peri-ictal and interictal, intracranial infraslow...

INVITED REVIEW

Peri-Ictal and Interictal, Intracranial Infraslow Activity

Tawnya Constantino* and Ernst Rodin†

Summary: It is widely assumed that the recording of EEG infraslow activity(ISA) requires direct current amplifiers. Yet, it has been shown during the pastdecade that conventional EEG systems can record activity between 0.01 and0.1 Hz and that this frequency band contains additional information,especially in regard to seizure onset. To delineate the characteristics ofbackground ISA, 24-hour scalp and intracranial recordings obtained from5 patients during long-term monitoring were investigated. Scalp recordingshad been sampled but intracranial tracings were continuous over periods of upto 3 days. Although scalp recordings were subject to artifact, intermittentgenuine ISA increase could occur episodically in the interictal state not onlydistant from the ictal onset zone but also in the contralateral hemisphere.Intracranial recordings were limited, in this study, to portions of onehemisphere but likewise revealed that distant areas could show ISA increaselasting minutes or hours. This was at times not detectable when only theconventional frequency band was viewed. It is concluded that ISAinformation is contained in the clinical setting of intensive video-monitoringstudies for the detection of the epileptogenic zone and can provide additionalinformation above and beyond what is seen in the conventional frequencies.

Key Words: EEG epilepsy monitoring, Infraslow preictal, Infraslow inter-ictal, Infraslow sleep recording, Seizure prediction.

(J Clin Neurophysiol 2012;29: 298–308)

Among the advantages digital EEG has provided over the formerlyused analog EEG systems is the ability for post hoc changes ofthe acquired data. Furthermore, because digital systems no longerhave a fixed time constant of 0.3 seconds, slower frequencies areroutinely recorded and these can be recovered during data analysis bychanges of filter settings. This has allowed the emergence of infor-mation, which previously could only be obtained with direct currentamplifiers (DC) amplifiers. Ikeda et al. (1996, 1999) were the firstinvestigators to demonstrate that, what is commonly referred to as,“DC shifts” can be recorded from the scalp and intracranially witha widely used commercial EEG system (Nihon Kohden), which hasan input filter of 0.016 Hz. The observation was subsequently con-firmed by several authors (Bragin et al., 2005; Hughes et al., 2005;Mader et al., 2005; Fell et al., 2007; Rodin and Modur, 2008; Rodinet al., 2008, 2009; Shi et al., 2012). They also noted, in agreementwith Ikeda et al. (1996, 1999), that these shifts have a smaller elec-trical field than conventional frequencies and may therefore haveclinical utility in delineating the epileptogenic zone. There was only

one report (Gross et al., 1999) that raised a serious question aboutclinical usefulness because the shifts, as recorded from stainless steeldepth electrodes, were encountered infrequently and at times unrelatedto the seizure onset zone as identified by the conventional frequencyband.

Although ictal onset baseline shifts are being recorded byconventional EEG systems because a time span of seconds ratherthan minutes is involved, Vanhatalo et al. (2003, 2010) have empha-sized that accurate recording of these shifts require DC amplifiers.These authors have also pointed that the recording of backgroundsleep infraslow activity (ISA), defined as 0.02 to 0.2, require DCamplifiers (Vanhatalo et al., 2004), which this article will refute.Although the commonly used EEG systems can attenuate amplitudesand shorten the duration of wave forms below the specified inputfilter, when compared with DC systems, they do not alter the topog-raphy of events, which is the most important aspect for clinicians(Rodin et al., 2006).

