Abstract
Background:
To study the characters of high-frequency oscillations (HFOs) in the seizure onset zones (SOZ) and the nonseizure onset zones (NSOZ) in the electrocorticography (ECoG) of patients with neocortical epilepsy.
Methods:
Only patients with neocortical epilepsy who were seizure-free after surgery as determined with ECoG were included. We selected patients with normal magnetic resonance imaging before surgery in order to avoid the influence of HFOs by other lesions. Three minutes preictal and 10 min interictal ECoG as recorded in 39 channels in the SOZ and 256 channels in the NSOZ were analyzed. Ripples and fast ripples (FRs) were analyzed by Advanced Source Analysis software (ASA, The Netherlands). Average duration of HFOs was analyzed in SOZ and NSOZ separately.
Results:
For ripples, the permillage time occupied by HFOs was 0.83 in NSOZ and 1.17 in SOZ during the interictal period. During preictal period, they were 2.02 in NSOZ and 7.93 in SOZ. For FRs, the permillage time occupied by HFOs was 0.02 in NSOZ and 0.42 in SOZ during the interictal period. During preictal period, they were 0.03 in NSOZ and 2 in SOZ.
Conclusions:
High-frequency oscillations are linked to SOZ in neocortical epilepsy. Our study demonstrates the prevalent occurrence of HFOs in SOZ. More and more burst of HFOs, especially FRs, means the onset of seizures.
Keywords: Electrocorticography, Epilepsy, High-frequency Oscillations, Seizure Onset Zones
INTRODUCTION
Epileptic high-frequency activity includes pathological activities with frequency above 80 Hz recorded in epileptic brains in vitro, in animal models and in patients.[1] Isolated high-frequency oscillatory events are the most common type of high-frequency activity and are called high-frequency oscillations (HFOs).[1] HFOs include ripples (80–250 Hz) and fast ripples (FRs) (250–500 Hz).[2,3] Different studies use slightly different frequency bands. Only events containing at least 4 consecutive oscillations above 80 Hz were regarded as HFOs.[1] It has been proposed that HFOs are related to the epileptic attack by animal trial.[4,5] Recent studies suggest the changes of HFOs in epileptic brains are related to epileptogenesis and seizure genesis.[6]
The characteristics of HFOs in mesial temporal epileptic patients during ictal and interictal periods have been well studied. Our study focused on neocortical epileptic patients who were seizure-free after surgery with normal magnetic resonance imaging (MRI) before surgery avoiding the influence of HFOs by other lesions. The seizure onset zones (SOZ) of the patients should be verified by the consequences of surgery. The removal of areas with HFOs seems to predict effective surgical interventions.[7,8]
METHODS
Selection of patients
Between December 2010 and January 2012, 18 patients with implanted subdural electrodes for epilepsy surgery evaluation were recorded at a sampling rate of 1600 Hz in our epilepsy center. Patients with a proven neocortical epilepsy and normal MRI before surgery were included in this study. Besides, We only selected patients that were seizure-free for more than 1-year after surgery. The details of the patients are listed in Table 1. Other patients were excluded because of three reasons: Abnormal MRI before surgery, still with seizures after surgery, not neocortical epilepsy.
Table 1.
Clinical and electrophysiological data of four patients
| Patient | Age (years)/gender | History of epilepsy before surgery (years) | AEDs ever tried | Seizure frequency before surgery | Electrode positions | Electrode numbers | Surgery site |
|---|---|---|---|---|---|---|---|
| 1 | 7/male | 2 | VPA, CBZ, LTG | 3-4/day | BF, BT | 80 | R-SMF |
| 2 | 19/male | 14 | VPA, CBZ | 2-3/day | LF, LT, LP | 76 | L-MIF |
| 3 | 16/male | 4 | VPA, CBZ, TPM, LEV | 1-2/month | RF, RT | 96 | R-PNT |
| 4 | 21/male | 18 | CBZ, LTG, VPA, OXC, TPM | 1/week | LF, LT | 64 | L-DF |
VPA: Sodium valproate; CBZ: Carbamazepine; LTG: Lamotrigine; TPM: Topiramate; LEV: Levetiracetam; OXC: Oxcarbacepine; B: Bilateral; L: Left; R: Right; F: Frontal lobe; T: Temporal lobe; P: Parietal lobe; SMF: Superior and middle frontal gyrus; MIF: Middle and inferior frontal gyrus; PNT: Posterior of neocortical temporal lobe; DF: Dorsolateral frontal lobe; AED: Anti-epileptic drug.
