Human interictal epileptiform discharges are bidirectional traveling waves echoing ictal discharges
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Evaluation Summary:
Smith et al. describes the propagation patterns of electrical activity in the brains of human epileptic patients. The authors demonstrate that interictal spikes, commonly observed electrical events in epileptic patients, propagate in a similar manner to seizures. This suggests that interictal spikes could be used in surgical planning, which would be of great interest to neurosurgeons and neurologists treating patients with medication refractory epilepsy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Although they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.
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Author Response
Reviewer #1 (Public Review):
The authors used microelectrode recordings in patients with drug-resistant epilepsy, automatically detected interictal and ictal epleptiform discharges, and measured the directions of travel of both. They found that most interictal discharges are traveling waves with two opposite-facing predominant directions of travel. Furthermore, they found that the direction of travel for interictal traveling waves was similar to that for ictal discharges. They conclude that studying interictal discharge propagation can reveal information about seizure propagation. This is an elegant approach to answering the important question of whether the spatiotemporal propagation of IEDs can elucidate seizure propagation.
The strengths of this paper are that it addresses an important question and uses elegant …
Author Response
Reviewer #1 (Public Review):
The authors used microelectrode recordings in patients with drug-resistant epilepsy, automatically detected interictal and ictal epleptiform discharges, and measured the directions of travel of both. They found that most interictal discharges are traveling waves with two opposite-facing predominant directions of travel. Furthermore, they found that the direction of travel for interictal traveling waves was similar to that for ictal discharges. They conclude that studying interictal discharge propagation can reveal information about seizure propagation. This is an elegant approach to answering the important question of whether the spatiotemporal propagation of IEDs can elucidate seizure propagation.
The strengths of this paper are that it addresses an important question and uses elegant quantitative techniques to try to answer it in human subjects. It is relevant to epilepsy clinical care as well as our understanding of how information spreads in the brain.
The authors' aims are largely met, but there are some questions about the methods and results that would be important to address to be sure that their conclusions are supported. These are:
- To be sure to demonstrate validation of their discharge detection methods. It would be important to report on positive predictive values for a random subset of detections, particularly on a testing set of data not used for training?
This is an important validation step and we apologize for its omission. We have had two clinician co-authors (JDR and CAS) validate IED detections on a dataset of 78 random IED detections, including those that were rejected in our denoising steps (n = 9), and now report the positive predictive value and inter-rater reliability directly in the results on page 4, line 16.
- The authors write in the abstract and discussion that interictal discharges (IEDs) traverse the same path as ictal discharges (SDs), but the angle between the SDs and IEDs was 24 degrees, and the IEDs weren't exactly opposite the ictal wavefront (150 degrees). This raises questions as to whether these two classes of abnormal activity really follow the same path. It would be important to account for the sizable angle between their observed paths. In some ways this seems to refute more than support the main conclusions.
We have taken steps to show that the angle discrepancies to which the reviewer refers are statistically insignificant and can be explained by expected biological variability. As discussed in response to each point below, we have added permutation tests showing that IED and SD distributions are significantly more similar than would be expected by chance, and that while we did not observe perfect antipodality in all distributions in all subjects, the amount and extent of antipodality we observed is highly improbable and supports the claims of the paper. Furthermore, that these empirical results in human participants were predicted by the computational model reported in (Liou et al., 2020) lends further contextual support for the results.
- The influence of sampling error and method of recording are important to discuss, and how they might alter the brain and its conduction of abnormal activity. It would be important to be clear about what effects if any these factors have on the conclusions and information recorded.
These are excellent topics of discussion related to the previous point and we have discussed them directly in the 4th paragraph of the discussion section, on page 11, line 10.
- It would be important to explain how seizures were defined and the rationale for this definition. This is an elusive topic and one in great debate, so this would be helpful to understand your thinking and also to assess the paper's relevance to clinical epileptic events.