Review of the existing literature on ISA shows that theliterature largely dealt with ictal baseline shifts, and information oninterictal ISA is currently missing. Yet these frequencies may also beimportant in a thorough assessment of the “epileptogenic zone.” It isa well-known fact that the results of surgical removal of epilepto-genic tissue tend to decay over time (de Tisi et al., 2011; Geller andDevinsky, 2006; Keogan et al., 1992; Moretti Ojemann and Jung,2006; Tanriverdi et al., 2008; Wieser et al., 2003) and even patientswho have enjoyed complete cessation of seizures may relapse whenanticonvulsant medications are withdrawn (Schmidt et al., 2004).This indicates that additional epileptogenic tissue remains undetectedwith currently used methods. In addition, efforts are being made byusing a variety of algorithms to predict when a seizure might occur.These results have so far not been very satisfactory because initialpromising observations were frequently not reproducible (Carneyet al., 2011; Hughes, 2008; Minasyan et al., 2010; Mormann et al.,2007). To address the possibility that ISA might provide additionalinformation in regard to these questions, the current preliminaryinvestigation was undertaken.

METHODSThe records of five consecutive patients who had undergone

long-term intracranial video-monitoring to further define the epilep-togenic zone were investigated. Previously archived data from scalprecordings were also available in four of them, and the EEG systemwas provided by XLTEK, which has an input filter 0.05 Hz. Thesampling rate for intracranial data was 512 Hz and 256 Hz for scalpdata. Intracranial strip and grid electrodes were of platinum(Ad-Tech Medical Instruments, Racine, WI), whereas the scalpelectrodes were of Ag/AgCl. Electrode coverage for intracranialrecordings ranged from 26 to 58 electrodes. Grids and strips hadbeen placed according to seizure semiology, interictal scalp data, andin four instances magnetoencephalography recordings and radiologicinformation. Electrode placement was always unilateral and limited

From the *Division of Neurology, Intermountain Medical Center, NeuroscienceInstitute, Murray, Utah, U.S.A.; and †Department of Neurology, University ofUtah, Salt Lake City, Utah, U.S.A.

Presented at American Clinical Neurophysiology Meeting, February 2012,San Antonio, TX.

Address correspondence and reprint requests to Tawnya Constantino, MD,Division of Neurology, Intermountain Medical Center, NeurosciencesInstitute, South Office Building, Suite 810, Murray, UT 84107, U.S.A.;e-mail: [email protected].

Copyright � 2012 by the American Clinical Neurophysiology SocietyISSN: 0736-0258/12/2904-0298

298 Journal of Clinical Neurophysiology � Volume 29, Number 4, August 2012

to the side of the suspected seizure origin. Scalp recordings wereobtained from 26 electrodes, which included T1/T2 and IO1/IO2 leads.

For intracranial recordings, the de-identified video and EEGdata for each day were placed separately on an external drive andsubsequently analyzed with the BESA software (MEGIS, Gräfelfing,Germany). Seizures were investigated for area of onset, with specialemphasis on the minute that preceded the occurrence of electricalchanges in the conventional frequencies (1 to 70 Hz). Thereafter, theindividual files were downsampled to 10 Hz to further assess preictaland interictal ISAs. The files were then viewed on the maximumwindow of 20 minutes. The high-pass filter of the software was leftopen and the low-pass filter was set to 0.1 Hz, which in all instancesrevealed pure ISA. To investigate whether consistent changes couldbe demonstrated that might herald a seizure 20 minutes before itsoccurrence, the data were also subjected to power spectral analysis.For these analyses, the raw data were used without software filters.

The reference electrode for the intracranial electrodes wasa needle electrode inserted into the temporalis muscle. This resultedfrequently in contamination of the interictal recordings and they were,therefore, routinely transformed to an average common reference of allartifact-free channels. Interictal scalp recordings showed motor/musclemovement and eye movement artifact to such an extent that reliableinterpretation of the waking state data was not possible and only sleepdata that were artifact free were evaluated. Scalp recordings were alsoreformatted to an average common reference montage.

Clinical or subclinical seizures occurred 21 times duringintracranial recording periods ranging up to 3 days. Partial seizureswere seen in 20 instances, and 1 patient had a tonic seizure characterizedby extension of both arms. During scalp recordings, 14 partial and 1tonic–clonic seizures were recorded over a period of up to 7 days.During scalp recordings, 14 partial seizures were found and analyzed.In contrast to intracranial recordings, those from the scalp were notcontiguous because they had been obtained at various times beforethe start of this investigation and archived data had to be used. Interictalepochs of only 1-minute duration had been saved except for epochswhen a “patient event” had occurred. In these instances, 35 minutes ofdata were available. The clinical characteristics of the patients and theareas of intracranial electrode coverage are shown in Table 1.