Electrocorticography recording
Patients were implanted subdural electrodes according to clinical history, seizure semiology and surface electroencephalogram (EEG) investigations. The electrodes have a 2.5 mm stainless steel central core, with a 10 mm interconnecting distance. The ECoG was sampled by a 128-channel Grass/Twins Monitoring System (Grass Technologies, USA) at the sampling rate of 1600 Hz with low-frequency cut of 0.1 Hz and high-frequency cut of 500 Hz. The ECoG was recorded for 3–14 days constantly in order to acquire at least three seizures to orient the epileptogenic zone. The data were visually inspected, and channels with artifacts were removed. In total, at last 295 channels of the ECoG were analyzed.
High-frequency oscillations analysis
Ten minutes ECoG data during interictal periods were selected. Interictal data imply that there was no seizure within 1 h before and after the selected section for each individual patient. For preictal period, 3 min data were selected. The ECoG data were transformed to European Data Format form in order to be read by the analysis software. Ripples and FRs were analyzed by Advanced Source Analysis (ASA) (ASA, The Netherlands) software. At last, 295 channels were analyzed including 39 channels from SOZ and 256 channels from nonseizure onset zones (NSOZ). The SOZ was identified as the area showing the earliest EEG change (ictal discharge) from baseline prior to or concomitant with clinical onset.[9] Ripples were analyzed with a filter from 80 to 250 Hz at the computer screen resolution ratio 1280 (0.8 s/page, 100 μV/cm). FRs were analyzed with 250 and 500 Hz filters at the computer screen resolution ratio 1280 (0.5 s/page, 30 μV/cm). The accurate starting and ending point and the numbers of HFOs can be read from the ASA [Figure 1]. The duration of every oscillation can be calculated by the starting and ending time. Permillage time occupied by HFOs can be calculated then.
Figure 1.
Ripple (a) and fast ripple (b) analyzed by Advanced Source Analysis.
Statistical analysis of average duration of high-frequency oscillations
Multiple comparison of rank sum test was used to compare the average duration of ripples and FRs inside and outside the SOZ. Statistical significance was set at P < 0.05.
RESULTS
The results of ripples and FRs are listed in Tables 2 and 3.
Table 2.
Result of ripples
| Period | Area | AD (ms) | PT |
|---|---|---|---|
| Interictal | SOZ | 83.64 ± 42.41 | 1.17 |
| NSOZ | 67.59 ± 27.16 | 0.83 | |
| Preictal | SOZ | 138.16 ± 92.06 | 7.93 |
| NSOZ | 133.02 ± 87.62 | 2.02 |
AD: The average duration of HFO; PT: The permillage time occupied by HFOs; SOZ: Seizure onset zones; NSOZ: Nonseizure onset zones; HFOs: High-frequency oscillations.
Table 3.
Result of FRs
| Period | Area | AD (ms) | PT |
|---|---|---|---|
| Interictal | SOZ | 25.04 ± 13.66 | 0.42 |
| NSOZ | 33.69 ± 12.36 | 0.02 | |
| Preictal | SOZ | 23.25 ± 10.28 | 2 |
| NSOZ | 29.14 ± 16.23 | 0.03 |
AD: The average duration of HFOs; PT: The permillage time occupied by HFOs; FRs: Fast ripples; SOZ: Seizure onset zones; NSOZ: Nonseizure onset zones; HFOs: High-frequency oscillations.
The average duration of ripples
The average duration of every ripple in the SOZ was longer than that in the NSOZ during interictal periods (Z = 6.94, P < 0.001). During the preictal periods, there was no different between in SOZ and NSOZ (Z = 1.44, P = 0.075).
The average duration of fast ripples
The average duration of every FRs inside the SOZ were shorter than that outside the SOZ during both interictal (Z = 7.16, P < 0.001) and preictal periods (Z = 2.35, P = 0.009). During interictal period, the PT of FRs in SOZ is more than 20 times than that in NSOZ. And during the preictal period, the PT of FRs in SOZ is about 67 times than that in NSOZ.
Permillage time occupied by ripples
For ripples, the permillage time occupied by HFOs was 0.83 in NSOZ and 1.17 in SOZ during the interictal period. During preictal period, they were 2.02 in NSOZ and 7.93 in SOZ.
Permillage time occupied by fast ripples
For FRs, the permillage time occupied by HFOs was 0.02 in NSOZ and 0.42 in SOZ during the interictal period. During preictal period, they were 0.03 in NSOZ and 2 in SOZ.
DISCUSSION
Multiple studies have investigated characteristics of HFOs in mesial temporal epileptic patients.[10,11] Our results indicate that HFOs links to SOZ in patients with neocortical epilepsy without a visible lesion on MRI. The study selected patients with normal MRI in order to avoid the influence of HFOs by other lesions. All our patients were seizure-free proved that the removed areas included the epileptogenic tissue.