We detected seizures from the times listed in the EMU reports and examined the corresponding time periods in the microelectrode data. Beyond this utilization of the gold standard (i.e. an attending neurologist’s definition) we didn’t formally operationally define what a seizure was, but anecdotally looked for a series of LFP discharges with the typical pattern of inter-discharge intervals, as in previous studies (Schevon et al., 2012; Smith et al., 2020, 2016). Once those discharges were discovered, we looked at whether multiunit activity phase locked to the LFP discharging in order to determine whether neurons recorded by the microelectrode array were ‘recruited’ into the seizure core, or remained in the ‘penumbra’ as described in the ‘seizure characterization’ section of the methods, starting on page 16, to which we have added text clarifying these points starting on page 15, line 6.
Overall this is a very interesting study on an important topic, and one that is relevant to both basic science research and the clinical evaluation and care of patients with epilepsy.
We thank the reviewer and agree with this assessment.
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Evaluation Summary:
Smith et al. describes the propagation patterns of electrical activity in the brains of human epileptic patients. The authors demonstrate that interictal spikes, commonly observed electrical events in epileptic patients, propagate in a similar manner to seizures. This suggests that interictal spikes could be used in surgical planning, which would be of great interest to neurosurgeons and neurologists treating patients with medication refractory epilepsy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors used microelectrode recordings in patients with drug-resistant epilepsy, automatically detected interictal and ictal epleptiform discharges, and measured the directions of travel of both. They found that most interictal discharges are traveling waves with two opposite-facing predominant directions of travel. Furthermore, they found that the direction of travel for interictal traveling waves was similar to that for ictal discharges. They conclude that studying interictal discharge propagation can reveal information about seizure propagation. This is an elegant approach to answering the important question of whether the spatiotemporal propagation of IEDs can elucidate seizure propagation.
The strengths of this paper are that it addresses an important question and uses elegant quantitative …
Reviewer #1 (Public Review):
The authors used microelectrode recordings in patients with drug-resistant epilepsy, automatically detected interictal and ictal epleptiform discharges, and measured the directions of travel of both. They found that most interictal discharges are traveling waves with two opposite-facing predominant directions of travel. Furthermore, they found that the direction of travel for interictal traveling waves was similar to that for ictal discharges. They conclude that studying interictal discharge propagation can reveal information about seizure propagation. This is an elegant approach to answering the important question of whether the spatiotemporal propagation of IEDs can elucidate seizure propagation.
The strengths of this paper are that it addresses an important question and uses elegant quantitative techniques to try to answer it in human subjects. It is relevant to epilepsy clinical care as well as our understanding of how information spreads in the brain.
The authors' aims are largely met, but there are some questions about the methods and results that would be important to address to be sure that their conclusions are supported. These are:
1. To be sure to demonstrate validation of their discharge detection methods. It would be important to report on positive predictive values for a random subset of detections, particularly on a testing set of data not used for training?2. The authors write in the abstract and discussion that interictal discharges (IEDs) traverse the same path as ictal discharges (SDs), but the angle between the SDs and IEDs was 24 degrees, and the IEDs weren't exactly opposite the ictal wavefront (150 degrees). This raises questions as to whether these two classes of abnormal activity really follow the same path.
It would be important to account for the sizable angle between their observed paths. In some ways this seems to refute more than support the main conclusions.3. The influence of sampling error and method of recording are important to discuss, and how they might alter the brain and its conduction of abnormal activity. It would be important to be clear about what effects if any these factors have on the conclusions and information recorded.
4. It would be important to explain how seizures were defined and the rationale for this definition. This is an elusive topic and one in great debate, so this would be helpful to understand your thinking and also to assess the paper's relevance to clinical epileptic events.
Overall this is a very interesting study on an important topic, and one that is relevant to both basic science research and the clinical evaluation and care of patients with epilepsy.
