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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Clin Neurophysiol. 2020 Oct 14;131(12):2781–2792. doi: 10.1016/j.clinph.2020.09.010

Effects of depth electrode montage and single-pulse electrical stimulation sites on neuronal responses and effective connectivity

Takumi Mitsuhashi 1,5,*, Masaki Sonoda 1,6,*, Hirotaka Iwaki 1,7, Aimee F Luat 1,2, Sandeep Sood 3, Eishi Asano 1,2,4,*
PMCID: PMC7704665  NIHMSID: NIHMS1638401  PMID: 33130438

Abstract

Objective:

To determine the optimal depth electrode montages for the assessment of effective connectivity based on single-pulse electrical stimulation (SPES). To determine the effect of SPES locations on the extent of resulting neuronal propagations.

Methods:

We studied 14 epilepsy patients who underwent invasive monitoring with depth electrodes and measurement of cortico-cortical evoked potentials (CCEPs) and cortico-cortical spectral responses (CCSRs). We determined the effects of electrode montage and stimulus sites on the CCEP/CCSR amplitudes.

Results:

Bipolar and Laplacian montages effectively reduced the degree of SPES-related signal deflections at extra-cortical levels, including outside the brain, while maintaining those at the cortical level. SPES of structures more proximal to the deep white matter, compared to the cortical surface, elicited greater CCEPs and CCSRs.

Conclusions:

On depth electrode recording, bipolar and Laplacian montages are suitable for measurement of near-field CCEPs and CCSRs. SPES of the white matter axons may induce neuronal propagations to extensive regions of the cerebral cortex.

Significance:

This study helps to establish the practical guidelines on the diagnostic use of CCEPs/CCSRs.

Keywords: pediatric epilepsy surgery, video EEG monitoring, electrocorticography (ECoG), stereo-electroencephalography (sEEG), effective connectivity, functional brain mapping, intracranial recording

1. Introduction

Invasive presurgical evaluation for patients with drug-resistant epilepsy includes the assessment of inter-regional effective connectivity, as rated by the extent of neuronal propagations induced by single-pulse electrical stimulation (SPES) via subdural or depth electrodes (Matsumoto et al., 2017). The magnitude of sharply-contoured neuronal responses to SPES is commonly quantified with cortico-cortical evoked potentials (CCEPs) and cortico-cortical spectral responses (CCSRs) with a latency of 11-50 ms (Matsumoto et al., 2004; Alarcón et al., 2012; Matsuzaki et al., 2013; Gkogkidis et al., 2017; Usami et al., 2019; Sugiura et al., 2020). Cortical sites showing such early near-field CCEP/CCSR components are inferred to have single-axonal effective connectivity from the SPES site (Matsumoto et al., 2007; Silverstein et al., 2020). Thereby, higher CCEP/CCSR magnitudes indicate more robust interregional effective connectivity (Silverstein et al., 2020). Many SPES studies suggest that early, near-field CCEP/CCSR components are useful to localize the eloquent pathways (Matsumoto et al., 2004; 2017; Nishida et al., 2017; Trebaul et al., 2018; Sugiura et al., 2020). Conversely, late CCEP/CCSR components with a latency of >100 ms may reflect either post-excitatory inhibitory responses, indirect responses via a cortico-thalamo-cortical propagation, or a mixture of both (Logothetis et al., 2010; van 't Klooster et al., 2011; Alarcón et al., 2012; Matsumoto et al., 2017). A study reported that SPES of the seizure onset zone (SOZ) elicited an early CCEP within 50 ms, deemed to be a physiological response, which was followed by a delayed high-frequency activity mimicking an interictal epileptiform discharge (van 't Klooster et al., 2011). The present study, while focusing on the early CCEP/CCSR components recorded on depth electrodes, determined the optimal analytic approach suitable for the assessment of inter-regional effective connectivity.

What electrode montage should be used for the clinical assessment of CCEPs and CCSRs recorded on depth electrodes? Using our empirical CCEPs and CCSRs recorded on stereo-electroencephalography (sEEG), we demonstrated what electrode montage is suitable to measure a near-field potential generated by a local cortical tissue receiving an SPES-induced propagation signal. We thereby assumed that the cerebral cortex is the source of CCEPs/CCSRs, whereas the structures outside the brain do not generate CCEPs/CCSRs. We defined a suitable montage as that on which CCEP/CCSR amplitudes are minimized at extra-cortical channels, particularly those outside the brain (Fig. 1). We tested the hypothesis that, on depth electrode recording, bipolar and Laplacian montages would be more suitable than common average reference montage (denoted as 'average montage' below). Bipolar and Laplacian montages were suggested to effectively eliminate the influence of electrical activities taking place at distant sources (also known as far-field potentials; Lachaux et al., 2003; Worrell et al., 2012; Tenke and Kayser, 2012).