The percentage of occupancy by HFOs in the SOZ-channels was significantly higher than that in the NSOZ-channels. This increase was seen in ripples and FRs, especially FRs. During interictal period, the PT of FRs in SOZ is more than 20 times than that in NSOZ. And during the preictal period, the PT of FRs in SOZ is about 67 times than that in NSOZ. This result is consistent with other study.[1] Nevertheless, the percentage of time occupied by HFOs in this study is less than Zijlmans’ study.[1] Perhaps there are three reasons. First, the patients in our study all have a nomal MRI. Lesions may increase the incidence of HFOs. Second, Zijlmans selected 10 s before seizure onset while we analyzed 3 m before seizure onset and HFOs tend to increase before seizure onset. Third, Zijlmans chose chronic sleep stage as the interictal period that usually showed more epileptiform discharge in patients. Although FRs have been more strongly linked to epileptogenesis than ripples,[7,12,13] we found that both were increased in the SOZ.
The percentage of occupancy by HFOs in the SOZ-channels was significantly higher than that in the NSOZ-channels, especially FRs. It indicates that FRs links to SOZ more closely than ripples. FRs proved to be a reliable epileptogenic marker since they were closely related to SOZ. Ripples are considered to play an important role in information processing, and consolidation of memory, which are thought as physiological HFO[14,15,16] The distinction between physiological and pathological HFO has remained unclear.[15,17] Recently, it was showed that pathological HFO had higher mean spectral amplitude, longer mean duration, and lower mean frequency than physiological-induced HFO.[18,19]
Perhaps there are different mechanisms for ripple and FRs in epilepsy.[2,20] FRs represent field potentials of population spikes from clusters of abnormal synchronously bursting neurons, in contrast to ripples, which represent field potentials of summated inhibitory postsynaptic potentials.[21] The average duration of every FRs was shorter in SOZ than in NSOZ during both interictal and preictal period. Maybe neurons producing the FRs focused on a limited area may cause shorter average duration in the SOZ.
Seizure onset zone is the area where a seizure originates.[22] HFOs are related to epilepsy. More and more burst of HFOs, especially FRs, means the onset of seizures. HFOs, especially FRs are linked to SOZ in neocortical epilepsy.
ACKNOWLEDGMENTS
We gratefully acknowledge three grants that supported this work, one (no. z121107001012007) from Beijing Municipal Science and Technology Commission, one (no. 2009-1052) from the Capital Health Research and Development of Special foundation, another from domestic visiting scholar program in higher education institution of Shandong province. We thank Professor G. van Luijtelaar (Radboud University Nijmegen, Netherlands) for revising the manuscript.
Footnotes
Edited by: De Wang and Ya-Lin Bao
Source of Support: We gratefully acknowledge three grants that supported this work, one (no. z121107001012007) from Beijing Municipal Science and Technology Commission, one (no. 2009-1052) from the Capital Health Research and Development of Special foundation, another from domestic visiting scholar program in higher education institution of Shandong province. We thank Professor G. van Luijtelaar (Radboud University Nijmegen, Netherlands) for revising the manuscript.
Conflict of Interest: None declared.
REFERENCES
- 1.Zijlmans M, Jacobs J, Kahn YU, Zelmann R, Dubeau F, Gotman J. Ictal and interictal high frequency oscillations in patients with focal epilepsy. Clin Neurophysiol. 2011;122:664–71. doi: 10.1016/j.clinph.2010.09.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Jefferys JG, Menendez de la Prida L, Wendling F, Bragin A, Avoli M, Timofeev I, et al. Mechanisms of physiological and epileptic HFO generation. Prog Neurobiol. 2012;98:250–64. doi: 10.1016/j.pneurobio.2012.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jacobs J, Zelmann R, Jirsch J, Chander R, Dubeau CE, Gotman J. High frequency oscillations (80-500 Hz) in the preictal period in patients with focal seizures. Epilepsia. 2009;50:1780–92. doi: 10.1111/j.1528-1167.2009.02067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Engel J, Jr, Wilson C, Bragin A. Advances in understanding the process of epileptogenesis based on patient material: What can the patient tell us? Epilepsia. 2003;44 Suppl 12:60–71. doi: 10.1111/j.0013-9580.2003.12002.x. [DOI] [PubMed] [Google Scholar]