RESULTS

Preictal Intracranial RecordingsThe determination of the precise moment of seizure onset can

at times be difficult even for experts in EEG. In the current study,this was facilitated in four patients because their seizures were

accompanied by high-frequency gamma activity and ictal onsetbaseline shifts in one or more channels when appropriate filtersettings were used. In the remaining patients, all seizures wereinitiated by a series of spikes that terminated in typical rhythmicseizure discharges in that electrode. In all instances, electrical seizureonset preceded clinical phenomena by several seconds.

When the viewing window was expanded to 1 minute fromseizure onset and the preceding minutes studied with open high-pass and a low-pass filter of 0.1 Hz, an increase in the usualbackground ISA was discernible in all but one seizure. An examplefor seizure onset (case 2 in the table), as seen by conventionalfrequencies and with open filters for a 1-minute segment, is shownin Figs. 1A and 1B as recorded on an average reference montage.The data consist of four 4-contact right-sided subtemporal stripsarranged from most anterior to most posterior (channels 1 to 16),and channels 17 to 26 reflect a lateral anterior temporal 5 · 2-strip.Electrode 1 was situated most anterior inferior (channel 17) at thetemporal pole and channel 22 its anterior superior counterpart.Channels 21 and 26 were recorded from the most posterior electro-des of the strip. With conventional filter settings (1 to 70 Hz,Fig. 1A), seizure onset was characterized by initial attenuation ofactivity in most channels, as demonstrated by the “marker,” and thehighest amplitude rhythmic discharges later during the seizure werein channel 7. When the high-pass filter was removed, several base-line shifts became apparent during the attenuation phase and ofeven higher amplitude in the lateral temporal strips, where phasereversals could also be observed at the beginning of rhythmicactivity. The earliest highest negative shifts were in channels 13and 14, which recorded from the most medial electrodes of themost posterior subtemporal strips. The amplitude at channel 13was 887 mV and for the highest deflection during the onset ofrhythmic activity in channel 23 was 2.5 mV.

When the viewing window was expanded to 20 minutes, theconventional frequency band, as shown in Fig. 2A, provided nofurther information. But when ISA was evaluated with an openhigh-pass filter and a 0.1 Hz low-pass filter (Fig. 2B), it wasapparent that a prolonged increase in amplitude was present inthe most anterior subtemporal strip. It started 11 minutes beforethe conventional seizure onset, and in its most lateral contact (chan-nel 4), it continued throughout the seizure into the postictal state. Itis also noteworthy that the lateral temporal strip showed earlyphase reversals. These were initially in channels 19 and 20, sub-sequently in channels 18 and 19, and just before conventionalseizure onset between channels 22 and 23. The amplitude at chan-nel 22 was 2.6 mV and toward the end of the seizure, the amplitudein channel 21 was 4.9 mV.

TABLE 1. Clinical Profile of Patients

PatientAge

(years)/GenderSeizure

SemiologyScalp EEG

(ictal) MRI MEGIC EEG(ictal)

1 48/F Temporal L F-T Cerebellar atrophy L MT L MT2 20/F Temporal R temporal Normal R temporal R MT3 33/M Temporal L temporal Previous T lobectomy L inf. F, L temporal L temporal

L ant. cingulate4 32/F Temporal L C-T Left frontal encephalomalacia L frontal L temporal

(insula)Multiple cav. Mal.5 29/M Temporal L F-T Small L hem. L MT L MT

R, right; L, left; F-T, fronto-temporal; C, central; T, temporal; MT, mesial temporal; MEG, magnetoencephalography; IC, intracranial; M, male; F, female; Multiple cav. Mal.,multiple cavernous malformations; Small L hem., small left hemisphere.