Fig. 1. Definition of brain regions.

Fig. 1.

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A given depth contact was classified into one of the following anatomical categories: (a) deep white matter (light green), (b) shallow white matter (light blue), (c) gray matter (red), (d) cerebrospinal fluid space (yellow), and (e) outside the brain (black).

We then tested the hypothesis that SPES of white matter channels, compared to gray matter ones, would elicit CCEPs/CCSRs at more extensive regions. We also tested another hypothesis that cortical SPES via depth electrodes, compared to that via subdural electrodes, would likewise elicit CCEPs/CCSRs more extensively. The present study should be able to address these hypotheses since given depth electrodes typically sampled both cortex and white matter, and we employed the same stimulus intensity and pulse width within and across patients. A previous sEEG study reported that subcortical SPES elicited CCEPs with a 61% higher probability compared to cortical SPES (Trebaul et al., 2018). We expected that our CCEP/CCSR data recorded with sEEG electrodes, as well as those measured with a combination of depth and subdural disk electrodes, would provide the observations consistent with that reported in Trebaul et al., 2018.

2. Methods

2.1. Participants

The inclusion criteria included: (a) extraoperative intracranial electroencephalography (iEEG) recording at Children's Hospital of Michigan in Detroit between February 2013 and January 2019, (b) usage of depth electrodes, and (c) assessment of SPES-based effective connectivity. We performed all procedures as part of our routine presurgical evaluation, and the spatial extent and duration of iEEG recording and electrical stimulation were determined based on clinical demands (Asano et al., 2009; Matsumoto et al., 2017; Kambara et al., 2018; Silverstein et al., 2020). The Wayne State University Institutional Review Board has approved the present study. We obtained written informed consent from the legal parents or guardians of patients. We likewise received written assent from children older than 13, and oral assent from younger children.

2.2. Intracranial electrode placement

We placed intracranial electrodes for subsequent localization of the boundaries between the presumed epileptogenic zone and eloquent pathways using extraoperative iEEG recording, SPES-related neuronal responses, and electrical stimulation mapping (Nakai et al., 2017; Kambara et al., 2018; Silverstein et al., 2020; Sugiura et al., 2020). A total of three patients (patients #1 - #3 in Table 1) underwent bilateral sEEG recording; these patients had multicontact depth platinum electrodes implanted stereotactically under MRI guidance in both hemispheres. An anchor bolt tightly secured each sEEG depth electrode and minimized movement-related artifacts. Each depth electrode had eight, 12, and 16 contacts (length: 2 mm; center-to-center distance: 3.5, 3.5, and 4.43 mm, respectively; PMT, Chanhassen, MN, USA). The remaining 11 patients underwent an open craniotomy and had implantation of a combination of subdural (3 mm exposed diameter, 10 mm center-to-center distance) and depth electrodes (six to eight contacts; length: 5 and 2 mm; center-to-center distance: 10 and 5 mm, respectively; PMT, Chanhassen, MN, USA) placed on the affected hemisphere.

Table 1.

Patients profile.

Patient
number		 Age
(years)		 Gender Sampled
hemisphere		 Number of
included electrodes
(depth/subdural)		 Antiepileptic
drugs		 Age of
epilepsy
onset (years)		 SOZ Pathology
1 12 Male Both 90 / 0 LTG, LAC 6 Both F Not applicable
2 12 Female Both 129 / 0 LEV, LAC, CLB 2 Lt F Dysplasia
3 16 Female Both 128 / 0 LEV, LTG, OXC 9 Rt F Gliosis
4 2 Male Right 8 / 125 LEV, OXC, CLB 0 F, P Dysplasia
5 4 Female Right 6 / 137 LAC 0 F, P Dysplasia
6 8 Male Left 13 / 99 LEV, OXC 6 P Dysplasia
7 8 Female Right 6 / 113 LAC, OXC, CLB 2.5 P Gliosis
8 12 Male Left 7 / 98 VPA, LEV 7 P Dysplasia
9 13 Male Left 11 / 96 LEV, LAC 10 O Dysplasia
10 13 Male Right 2 / 128 LEV, OXC 11 F Dysplasia
11 16 Female Left 15 / 110 OXC 7 P, T Dysplasia
12 16 Female Right 8 / 116 ZNS, LTG 6 P Gliosis
13 17 Female Left 8 / 114 LTG 15 T Gliosis
14 19 Male Right 8 / 116 LEV, OXC 0 O Dysplasia
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SOZ: Seizure onset zone. LTG: Lamotrigine. LAC: Lacosamide. LEV: Levetiracetam. CLB: Clobazam. OXC: Oxcarbazepine. VPA: Valproate. ZNS: Zonisamide. F: Frontal. P: Parietal. T: Temporal. O: Occipital.