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Reviewer #2 (Public Review):
In this manuscript, Smith et al analyze a dataset comprising multi-day microelectrode recordings acquired for the purpose of surgical planning in human epilepsy patients. The authors evaluate the propagation of 3 activity modes: 1) interictal epileptiform discharges (IEDS); 2) the ictal wavefront (IW), which is a slowly expanding wave of tonic neural firing; and 3) Seizure discharges (SD), which are rapidly travelling waves of activity that follow the IW. Specifically, the key findings are: 1) IED propagation direction is non-uniform and most commonly bimodal, with the two modes being antipodal. 2) SDs and IEDs propagate in approximately the same direction, which is approximately antipodal from the IW 3) there is a strong relationship between the predominant IED direction and recruited SD direction, also …
Reviewer #2 (Public Review):
In this manuscript, Smith et al analyze a dataset comprising multi-day microelectrode recordings acquired for the purpose of surgical planning in human epilepsy patients. The authors evaluate the propagation of 3 activity modes: 1) interictal epileptiform discharges (IEDS); 2) the ictal wavefront (IW), which is a slowly expanding wave of tonic neural firing; and 3) Seizure discharges (SD), which are rapidly travelling waves of activity that follow the IW. Specifically, the key findings are: 1) IED propagation direction is non-uniform and most commonly bimodal, with the two modes being antipodal. 2) SDs and IEDs propagate in approximately the same direction, which is approximately antipodal from the IW 3) there is a strong relationship between the predominant IED direction and recruited SD direction, also between the auxillary IED direction and pre-recruited SD direction. These findings support the potential utility of interictal spikes in surgical planning for refractory epilepsy. The ability to use IEDs would be particularly beneficial as they are considerably more frequent than seizures and typically occur without withdrawal of patients from their medication. This work is interesting and potentially important, however some additional analysis is necessary to support the potential translational utility of this approach as well as revision to improve readability.
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Reviewer #3 (Public Review):
Interictal epileptiform discharges, known to occur between seizures in patients with epilepsy are not thought to provoke an ictal event. Pre-ictal epileptiform or seizure discharges on the other hand, occur prior to a seizure. However, it is unclear if these two pathological events are connected spatiotemporally or at single- or multi-unit level. This question is fundamental to our understanding of epileptogenesis, because there exists a subgroup of patients who have interictal epileptiform discharges on their scalp electroencephalogram (EEG) and seldom have a seizure. At the same time, there are patients who have completely normal EEGs but have frequent unprovoked epileptic seizures.
Smith et al., using complex computational methods were able to model epileptiform discharges in the seizure core versus away …
Reviewer #3 (Public Review):
Interictal epileptiform discharges, known to occur between seizures in patients with epilepsy are not thought to provoke an ictal event. Pre-ictal epileptiform or seizure discharges on the other hand, occur prior to a seizure. However, it is unclear if these two pathological events are connected spatiotemporally or at single- or multi-unit level. This question is fundamental to our understanding of epileptogenesis, because there exists a subgroup of patients who have interictal epileptiform discharges on their scalp electroencephalogram (EEG) and seldom have a seizure. At the same time, there are patients who have completely normal EEGs but have frequent unprovoked epileptic seizures.
Smith et al., using complex computational methods were able to model epileptiform discharges in the seizure core versus away from the core. They showed that interictal discharges are predominantly bidirectional, whether in the seizure core or away from it. The technique to model MUA is difficult because the units can be heterogenous in the seizure core. The process to sort through MUAs and IED waveforms from multiple days of data, is labor intensive and requires intense dedication. Their strengths are using a technique that they have showed to be reproducible from multiple groups. In this paper, the authors employ their traveling waveform modeling from their prior well published work to interictal discharges that were collected over multiple days with or without seizures. The strengths of being able to study traveling ictal wavefront and compare seizure discharges to interictal discharges can only be achieved on a Utah array. This is also their weakness. The Utah array is implanted on the neocortex and close to the seizure zone, it is hard not to imagine the bias that exists when they model the traveling wavefront of the IEDs to that of their seizure discharges. It is unclear if this bidirectional IED hypothesis applies to mesial temporal lobe seizures where the ictal onset is far from the neocortex.
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