Journal of Clinical Neurophysiology � Volume 29, Number 4, August 2012 Interictal, Intracranial Infraslow Activity

Copyright � 2012 by the American Clinical Neurophysiology Society 299

FIG. 1. A, Subdural strip recordings of the onset of a partial seizure in patient 2. Total display time is 1 minute, vertical stripesdelineate 1 second, calibration bar ¼ 500 mV. Filter setting 1 to 70 Hz. Electrode array: first 16-channel 4 subtemporal strips fromthe anterior to the middle temporal lobe; channels 17 to 26, 5 · 2 lateral anterior temporal strip. The seizure starts withattenuation of activity at the marker. B, Same data but filter setting changed; high-pass filter open and low-pass filter set to 0.1 Hz.Several early baseline shifts are present during the attenuation phase and of higher amplitude at the time of rhythmic seizureonset. Amplitude at channel 13 was 887 mV and 2.5 mV at channel 23.

T. Constantino and E. Rodin Journal of Clinical Neurophysiology � Volume 29, Number 4, August 2012

300 Copyright � 2012 by the American Clinical Neurophysiology Society

FIG. 2. A, Same patient, same seizure but on a 20-minute window. Vertical stripes delineate 10 seconds. Filter settings 1 to3.3 Hz. The seizure is at the end of the display window. Calibration bar ¼ 300 mV. B, Same data but high-pass filter open and low-pass filter set to 0.1 Hz. Calibration bar ¼ 1 mV. Infraslow activity buildup most marked in the first (most anterior) subtemporalstrip that starts 11 minutes before conventional seizure onset. At higher amplifications, still earlier involvement of the inferiorelectrodes of the lateral temporal strip was seen. Amplitudes of early activity in channel 20 (note the phase reversal with channel19) 1.2 mV, channel 4 at onset 1.3 mV, channel 22 immediately before conventional electrical seizure onset 2.6 mV, and channel21 before the end of the seizure 4.9 mV.



Preictal Scalp RecordingsFor this aspect of the study, reliable data were severely limited

because, in all but one instance, seizures arose from the waking stateand the onset was contaminated by artifacts. In the seizure, whicharose from sleep, an increase in ISA background amplitudes wasobserved 4 minutes before conventional electrical seizure onset.Because of the limited case material and inasmuch as othermanuscripts in this issue deal with this topic, it was not furtherinvestigated.

Interictal Intracranial Raw DataWhen the high-pass filter was left open and the low-pass filter

was set to 0.1 Hz, interictal background ISA amplitudes variedconsiderably between channels and between patients. Furthermore,there was a difference in regard to the waking and sleeping states.A typical example from the patient whose ictal data have been shownin the previous figures is presented in Figs. 3A and 3B for a20-minute epoch. The data were obtained on a day when no clinicalor subclinical seizures had occurred. As Fig. 3A demonstrates, back-ground activity ranged from 105 mV (channel 3) to 315 mV (channel15) in the waking state and 46 to 151 mV for the same channelsduring sleep, Fig. 3B. From this background emerged intermittentlyhigher amplitude activity ranging from100 mV up to 3 mV in a wax-ing and waning manner when the raw data were viewed on screensshowing 20 minutes. These increases in activity could be limited toone channel in various portions of the file but frequently involvedtwo or more neighboring electrodes and at times even all of theavailable electrodes. When only one channel was involved, electrodeartifact had to be considered. But the classic “electrode pops” wereclearly discernible as a sudden high-amplitude, 14 to 30 mV, mono-phasic or biphasic sequence that returned to the baseline withinapproximately 80 seconds.

In these five cases, ISA amplitude increase was not limited, inall but one patient, to a discrete area that could be regarded as theepileptogenic zone but also occurred independently in distant stripsor grids. It could last several minutes up to 2.5 hours. A 20-minuteexample is shown in Fig. 4A with conventional filter settings andFig. 4B for ISA. The patient was asleep at the time, and the con-ventional filter settings did not reveal diagnostic changes. The cor-responding ISA in Fig. 4B, however, showed marked discharges inthe lateral temporal 5 · 2-strip (channels 17–26), which appeared toprogress from the anterior inferior tip to the superior row of electro-des. The highest discharge in channel 24 had amplitude of 2.9 mV.