2.3. Imaging process

We acquired a presurgical T1-weighted spoiled gradient-recalled echo sequence MRI and a post-implant CT image and created a fusion image accurately registering intracranial electrodes with the brain (Nakai et al., 2017; Stolk et al., 2018). Based on the assessment on coronal, axial, and sagittal fusion images, a given depth contact was classified into one of the following anatomical categories (Fig. 1): (a) deep white matter (white matter deeper than the bottoms of two adjacent sulci), (b) shallow white matter (white matter more superficial than the bottoms of two adjacent sulci), (c) gray matter (i.e., cerebral cortex), (d) cerebrospinal fluid (CSF) space (i.e., ventricle and subarachnoid space), and (e) outside the arachnoid surface of the brain. Two board-certified clinicians (a neurosurgeon [T.M.] and a neurosurgeon/epileptologist [M.S.]) independently classified depth electrode channels based on the anatomical locations. Inter-observer variability was measured using Cohen's kappa statistic (Cohen, 1960). We later achieved a consensus on the anatomical classification following group discussions. We treated all subdural electrodes as gray matter channels.

2.4. iEEG recording

We continuously acquired iEEG data at the bedside with a sampling rate of 1,000 Hz and amplifier bandpass at 0.016 - 300 Hz, using a Neurofax 1100A Digital System (Nihon Kohden America Inc., Foothill Ranch, CA, USA). The original reference was the averaged voltage of a pair of white matter contacts for sEEG recording and a pair of nonepileptic contacts for subdural iEEG recording. Such an original reference is often referred to as a system reference (Lesser et al., 2010; Nariai et al., 2011). We clinically assessed iEEG signals using average montage (Crone et al., 2001) as well as bipolar montage (Zijlmans et al., 2011; Isnard et al., 2018; Shimamoto et al., 2018). We excluded SPES-induced neuronal responses recorded at SOZ, irritative zone, or artifactual channels from further analyses of the present study. We defined the irritative zone as regions showing interictal spike discharges (Asano et al., 2009; Kural et al., 2020). Neuronal responses recorded at contacts within <1 cm from the stimulus site were also excluded from analysis (Sugiura et al., 2020; Prime et al., 2020b).

2.5. The protocol of single-pulse electrical stimulation (SPES)

We performed SPES using the method previously described (Silverstein et al., 2020; Sugiura et al., 2020). Each patient was given Fosphenytoin intravenously before initiating the SPES session. During resting sleep state, in each SPES trial, we delivered a train of electrical stimuli to a contiguous pair of depth or subdural electrodes at a frequency of 1 Hz for 40 s during a resting period of sleep. We routinely stimulate all electrode contacts placed within the brain (Cuello Oderiz et al., 2019). Each electrical stimulus consisted of a square wave pulse of 0.3 ms duration, 5 mA intensity, and biphasic polarity. The stimulus intensity was smaller than those previously reported to be safe (Valentín et al., 2002; Matsumoto et al., 2004; Koubeissi et al., 2012; Crowther et al., 2019). None of the patients showed or reported adverse events related to the SPES procedures.

2.6. Selection of electrode montage for assessment of SPES-related neuronal propagations

We determined the effects of electrode montage on the magnitude of neuronal responses recorded at sites receiving SPES-related neuronal propagations. We re-referenced iEEG signals using EEGLAB v2019.1 (Delorme and Makeig, 2004) and analyzed neuronal responses to SPES using the four different montages. [Bilateral average montage] The reference consisted of the average of iEEG signals of all channels in both hemispheres. We computed the average reference voltage by excluding all of the iEEG signals at SOZ, irritative zone, and artifactual channels (Asano et al., 2009), those outside the brain (Isnard et al., 2018), as well as those within 3 cm from the midpoint of the SPES sites (Swann et al., 2012; Shimada et al., 2017). [Ipsilateral average montage] The reference consisted of the average of iEEG signals of all channels in the hemisphere ipsilateral to the one recording a given SPES-related neuronal response. [Bipolar montage] Each electrode was referenced to the adjacent electrode on a deeper side. [Laplacian montage] Each electrode was referenced to the average of adjacent electrodes on both sides (Mercier et al., 2017; Li et al., 2018).

2.7. Quantification of direct effective connectivity using early CCEP4-60 Hz

We employed a root mean square (RMS) analysis (Prime et al., 2020a) to quantify the amplitude of CCEPs on each electrode montage. We averaged iEEG signals time-locked to SPES onset, across 40 stimuli, with a time window of −200 to +800 ms with a low-frequency filter of 4.0 Hz and a high-frequency filter of 60 Hz. We computed the square root of the mean of the squares of amplitude values from 11 to 50 ms (1-ms slide) at each channel. This analytic approach was designed to measure the magnitude of early SPES-related response, also known as N1 (Matsumoto et al., 2004). We excluded the initial 10 ms period from analysis to reduce the effect of stimulus artifact on iEEG (Swann et al., 2012). With visual assessment, we confirmed the reproducibility of CCEPs at given channels.

