they see other types of epileptiform activity, because these periods are highly likely to show HFOs. 

[00:05:50] Dr. Cecilie Nome: So HFOs, they had been proposed as a potential biomarker for epilepsy. And they have even been proposed to be able to help the physicians or guide them to localize the seizure onset zone and also even to predict outcomes after surgeries. Could you explain how this concept works?

Professor Zijlmans. 

[00:06:12] Dr. Maeike Zijlmans: The mainstream idea, so to say, is now that HFOs occur, especially the pathological HFOs, because there are groups of neurons that are on the one hand per group are firing very hyper synchronously. And on the other hand, there's different groups of neurons that fire out of phase. And that's how these very high frequencies can be produced by the brain tissue. 

And then your question about can it help to predict where the seizure starts or to say where the which tissue should be resected…Well, there have been, by now, quite an amount of studies on that and I think most studies answered a yes to that question and some say no.

We have a big multi-center study coming up soon and there we do show that it can be informative. Personally, I think it can, but I think you have to be aware that it's difficult to measure them sometimes with invasive EEG.

If you're not close to the source, you may miss the source, and you will always pick up seizure onset but then you may not pick up your HFOs. So then you don't predict your seizure onset zone, but maybe your seizure onset zone is also a little bit off. And yeah, so a better answer is “maybe.”

Can they predict or can they, if they are resected, yes or no, do they predict the outcome after surgery? And that seems to work out mostly okay, but there you also, you always have this question of the area which is resected, it can also include brain tissue that is totally normal on the one hand, or you can leave abnormal tissue but still your epilepsy is gone because you removed enough pathological network.

So that's the difficulty I think in epilepsy and for any biomarker we try to use that you never have a true gold standard. But as I said, I'm a believer that it can help us in the clinic.

[00:08:25] Dr. Cecilie Nome: Thank you so much. So I understand that there's a lot of things that need to work out for this method to work. And I mean, you need to get the right area and you need to be on the seizure onset zone. And you also probably would need to have EEG electrodes inside the brain.

 Dr. Lisgaras, could you tell us more about what we have learned from basic neuroscience about HFOs in epilepsy in regards to HFOs and to methods and how to measure them? 

[00:08:56] Dr. Christos Lisgaras: Neuroscience has been very critical in HFO research. Actually, HFOs were first discovered in animal models of epilepsy, in epileptic rats, and then they were recorded in humans with epilepsy.

The circuits and the mechanics underlying HFOs have been extensively studied, both in vitro and in vivo, and these approaches allow the neuroscientists to investigate which channels may be involved in generating HFOs and these manipulations are very important because it can tell us what can trigger an HFO or what can abate an HFO.

Also recordings of HFOs in the brain of animals with seizures have uncovered that HFOs occur before a seizure starts and can be associated with a specific seizure onset pattern. So that tells us probably mechanics underlying different seizure patterns. Moreover studies in animal models with different etiologies, like brain trauma or status epilepticus, have been very valuable because they tell us that HFOs are quite common in various different epileptogenic insults. 

[00:10:14] Dr. Cecilie Nome: Thank you so much. You mentioned that that you see different types of seizure patterns and also that different models of epilepsy also have HFOs. So this leads me to my next question. Do HFOs exist in all types of epilepsy? Are there any variants between different types of epilepsy, and can HFOs also be influenced by other factors?

[00:10:38] Dr. Maeike Zijlmans: Yeah. So I think there are differences. We see, at least in the clinic, differences between for instance, if you have mesial temporal lobe sclerosis, typically you see these giant spikes with HFOs. But as we just discussed there are physiological HFOs in the mesial temporal structures as well. So there is always a question of what we are actually looking at. In focal cortical dysplasia, we typically find clear HFOs, but again, the underlying spike pattern can be a bit different as often these multi spikes underlie them. And it's typically coming from more like the depth and the focal cortical dysplasia itself.

 If you look in tumors, we do not see that many HFOs. And when we see them, we see them more distant from the tumor. But on the other hand, we know that the epilepsy is also often far from the tumor. So, yeah, we do see differences in different pathologies.

And yeah, there are other factors that affect the amount of HFOs. For instance, the moment in time, as Dr. Lisgaras already discussed, like sleep has an important impact on the occurrence of HFOs. We often see more HFOs during sleep. And other influences. You can think that age has an influence, but it's a bit difficult to determine that I think, because I think that pathology is also very dependent on age. So I don't, I'm not sure to be honest, if that's a big factor. 