- 5.Frost JD, Jr, Lee CL, Le JT, Hrachovy RA, Swann JW. Interictal high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis. 2012;46:377–88. doi: 10.1016/j.nbd.2012.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jacobs J, Staba R, Asano E, Otsubo H, Wu JY, Zijlmans M, et al. High-frequency oscillations (HFOs) in clinical epilepsy. Prog Neurobiol. 2012;98:302–15. doi: 10.1016/j.pneurobio.2012.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bragin A, Engel J, Jr, Wilson CL, Fried I, Buzsáki G. High-frequency oscillations in human brain. Hippocampus. 1999;9:137–42. doi: 10.1002/(SICI)1098-1063(1999)9:2<137::AID-HIPO5>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
- 8.Jacobs J, Zijlmans M, Zelmann R, Chatillon CE, Hall J, Olivier A, et al. High-frequency electroencephalographic oscillations correlate with outcome of epilepsy surgery. Ann Neurol. 2010;67:209–20. doi: 10.1002/ana.21847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Andrade-Valença L, Mari F, Jacobs J, Zijlmans M, Olivier A, Gotman J, et al. Interictal high frequency oscillations (HFOs) in patients with focal epilepsy and normal MRI. Clin Neurophysiol. 2012;123:100–5. doi: 10.1016/j.clinph.2011.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lévesque M, Bortel A, Gotman J, Avoli M. High-frequency (80-500 Hz) oscillations and epileptogenesis in temporal lobe epilepsy. Neurobiol Dis. 2011;42:231–41. doi: 10.1016/j.nbd.2011.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Usui N, Terada K, Baba K, Matsuda K, Nakamura F, Usui K, et al. Clinical significance of ictal high frequency oscillations in medial temporal lobe epilepsy. Clin Neurophysiol. 2011;122:1693–700. doi: 10.1016/j.clinph.2011.02.006. [DOI] [PubMed] [Google Scholar]
- 12.Staba RJ, Frighetto L, Behnke EJ, Mathern GW, Fields T, Bragin A, et al. Increased fast ripple to ripple ratios correlate with reduced hippocampal volumes and neuron loss in temporal lobe epilepsy patients. Epilepsia. 2007;48:2130–8. doi: 10.1111/j.1528-1167.2007.01225.x. [DOI] [PubMed] [Google Scholar]
- 13.Malinowska U, Bergey GK, Harezlak J, Jouny CC. Identification of seizure onset zone and preictal state based on characteristics of high frequency oscillations. Clin Neurophysiol. 2014;(x):xxx–xxx. doi: 10.1016/j.clinph.2014.11.007. (available online) [DOI] [PubMed] [Google Scholar]
- 14.Siapas AG, Wilson MA. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron. 1998;21:1123–8. doi: 10.1016/s0896-6273(00)80629-7. [DOI] [PubMed] [Google Scholar]
- 15.Bragin A, Engel J, Jr, Staba RJ. High-frequency oscillations in epileptic brain. Curr Opin Neurol. 2010;23:151–6. doi: 10.1097/WCO.0b013e3283373ac8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kucewicz MT, Cimbalnik J, Matsumoto JY, Brinkmann BH, Bower MR, Vasoli V, et al. High frequency oscillations are associated with cognitive processing in human recognition memory. Brain. 2014;137:2231–44. doi: 10.1093/brain/awu149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Worrell G, Gotman J. High-frequency oscillations and other electrophysiological biomarkers of epilepsy: Clinical studies. Biomark Med. 2011;5:557–66. doi: 10.2217/bmm.11.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Matsumoto A, Brinkmann BH, Matthew Stead S, Matsumoto J, Kucewicz MT, Marsh WR, et al. Pathological and physiological high-frequency oscillations in focal human epilepsy. J Neurophysiol. 2013;110:1958–64. doi: 10.1152/jn.00341.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kondylis E, Zenonos G, Richardson M. High-frequency oscillations as discreet markers of cognitive processing. Neurosurgery. 2014;75:N14–6. doi: 10.1227/01.neu.0000454757.91754.d5. [DOI] [PubMed] [Google Scholar]
- 20.Köhling R, Staley K. Network mechanisms for fast ripple activity in epileptic tissue. Epilepsy Res. 2011;97:318–23. doi: 10.1016/j.eplepsyres.2011.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Engel J, Jr, Bragin A, Staba R, Mody I. High-frequency oscillations: What is normal and what is not? Epilepsia. 2009;50:598–604. doi: 10.1111/j.1528-1167.2008.01917.x. [DOI] [PubMed] [Google Scholar]
- 22.Jacobs J, Levan P, Châtillon CE, Olivier A, Dubeau F, Gotman J. High frequency oscillations in intracranial EEGs mark epileptogenicity rather than lesion type. Brain. 2009;132:1022–37. doi: 10.1093/brain/awn351. [DOI] [PMC free article] [PubMed] [Google Scholar]