On bipolar montage, we computed the RMS at an electrode N as the mean of RMS at N−1/N pair and N/N+1 pair. We regarded the RMS value as a CCEP amplitude below.

2.8. Quantification of direct effective connectivity using early CCSR4-60 Hz

We quantified the magnitude of the neuronal response to SPES using a time-frequency analysis similar to that reported previously (Tallon-Baudry et al., 1997; Oostenveld et al., 2011; Sugiura et al., 2020). The Morlet wavelet method, as implemented in the FieldTrip (http://www.fieldtriptoolbox.org), transformed iEEG voltage signals into time-frequency bins (2 Hz frequency bins; three cycles for each frequency) sliding in 1 ms steps at a time window of 11-50 ms with a bandpass of 4-60 Hz. We previously reported that this analytic time window and spectral frequency band were minimally affected by the effect of SPES-related artifacts (Sugiura et al., 2020). We defined a CCSR amplitude as the square root of the power averaged across 40 stimuli. We also computed the percent change of CCSR amplitude relative to that during the 50-200 ms pre-stimulus baseline period (Nakai et al., 2017; Sugiura et al., 2020). The cluster-based permutation test determined whether a given channel showed a significantly reproducible CCSR amplitude augmentation (Maris and Oostenveld, 2007).

2.9. Assessment of the validity of CCSRs recorded on bilateral and ipsilateral average montages

The goal of this analysis was to determine whether bilateral or ipsilateral average montages would be unsuitable for the measurement of near-field SPES-related responses in patients who underwent bilateral depth electrode placement. We deemed an electrode montage unsuitable if a large proportion of channels outside the brain showed significantly reproducible iEEG signal deflections at an 11-50 ms latency.

2.10. Assessment of the validity of CCSRs recorded on average, bipolar, and Laplacian montages

The goal of this analysis was to test the hypothesis that bipolar montage, compared to average montage, is more suitable for measurement of near-field CCSRs in patients undergoing bilateral depth recording. We assumed that near-field CCSRs could be measured at channels proximal to a cortical generator but should be absent or markedly attenuated outside the brain with the optimal electrode montage and amplitude threshold employed. We determined what amplitude-based threshold (%) (e.g., at least 80% amplitude increase compared to the baseline) should be implemented, in addition to the cluster-based permutation test, for defining a significant CCSR. We also determined whether consideration of montage-dependent changes in CCSR amplitudes would further improve the definition of a significant CCSR. Investigators previously suggested that a far-field potential from a common distant source should be canceled out on bipolar montage (Lachaux et al., 2003; Worrell et al., 2012; Tenke and Kayser, 2012). Thus, we hypothesized that contacts outside the brain, compared to those within the cortex, would have a smaller bipolar-to-average amplitude ratio (%), defined as [CCSR amplitude on bipolar montage × 100%] divided by [CCSR amplitude on average montage]. We determined the optimal combination of 'amplitude-based threshold' and 'bipolar-to-average amplitude ratio' that minimized an unwanted observation of significant CCSRs at contacts outside the brain.

Likewise, we tested the hypothesis that Laplacian montage, compared to average montage, would be more suitable for the measurement of near-field CCSRs in patients undergoing bilateral depth recording.

2.11. The similarity of spatial profiles of CCEPs/CCSRs among different electrode montages

The Spearman's correlation tested the hypothesis that the rank order of CCEP amplitudes across contacts would be very similar between bipolar and Laplacian montages but not necessarily between average and bipolar montages. Likewise, we determined how similar the rank order of CCSR amplitudes was among different montages.

2.12. Assessment of the effect of SPES locations on the extent of resulting neuronal propagations

We tested the hypothesis that SPES of structures more proximal to the deep white matter, compared to the cortical surface, would elicit larger CCEPs and CCSRs. We employed a mixed model analysis, in which the amplitude of CCEP/CCSR was treated as a dependent variable. Fixed effect predictors included (a) the number of SPES electrodes at deep white matter (range: 0 to 2), (b) that at shallow white matter (range: 0 to 2), (c) that at gray matter (range: 0 to 2), (d) the recording hemisphere (1 if contralateral and 0 if ipsilateral to SPES), and (e) the type of recording contacts (1 if depth electrode; 0 if subdural electrode). Intercept and patient were treated as random factors.

Likewise, the mixed model analysis determined whether cortical SPES via depth electrodes, compared to that via subdural electrodes, would elicit larger CCEPs and CCSRs.

2.13. Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics version 22 (IBM Corp., Armonk, NY, USA) as well as Statistical and Machine Learning Toolbox MATLAB 2018b (The MathWorks Inc., Natick, MA, USA). The significance was set at a p-value of 0.05.