For instance, on the surface EEG, we see HFOs in Rolandic epilepsy, but yeah, the Rolandic spikes occur from a very superficial part of the brain. So it's not surprising that you are more likely to see these ripples occurring on the Rolandic spikes. So I'm not sure how much that is a matter of the underlying pathology and the age, or it's just a coincidence that's where it occurs also.

[00:12:57] Dr. Cecilie Nome: Thank you. So that also leads me to my next question. What happens when patients start anti-seizure medications? Do you still see the HFOs? Do they change? 

[00:13:08] Dr. Maeike Zijlmans: Yeah, they definitely change. We know there's some effect of seizure medication. We could see that when you reduce the medication, there's an increase of ripples and fast ripples. You don't see that increase that clearly in spikes, so there's a difference between the HFOs and the interictal spikes. 

And also, for instance, anesthetics have an effect so anesthetics often reduce them, although for instance, cephalofluorane can also increase the HFOs, so there are different effects of different medications I think, but yeah, in general, there's a decrease by anti-epileptic drugs. And for instance, other treatments like ACTH treatment in West syndrome, there you also see a decrease in the ripples.

[00:13:59] Dr. Cecilie Nome: HFO, it seems to be a very promising biomarker. There's a lot of research going on. But in the later years there has also been some studies questioning the reliability of HFOs as a biomarker both for identifying the epileptic zone and for predicting the outcome after surgery.

So for example, in 2018 Roehri et al. found that HFO might not be superior to interictal spikes as a biomarker. In the same year, Jacobs et al., they found that HFO could predict surgical outcomes in only 67 percent of the study patients. What are your thoughts on these studies and these results?

[00:14:43] Dr. Maeike Zijlmans: Yeah, I think a big thing lies in the recording and the analysis of the signal, and we do not put enough attention on that, I think. So for instance, the study by Jacobs, she studied three different centers and there were actually big differences among the different centers. And I think that depends a lot on, for instance, simply the recording device, the type of recording electrodes and then the software you have and how you visualize the events. 

So there are big differences in that and we experienced that ourselves very recently, two things during the trial. We had different recording systems and we found out that yeah, there was a recording system from the same company with which we could see less events, just because of the head box we were using. We recorded with different electrodes, high-density and low-density electrode configurations. And then you see that if you record with high-density electrodes, you just see more events, especially the fast ripples, because they occur in very small area. So again, I think it's mainly a matter of sometimes missing the right spot.

And it, of course, also depends on your selection of patients. And yeah, there are many influences there.

[00:16:13] Dr. Cecilie Nome: Thank you. So you said that even from, from the same company and the same type of device, and you still had different results. So the HFO seems to be well, it seems to depend on what kind of recording equipment you're using then. 

[00:16:25] Dr. Maeike Zijlmans: Yeah. Yeah. And I think we should, if we should push the field somewhere, it should be towards better recordings, better analysis.

[00:16:34] Dr. Cecilie Nome: Dr. Lisgaras, what, what are your thoughts on this? 

[00:16:37] Dr. Christos Lisgaras: Yeah, I think I echo what Maeike mentioned. And from the basic science perspective, there are many studies that appear to contradict or not replicate, but in the end it may be that we don't use the same equipment, we don't use the same exactly the same animal model. So there's always limitations in its study and the more information I think is always better.

[00:17:02] Dr. Cecilie Nome: I think this is good to bring up that if this field is going to move forward, it may be important for researchers and clinicians to collaborate more and to come up with standardized protocols and standardized equipment and how to record this.

I was also wondering because there has been a different report on HFO and I think there they found that the rates varied over time and in different locations in the brain. You briefly also touched upon this in the beginning, but how could this affect the results if the HFOs are kind of also other places in the brain and it might be hard to sort of find the epileptic zone. 

Professor Zijlmans in your paper that you published in Lancet Neurology in 2022, you also compared HFO guided and spike guided tailoring for epilepsy surgery. And here you actually grouped the patients in either temporal or extratemporal lobe epilepsy. Is this because there are differences between those two groups in how the HFOs are detected? Could you just tell us more about this? 