This local increase in amplitudes was usually unrelated toclinical or subclinical seizures, although in two instances the eventbutton was pressed by the patient during these discharges because ofthe subjective awareness of a possible seizure. But since inspectionof the conventional frequency band had failed to reveal obviouschanges in the recording, it was regarded as a false alarm.

Figures 5 and 6 show examples of interictal ISA increase inpatient 5 and demonstrate that the previous examples were not anisolated finding. The recording electrode array was similar to case 2but an additional 4-contact strip had been placed on the inferiorfrontal gyrus (channels 27 to 30). Although Fig. 5 shows highestactivity in the second subtemporal strip, it is highest in the first onein Fig. 6. In both instances, there is spread to other strips, includingthe frontal one. Seizure onset, as determined by conventional fre-quencies and baseline shifts, was in the most medial contacts of thefirst and second subtemporal strip. These findings are typical forwhat can be expected when long-term recordings are available andthe software filters are set to record pure ISA.

Power Spectral Analysis for Preictal and InterictalIntracranial Data

When only the first seizure of the day, which had lasted atleast 50 seconds, was considered, the power for a 1-minute segment,starting with seizure onset, ranged from 404 mV2 to a maximum of110,414 mV2. The data are, however, better appreciated in the con-text of background activity when the seizure was placed in thecenter of a 20-minute window. Tables 2 and 3 present the results of20-minute epochs for the waking state, the seizure epoch, and mid-night sleep. Table 2 deals with patients 1, 2, and 4, whereas table 3shows the results from patients 3 and 5. The data were separatedbecause, as will be seen, the values for the patients in Table 3differed for unknown reasons, by a factor of 10, from those in Table2 and only the ictal days are shown. For the other three patientsadditional data for a day when no seizure had occurred are alsopresented. Although the absolute values for patients 3 and 5, asshown in Table 3, are not meaningful, it will be seen that the relativedistributions are similar to the ones in Table 2. The first column ofthe tables shows in the top row the state of the patient and the time ofthe start of the 20-minute epoch, the next three columns show thepower in square micovolts, and in the fourth column, the range offrequencies is observed. The bottom row shows the number of chan-nels involved in each of these power bands and provides informationon spread of ISA increase. Although the seizures were partial, it isapparent that power was markedly increased in the ictal state notonly in absolute values but also in the number of channels involved.Contrary to expectations, it was decreased during sleep as comparedwith the waking state. Furthermore, Table 2 shows that midnightsleep power was even lower during the interictal than on the ictalnight.

The data were also investigated for the 20-minute preictal andsubsequent postictal period and for possible differences betweenmidnight and early morning sleep. There was, however, only onepatient (2) who had a tonic seizure in this group, whereas the othershad only features of automatic behavior. In this patient, a preictalpower buildup was noted, which persisted into the postictal epoch.This did not occur in the other patients. There were suggestivedifferences between midnight and early morning sleep, with thelatter showing more power, at times approaching the waking levels,but the current data were insufficient to make a conclusive statement.

Interictal Scalp DataBecause these data were not from contiguous EEG epochs and

waking portions were in part contaminated by artifact, only the sleepdata will be presented. With windows of 10 to 20 minutes,background activity had amplitudes ranging from 5 to 20 mV indifferent channels, and it was usually highest in the anterior quadrantbilaterally. From this background arose intermittently higher ampli-tude discharges (50 to 150 mV) lasting several minutes that usuallywere also maximal in the frontotemporal areas. Although grid andstrip implantation was on the left in these four patients, the scalpamplitude increases were always bilateral and could be higher on theside contralateral to the intracranial data.

DISCUSSIONAlthough this was a preliminary study and as such had

limitations, which will be discussed later, it showed what the clinicalelectroencephalographer can expect to see in archived data, when thehigh-pass filter is left open and the low-pass filter is set to 0.1 Hz. In



FIG. 3. A, Same patient interictal background activity in the waking state. Calibration bar ¼ 200 mV; 20-minute epoch, high-passfilter open and low-pass filter set to 0.1 Hz. Amplitudes range from 105 to 315 mV. B, Same patient interictal background duringmidnight sleep. Same amplifications and filter settings as in (A). The amplitude of background activity is considerably reduced andranges from 36 to 151 mV.