3. Results

3.1. Configurations and anatomical locations of implanted electrodes

We analyzed the empirical data from 14 patients who underwent SPES during extraoperative iEEG recording (Table 1). Bilateral sEEG recording was done with 115.7 [±12.8] analyzed depth electrodes per patient on average [standard error]. The subdural-depth combined recording was done with 113.8 [±3.9] analyzed subdural electrodes, and 8.4 [±1.1] analyzed depth electrodes per patient on average. The concordance of anatomical classification between two observers was substantial (Cohen's kappa = 0.78, p < 0.001). According to the consensus following group discussions, 86 depth electrodes were located at the deep white matter, 59 at the shallow white matter, 213 at the gray matter, 37 at the CSF space, and 89 outside the brain (Fig. 2; Videos S1 and S2).

Fig. 2. The locations of depth electrode contacts.

Fig. 2.

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(A) Depth electrodes placed stereotactically. (B) Those placed via craniotomy. Light green: deep white matter. Light blue: shallow white matter. Red: gray matter. Yellow: cerebrospinal fluid space. Black: outside the brain.

SPES was delivered to a total of 120 depth electrode pairs (91 sEEG pairs). The cumulative number of CCEP/CCSR recording channels was 14,165.

3.2. CCSRs measured on bilateral and ipsilateral average montages on sEEG recording

Our empirical sEEG data indicated that ipsilateral average montage was more suitable to measure a near-field neuronal response to SPES compared to bilateral average montage. The Wilcoxon-Signed rank test showed that the CCSR amplitude outside the brain was larger on bilateral than ipsilateral average montage (Median difference: 28.0 μV; p<0.01). Based on the cluster-based permutation test, a large proportion of contacts outside the brain were suggested to show a significantly reproducible early CCSR component on bilateral average montage (54.2%) and ipsilateral average montage (49.7%). In other words, bilateral average montage was more unsuitable than ipsilateral average montage in our bilateral sEEG cohort.

3.3. Visual assessment of CCEPs and CCSRs measured on bipolar, Laplacian, and ipsilateral average montages

Our empirical sEEG data supported the notion that bipolar montage, compared to average montage, may be more suitable to measure a near-field neuronal response to SPES. Fig. 3 presents representative CCEPs measured on bilateral average montage, ipsilateral average montage, and bipolar montage. On bilateral and ipsilateral average montages, the amplitudes of an early negative response (also known as N1) at electrodes at the deep white matter (i.e., C1-C5) appeared larger than those at the gray matter (C6 and C10). Bipolar montage made the N1 CCEP amplitudes at the deep white matter contacts drastically reduced. Thus, large N1 CCEP responses at the white matter level, specifically seen on average montages, were suggested to be far-field potentials (Lachaux et al., 2003; Worrell et al., 2012; Kambara et al., 2018).

Fig. 3. Cortico-cortical evoked potentials (CCEPs) measured on different montages (patient #2).

Fig. 3.

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(A) The yellow arrow denotes the stimulus pair. Electrode sites C1 to C10 recorded CCEPs. CCEPs measured on (B) bilateral average montage, (C) ipsilateral average montage, and (D) bipolar montage. Low-frequency filter: 0.016 Hz. High-frequency filter: 300 Hz.

Fig. 4 presents another representative CCEPs and CCSRs measured on bipolar, ipsilateral average, and Laplacian montages. This figure supports the notion that bipolar and Laplacian montages, compared to ipsilateral average montage, may be more suitable to measure a near-field neuronal response to SPES. On ipsilateral average montage, a large N1 CCEP was noted at electrode contacts outside the brain (Fig. 4C). Conversely, bipolar (Fig. 4B) and Laplacian montages (Fig. 4D) made the N1 CCEP amplitude at contacts outside the brain drastically reduced.

Fig. 4. Cortico-cortical evoked potentials (CCEPs) and cortico-cortical spectral responses (CCSRs) on different montages (patient #2).

Fig. 4.

Fig. 4.

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(A) The yellow arrow suggests the stimulus pair to elicit CCEPs and CCSRs. Electrode sites I1 to I11 recorded CCEPs and CCSRs. CCEPs measured on (B) bipolar, (C) ipsilateral average, and (D) Laplacian montages. Low-frequency filter: 0.016 Hz. High-frequency filter: 300 Hz. CCSRs measured on (E) bipolar, (F) ipsilateral average, and (G) Laplacian montages.

Likewise, on ipsilateral average montage, early CCSRs were noted at contact outside the brain (Fig. 4F). Bipolar (Fig. 4E) and Laplacian montages (Fig. 4G) reduced the amplitude of early CCSRs at contacts outside the brain.