[00:18:12] Dr. Maeike Zijlmans: Yeah, so we indeed grouped them into temporal and extratemporal lobe epilepsies. And we found, well, at least we found differences in the outcome.

So if you looked at the outcome and we corrected it for reasons why we would expect a better or worse outcome based on the patient themselves, and then we looked at the differences, we did see actually in the extratemporal lobe epilepsy that the fast ripples were a little bit on the, or the HFOs were a little bit on the positive side. And it showed that at least they were not inferior to the spikes. Well, actually in the group of temporal lobe epilepsy this was not so clear. And it was even, it even seemed that the group where we looked at the HFOs was doing worse. 

And I think that is caused by the fact that as we discussed before, nowadays there are these maps of physiological activity. And there you can see that most physiological HFOs occur in the mesiotemporal structures. So just taking into account the number of HFOs and if they occur may be not the best predictor for surgery. 

And I do think that they are the most useful, like what we often have, because we use them intraoperatively and what we then often have is the situation, there's a lesion. And you want to know if you resect the lesion well enough. So you resect the lesion, you record the electrocorticography after the resection, and you see if there are still especially fast ripples left. And if that's the case, you may want to extend your resection a little bit. That may be a clinically useful method. 

I say may be because of course we did not prove that. We only have proven that it may not be worse, at least, for the mesiotemporal structures. If the question was just like, should we also remove the hippocampus, yes or no? I don't think they help enough, because, at least not in the way we looked at it, because you have this physiological activity there as well. So that shouldn't be guiding you, at least not in the way that we did it during the trial.

[00:20:33] Dr. Cecilie Nome: Thank you. So I guess this means that it's both important that we have a standardized way of detecting the HFOs and maybe it would also then be important to group patients, for example, like you did, temporal lobe epilepsy or extra temporal lobe epilepsy, and maybe even further down in the future to kind of tailor the treatment as good as possible to the patients then.

[00:20:59] Dr. Maeike Zijlmans: So there are these atlases nowadays, and that may help because then you may say, okay, I have a finding and I compared it to what is physiological and I sort of subtract that. So that may be a future way to deal with this.

[00:21:15] Dr. Cecilie Nome: Dr. Lisgaras, how can researchers enhance their understanding of HFOs and the significance in epilepsy and seizure disorders in the future? 

[00:21:26] Dr. Christos Lisgaras: Yeah, I think basic neuroscience can contribute a lot to the understanding of HFOs, thanks to modern neuroscience tools that are available to study the brain and which can also be applied in HFO research.

For instance, there are approaches that can reversibly switch on and switch off a neuronal population of interest in the mouse brain to determine how that manipulation can affect neuronal activity and HFOs. This approach can inform about which circuits are involved and shed light into the mechanisms, and help in identifying treatments for the future.

Moreover HFOs can be studied in disorders that have a lot of in common with epilepsy, as well as epilepsy comorbidities, thanks to animal models. We have found that HFOs occur in animal models of Alzheimer's disease and Down syndrome. And as you know, these disorders have a lot in common with epilepsy, there is a bidirectional relationship. And there are reports showing that HFOs may contribute to memory deficits. 

I think overall, modern neuroscience can expand the use of HFOs. And perhaps the role of HFOs may be wider than previously thought in brain disorders. So I think that the future is bright and more HFO research is needed to uncover the mysteries underlying HFOs.

[00:23:03] Dr. Cecilie Nome: Thank you. And so for my final question, I would like to ask both of you if there is anything else you would like to discuss or to bring up.

[00:23:15] Dr. Maeike Zijlmans: So there will be a new workshop coming up about HFOs, that will be in 2028, probably, in Utrecht or at least in the Netherlands. And yeah, excited about that.

 I hope the field will indeed continue working. I expect a lot from the basic science. And on the other hand, the clinical science is more and more moving towards better detections, easier detections, maybe more clinical use. And as I said, I hope we can improve our recording methods so we can more easily recognize the events, so we don't have to debate about if they exist and we can start using them clinically.

[00:24:02] Dr. Christos Lisgaras: I also think that forums like this and conferences and symposia around HFOs are really important for increasing the collaboration between clinical teams, basic science teams, and also clinical and basic so that we can move the field forward.

[00:24:23] Dr. Cecilie Nome: So, thank you so much, both of you, and I think it's great that the clinical side and the basic science side get to work together to understand this phenomenon.