FIG. 4. A, Same patient, another 20-minute interictal epoch during early morning sleep. Calibration bar ¼ 500 mV. High-passfilter set to 1 Hz and low-pass filter set to 3.3 Hz; the tracings appear unremarkable. B, Same epoch but high-pass filter open andlow-pass filter 0.1 Hz. Calibration signal ¼ 1 mV. Marked infraslow activity increase is apparent, which initially involves the lateraltemporal strip electrodes but subsequently spreads to the most anterior subtemporal strip. Maximum amplitude in channel 18 is2 mV and in channel 24 is 2.9 mV.



FIG. 5. Interictal 20-minute epoch from patient 5. High-pass filter open and low-pass filter set to 0.1 Hz. Calibration bar ¼ 200 mV.Same electrode array as in patient 1 but the additional channels labeled “clear” record activity from a lateral inferior frontal gyrusstrip. Infraslow activity buildup is most pronounced in channel 6, 580 mV, but present with lower amplitudes also in other strips.

FIG. 6. Another 20-minute interictal epoch from the same patient with the same amplifications and same filter settings.Infraslow activity increase is highest in the most mesial contact of the most anterior subtemporal strip, 600 mV, but involves inaddition portions of all the other strips.



addition, it provided new information, on which further investiga-tions can be based. The most important observation was thatcurrently used EEG systems, even with an input filter of 0.05 Hz,can reveal aspects of ISA that are not apparent when only theconventional frequency band is used. As mentioned in theIntroduction, this fact was known for ictal activity but had notpreviously been demonstrated for interictal data. The study has alsoshown that from a lower-amplitude interictal ISA background,higher-amplitude waves in the infraslow range can arise, which arenot merely in proximity to the epileptogenic zone, as defined byseizure onset in the conventional frequency band, but can also occurin more distant areas. Although one may have to disregard a buildupas artifact when only one electrode contact is involved, this isunlikely when it occurs in neighboring electrodes of the same orneighboring strips. These observations are most reliable for

intracranial data and may well reflect a larger potentially epilepto-genic network (Bertram, 2003). This may be one of the reasons forthe previously mentioned decay of surgical results when long-termfollow-up studies are performed. But this cannot be appreciated withthe conventional frequency bands and is only detected when ISA isadded to the evaluation of the data.

The observation that background ISA was decreased duringsleep, rather than increased, was likewise unexpected. Yet it was notartifact due to small sample size but constituted a genuine findingbecause it has also been seen in another case where bilateralhippocampal depth electrodes had been inserted via occipital burrholes (Shi et al., 2012). Furthermore, Picchioni et al. (2011) haveshown in a combined EEG/functional magnetic resonance imagingstudy that sleep ISA did not correspond to what was seen in the deltaand subdelta (defined as 0.55 to 0.99 Hz) bands. A similar

TABLE 2. Comparison of ISA Power Spectra for Ictal and Interictal State (Waking and Asleep) on a Day When a Seizure HadOccurred and Interictal Waking and Sleep Activity on a Seizure-Free Day