3.4. Quantitative assessment of CCEPs and CCSRs measured on bipolar, Laplacian, and ipsilateral average montages

Fig. 5 presents how well bipolar and Laplacian montages reduced the amplitude of CCEPs (Fig. 5A) and CCSRs (Fig. 5B) recorded at contacts outside the brain. Compare to those measured on ipsilateral average reference, the CCEP/CCSR amplitudes at contacts outside brain was 69-72% smaller on bipolar montage (CCEPs: 27.6% of that seen on average montage [95% CI: 23.5% to 31.7%]; CCSRs: 31.3% [95% CI: 28.7% to 34.0%]). Likewise, the CCEP/CCSR amplitudes at contacts outside brain was 77% smaller on Laplacian montage (CCEPs: 22.8% [95% CI: 18.9% to 26.6%]; CCSRs: 22.6% [95% CI: 20.6% to 24.6%]).

Fig. 5. Stereo-electroencephalography-based cortico-cortical evoked potential and spectral response (CCEP/CCSR) amplitudes on ipsilateral average reference, bipolar, and Laplacian montages.

Fig. 5.

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(A) The mean relative N1 CCEP size (compared to that on ipsilateral average montage) at different anatomical levels is presented. Bar: 95% confidence interval. Electrode contacts outside the brain showed a relative CCEP size of 27.6% on bipolar montage; this indicates that the CCEP amplitude outside the brain was, on average, 72.4% smaller on bipolar montage compared to on ipsilateral average montage. (B) The mean relative CCSR size at different anatomical levels is likewise presented. Here, N1 size was defined as the square root of the mean of the squares of CCEP amplitude values from 11 to 50 ms.

Conversely, the CCEP/CCSR amplitudes at the gray matter was well maintained on bipolar montage (CCEPs: 89.5% [95% CI: 85.5% to 93.6%]; CCSRs: 90.8% [95% CI: 88.8% to 92.9%]). The CCEP/CCSR amplitudes at the gray matter was 36-38% smaller on Laplacian montage compared to those measured on ipsilateral average montage (CCEPs: 62.2% [95% CI: 58.9% to 65.6%]; CCSRs: 63.5% [95% CI: 61.8% to 65.2%]).

As shown in Fig. 5, compared to those measured on ipsilateral average montage, the CCEP/CCSR amplitudes at the white matter was about 30-50% smaller on bipolar montage and 60-80% smaller on Laplacian montage.

3.5. The 3-step procedure optimally avoids the unwanted detection of CCSRs at contacts outside the brain

Fig. 6 indicates the thresholds optimally detecting CCSRs at gray matter contacts but not outside the brain. In our sEEG cohort of patients, the following 3-step procedure resulted in the successful detection of significant CCSRs specifically at the gray matter level. [Step A] iEEG must show a significantly reproducible amplitude augmentation based on the cluster-based permutation test (Maris and Oostenveld, 2007). [Step B] iEEG must show >80% augmentation of iEEG amplitude at 4-60 Hz at 11-50 ms. [Step C] The bipolar-to-average amplitude ratio must be >60%. In other words, iEEG must maintain at least 60% of amplitude on bipolar montage compared to that on ipsilateral average montage. With the aforementioned 3-step procedure employed, 5.3% of gray matter contacts turned out to show significant CCSRs on bipolar montage, whereas only 1.8% of the contacts outside the brain showed significant CCSRs. Likewise, with the 3-step procedure mentioned above, 2.6% of gray matter contacts turned out to show significant CCSRs on Laplacian montage, whereas 1.0% of the contacts outside the brain showed significant CCSRs.

Fig. 6. The 3-step procedure to define significant cortico-cortical spectral responses (CCSRs) on stereo-electroencephalography depth recording.

Fig. 6.

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The proportion of the number of electrode contacts showing significant CCSRs among all contacts at a given anatomical location (Black: outside the brain; Red: gray matter; Light blue: shallow white matter; Light green: Deep white matter). With different amplitude-based thresholds (>40%, >60%, >80%, >100%, >200% increase in amplitude) and bipolar-to-average amplitude ratio-based thresholds ([A] not employed, [B] >30%, [C] >60%, and [D] >90%), the proportion of contacts showing significant CCSRs was altered.

Without the bipolar-to-average amplitude ratio-based threshold, 16.1% (Fig. 6A) of sEEG contacts outside the brain were suggested to show significant CCSRs. Employment of the bipolar-to-average amplitude ratio-based threshold of >30%, >60%, and >90% reduced the proportion of sEEG contacts outside the brain showing significant CCSRs to 3.7% (Fig. 6B), 1.8% (Fig. 6C), and 1.2% (Fig. 6D). Conversely, with the employment of the bipolar-to-average amplitude ratio-based threshold of >30%, >60%, and >90%, the proportion of gray matter contacts showing significant CCSRs was reduced from 6.4% (Fig. 6A) to 6.0% (Fig. 6B), 5.3% (Fig. 6C), and 4.0% (Fig. 6D), respectively. Thus, we considered the bipolar-to-average amplitude ratio-based threshold of >60% to be most reasonable for the detection of significant CCSRs in our sEEG cohort.