Clinical State Power in mVsq Frequency Range

Patient 1Ictal dayAwake 85 159–985 1000–1786 .10000 0.00–0.02Hz

2 43 11 0Ictal 0 289–970 1012–6763 0.00

16 40 0Sleep 31–84 101–556 0.00–0.1

14 41 0 0Interictal dayAwake 32–94 135–868 1222–1564 0.00–03

26 30 2 0Sleep 17–96 107–481 0.00–0.1

41 16 0 0Patient 2

Ictal dayAwake 53–76 190–555 1415–1864 0.00–0.05

2 22 2 0Ictal 2494–9509 10410–40329 0.00–0.01

0 0 18 7Sleep 27–94 118–915 1156–2888 10385 0.00–0.01

7 12 6 1Interictal dayAwake 18–79 125–595 1049–1221 0.00–.007

6 17 3 0Sleep 11–77 106–118 2803 0.00–0.06

23 2 1 0Patient 4

Ictal dayAwake 25–97 197–820 2623–5968 0.00–0.08

31 11 2 0Ictal 248–930 1020–8574 10142–18568 0.00

0 13 35 2Sleep 01:28 17–89 100–602 0.00–0.09

34 16 0 0Interictal dayAwake 22–94 101–519 1341–1372 0.00–0.09

27 38 2 0Asleep 00:12 19–80 103–655 1957–2855 0.00–0.09

42 7 2 0

The first column shows the clinical state. In the second column, the top line shows the power for the ranges between 0 and 100 mVsq, 101 and 999 mVsq, 1000 and 9999 mVsq, and.10,000 mVsq. The numbers underneath show how many channels of the record these values were present, during that epoch. The third column gives the ISA frequency range fromminimum to maximum. In all instances, power is always highest and more widely distributed in the ictal than interictal state and lower during sleep than awake.



discrepancy was also observed for background multiple unit activityin experimental animals. It was increased in the waking state andmore markedly during seizures, whereas it was decreased duringslow wave sleep and increased again in the rapid eye movementsleep stage (Rodin et al., 1973). These observations provide addi-tional evidence that the extreme low- and extreme high-frequencybands reflect different neurophysiologic mechanisms from those thatare responsible for the conventional frequencies (Vanhatalo et al.,2010; Voipio et al., 2003). The data may also be analogous to theobservation by Caspers and Schulze (1959) in regard to the steadycortical potential, recorded with DC amplifiers. It became more neg-ative in the waking state, increased further during activity, and evenmore so during seizures; it became positive with increasing depth ofsleep.

The finding that ISA preceded seizure onset in case 2 by11 minutes is additional confirmation of previous literature reports.Ren et al. (2011) had noted in three patients that ISA buildup hadpreceded seizure onset from 8 to 22 minutes, and Federico et al.(2005) had detected functional magnetic resonance imaging changesin 3 cases ranging from 3 to 11 minutes before the seizure. Litt et al.(2001) had reported in five patients that “burst activity” could beseen seven hours before a seizure and accumulated energy increased50 minutes before seizure onset. These data also have relevance forthe problem of the prediction when a given seizure may occur,which, as mentioned previously, has recently received a great dealof attention. Up to now, studies on seizure onset prediction havebeen based on the conventional frequency band and have not yieldedreliable, reproducible results. Since, as presented here, ISA powershows marked regional waxing and waning in the interictal statelasting at times for more than an hour, which did not lead to a seizure,future algorithms for seizure prediction should include the assess-ment of ISA. It might be advisable to proceed initially with intra-cranial data, which have fewer artifacts, and they can subsequentlybe validated on scalp recordings.

Scalp data have to be used, however, with considerablecircumspection. Not only because of excess of movement artifact,and especially eye movement artifact, but even during sleep lateraleye movements can persist, which can make interpretation of sleep

recordings difficult. This applies especially to studies that rely onfrequency spectra because these cannot distinguish polarity. Never-theless, when raw data were examined, it was apparent that althoughout-of-phase activity did occur in the anterior temporal regions,which could extend to the T7/T8, A1/A2 contacts, in phasedischarges were likewise seen with higher amplitudes on one sidethan the other. Although in the current study, these patients wereregarded as having had unilateral left temporal lobe disease, shiftinginterictal higher amplitude right temporal ISA was also observed inthree of the cases and in one instance independent frontal lobeinvolvement could be seen. To what extent this finding may beimportant clinically will depend on long-term follow-up of patientswhose presumed epileptogenic area, based on conventional frequen-cies, has been surgically removed.