3.6. The similarity of the rank order of CCEP/CCSR amplitudes among different electrode montages

We found that the spatial distributions of CCEPs/CCSRs were extremely similar between bipolar and Laplacian montages but moderately similar between bipolar and ipsilateral average montages in our sEEG cohort. Figs. 7A and 7B demonstrate that the rank order of CCEP amplitudes across contacts was highly correlated between bipolar and Laplacian montages (mean Spearman's rho across patients: 0.88; p<0.001) but the degree of correlation between bipolar and ipsilateral average montage was moderate (mean Spearman's rho: 0.55; p<0.001).

Fig. 7. The similarity of the rank order of cortico-cortical evoked potential (CCEP) and cortico-cortical spectral response (CCSR) amplitudes among different electrode montages.

Fig. 7.

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Scatter plots of CCEP amplitude ranks (A) on bipolar and Laplacian montages and (B) on bipolar and ipsilateral average montages. Scatter plots of CCSR amplitude ranks (C) on bipolar and Laplacian montages and (D) on bipolar and ipsilateral average montages. The highest neuronal response within a given patient was given a rank of 1.

Likewise, Figs. 7C and 7D show that the rank order of CCSR amplitudes was highly correlated between bipolar and Laplacian montages (mean Spearman's rho: 0.96; p<0.001) but the degree of correlation between bipolar and ipsilateral average montage was moderate (mean Spearman's rho: 0.61; p<0.001).

3.7. Effects of the SPES sites (white matter vs. gray matter) on the CCEP/CCSR amplitudes in our sEEG cohort

SPES of structures more proximal to the deep white matter, compared to the cortical surface, elicited larger CCEPs and CCSRs (Fig. 8). The mixed model analysis revealed that SPES to deep white matter contacts was associated with larger CCEP amplitudes (mixed model estimate: +13.3 μV; p<0.001; Table 2). Conversely, the hemisphere contralateral to the SPES sites (mixed model estimate: −21.6 μV; p<0.001) was independently associated with smaller CCEP amplitudes.

Fig. 8. Effects of single-pulse electrical stimulation (SPES) locations on the cortico-cortical evoked potential (CCEP) and cortico-cortical spectral response (CCSR) amplitudes (patient #2).

Fig. 8.

Fig. 8.

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(A) Green arrow: SPES at the deep white matter. Red arrow: SPES at the gray matter. C1-C10: recording electrode sites. (B) CCEPs elicited by SPES at the deep white matter. Low-frequency filter: 0.016 Hz. High-frequency filter: 300 Hz. (C) CCEPs elicited by SPES at the gray matter. (D) CCSRs elicited by SPES at the deep white matter. (E) CCSRs elicited by SPES at the gray matter.

Table 2.

Mixed model analysis to characterize the amplitude of cortico-cortical evoked potentials (CCEPs) elicited by stimulation of different regions.

Parameters Estimate S.E. df t Pr(>∣t∣) 95% CI
L.L. U.L.
(Intercept) +0.0 5.3 9.8 0.001 0.999 −11.8 11.8
Deep white matter stimulation +13.3 1.3 6343.8 10.352 <0.001 10.8 15.8
Shallow white matter
stimulation		 +10.9 1.3 7000.6 8.560 <0.001 8.4 13.4
Gray matter
stimulation		 +0.7 1.2 5241.6 0.568 0.570 −1.6 2.9
Recording with
depth electrodes		 +9.3 5.6 7.6 1.650 0.140 −3.8 22.5
Recording in the
contralateral contacts		 −21.6 1.3 8526.2 −17.155 <0.001 −24.0 −19.1
Open in a new tab

S.E.: Standard error. df: Degree of freedom. Pr: Probability. CI: Confidence interval. L.L.: Lower limit. U.L.: Upper limit. Each increase of a deep white matter contact was associated with an increase of the CCEP amplitude by 13.3 μV. Recording contacts contralateral to the SPES sites were independently associated with a smaller CCEP amplitude by 21.6 μV.

Likewise, SPES to deep white matter contacts was associated with larger CCSR amplitudes (mixed model estimate: +224.6 μV; p<0.001; Table 3). Conversely, the hemisphere contralateral to the SPES sites (mixed model estimate: −403.0 μV; p<0.001) was independently associated with smaller CCSR amplitudes.

Table 3.

Mixed model analysis to characterize the amplitude of cortico-cortical spectral responses (CCSRs) elicited by stimulation of different regions.