Inasmuch as our data were not obtained from a specificallydesigned research project but resulted from inspection of clinicallyobtained material, they had, by necessity, several limitations. Ofthese, the most important was intracranial electrode coverage. It hadbeen based on previous clinical information, and in all instanceselectrodes had been implanted unilaterally. They were usuallycentered on one lobe and although the basal temporal areas wereexplored in all instances, no information was available from thebasofrontal regions or the island of Reil. Nevertheless, thesestructures are known to be of importance in epileptogenesis, andbecause ISA has a smaller electrical field than conventionalfrequencies (Gumnit and Takahashi, 1965), valuable informationmay have been missed. Even in scalp recordings, only T1/2 ratherthan the complete inferior row of the 10/10 system had been avail-able although infraorbital electrodes had been placed, which pro-vided some information on basofrontal activity.

Another potential limitation was the input filter of theamplifiers at 0.05 Hz, which attenuated slower activity. As such,the values for amplitudes and power are to be regarded as minima.The values in the three cases where there were no technical problemsagree, however, with previously published ones obtained on a NihonKohden system and even with those reported by Kim et al. (2009)who had assessed ictal onset baseline shifts with DC amplifiers. Intheir study of 11 patients, the baseline shift values ranged from800 mV to 3.4 mV, with one outlier at 10 mV.

The software that was used in this study also had limitationsnot only in regard to the viewing window, which covered atmaximum 20 minutes, but also in regard to filter settings. For rawdata viewing, the lower limit was 0.001 Hz before the systemautomatically reset to the default value of 0.5 Hz. For spectralanalysis, the lower limit was 0.00 Hz but as can be seen in thisstudy, as well as a previous one (Rodin and Modur, 2008), powerspectra are at times maximal at the lowest point, indicating thepresence of still slower frequencies. In addition there is the problemof electrode polarization. Although Ag/AgCl electrode material forscalp electrodes and platinum for intracranial recordings reducepolarization effects, they may not abolish them and this is whyintermittent slow wave activity, which is not clearly electrode arti-fact, may or may not be trustworthy when it appears in only onechannel at a time. Yet as mentioned above, despite these limitations,this investigation can be regarded as a starting point for future stud-ies, which deal with the area(s) of potential epileptogenicity inpatients who have no demonstrable anatomic lesion.

As mentioned, the clinical significance of the larger thanexpected extent of intermittent interictal ISA buildup is at presentunclear but may well be important in relation to long-term seizurefreedom after surgical resections of suspected epileptogenic brain tissue.Since these data are archived in laboratories that carry out intensive

TABLE 3. Comparison of ISA Power Spectra for Ictal andInterictal State (Waking and Sleep) in Patients 3 and 5

Clinical State Power in mVsq Frequency Range

Patient 3Awake 2–9 10–45 416 .1000 0.02–0.1

17 12 1 0Ictal 8–9 12–57 101–106 0 0.01–0.1

2 26 2 0Sleep 4–9 12–84 0 0.02–0.1

6 24 0Patient 5

Awake 5–8 13–58 124–445 0 0.02–0.1Hz9 17 3 0

Ictal 13–81 120–220 0 0.06–0.10 25 4

Sleep 2–6 14–50 0 0.02–0.115 14 0 0

The format is the same as in Table 2, but for unknown reasons (technical?), thepower values were apparently reduced by a factor of 10 in contrast to those of Table 2.Nevertheless, the relationship in terms of highest values and number of channels in-volved in the ictal state and the decrease of power during sleep is preserved.



monitoring of seizure patients, long-term follow-up studies of operatedpatients should now be undertaken to investigate the presumed “epilep-togenic zone” not only in relation to the conventional frequency bandbut also ISA. Furthermore, the fact that ISA can be recorded on a long-term basis from intracranial recordings, with conventional EEG ampli-fiers, should encourage basic scientists to include these frequencies intheir studies of experimental animals not only in regard to seizuregenesis but also their relationship to underlying mechanisms. Inasmuchas ISA is a physiologic concomitant of cerebral electrical activity, itsinclusion in the study of normal electromagnetic phenomena, and otherpathologic entities, apart from epilepsy, is also warranted.

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peri-ictal and interictal, intracranial infraslow...

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