Parameters Estimate S.E. df t Pr(>∣t∣) 95% CI
L.L. U.L.
(Intercept) +412.5 162.9 10.8 2.532 0.028 53.2 771.8
Deep white matter
stimulation		 +224.6 27.8 8084.5 8.081 <0.001 170.1 279.1
Shallow white matter
stimulation		 +173.0 27.5 8255.1 6.288 <0.001 119.0 226.9
Gray matter
stimulation		 −13.6 25.2 7662.1 −0.538 0.590 −63.0 35.9
Recording with
depth electrodes		 −821.4 180.1 9.6 −4.560 0.001 −1225.2 −417.6
Recording in the
contralateral contacts		 −403.0 27.1 8527.6 −14.875 <0.001 −456.1 −349.9
Open in a new tab

S.E.: Standard error. df: Degree of freedom. Pr: Probability. CI: Confidence interval. L.L.: Lower limit. U.L.: Upper limit.

SPES of two white matter contacts elicited significant CCSRs in 3.4% of contacts, whereas SPES of directly overlying gray matter contacts elicited significant CCSRs in 2.7% of contacts (Fig. 9).

Fig. 9. Effects of single-pulse electrical stimulation (SPES) locations on the proportion of channels showing significant cortico-cortical spectral responses (CCSRs).

Fig. 9.

Open in a new tab

The proportion of electrode sites showing significant CCSRs elicited by SPES of different anatomical locations. Compared to SPES of a pair of gray matter contacts, that including a white matter contact elicited significant CCSRs more extensively (by 28-31%).

3.8. Effects of the cortical SPES via different types of electrodes (depth vs. subdural) on the CCEP/CCSR amplitudes

The mixed model analysis revealed that cortical SPES via depth electrodes, compared to that via subdural electrodes, was associated with minimally larger CCEP amplitudes (mixed model estimate: +3.1 μV; p=0.147 [not significant]) but significantly larger CCSR amplitudes (mixed model estimate: +249.4 μV; p<0.001).

Cortical SPES via depth and subdural electrodes elicited significant CCSRs at 5.1% and 2.6% of contacts, respectively.

4. Discussion

4.1. A practical guide for the assessment of CCEPs/CCSRs on depth recording

The present study suggests that the application of multiple electrode montages, including either bipolar or Laplacian montage, may be appropriate for the analysis of SPES-related neuronal responses recorded on depth iEEG recording. We recommend the following 3-step procedure, in any order, in the diagnostic use of CCEPs/CCSRs.

[Step A] Confirmation of reproducibility. One needs to confirm that SPES-related iEEG signal deflections are reproducible across single-pulse stimuli. This procedure can be done using visual assessment or statistical analysis (Matsumoto et al., 2004; Maris and Oostenveld, 2007; Sugiura et al., 2020). The purpose is to minimize the risk to erroneously interpret a single excessively large-signal deflection (Kambara et al., 2018) as a significant SPES-related neuronal response. In the present study, we visually confirmed the reproducibility of CCEPs with visual assessment and that of CCSRs with a cluster-based permutation test (Maris and Oostenveld, 2007; Silverstein et al., 2020).

[Step B] Quantification of responses. One can quantify the magnitude of SPES-related neuronal responses, either using an averaging procedure (i.e., CCEP) or a time-frequency approach (i.e., CCSR). We assume that the CCEP/CCSR amplitude at 11-50 ms can reflect neuronal responses via a single axonal propagation (Matsumoto et al., 2017; Sugiura et al., 2020). Our recent study showed that the N1 CCEP amplitude was negatively correlated to the length of the single-axonal white matter pathway measured on diffusion-weighted imaging tractography (Silverstein et al., 2020).

[Step C] Identification of near-field potentials. A comparison of the size of a given iEEG signal deflection between average montage and bipolar montages allows us to estimate whether a given signal deflection is a near-field potential generated by the adjacent cortex receiving SPES-related neuronal propagation. We agree with the notion that one may treat an iEEG signal deflection discernible on average montage but disappearing on bipolar montage as a potential generated by a distant source (or sources) (Lachaux et al., 2003; Worrell et al., 2012; Kambara et al., 2018). We found that the employment of bipolar montage, as compared to average montage, reduced the size of SPES-related iEEG deflections at the majority of contacts outside the brain (Fig. 6). In other words, reproducible SPES-related signal deflections of which amplitude is well maintained on bipolar montage are likely to reflect near-field potentials from the adjacent cortex effectively connected from the stimulus site.

Our empirical sEEG data externally support the validity of the historical preference of bipolar montage in SPES studies using depth electrodes, as shown in the results of literature review (Supplementary Figure S1).

4.2. What is the single best electrode montage?

Each electrode montage has the pros and cons. We do not suggest one is better than the other in every aspect. Thus, we recommend the CCEP/CCSR assessment using multiple montages. The rank order of CCEP/CCSR amplitudes in a given patient was extremely similar between bipolar and Laplacian montages (Fig. 7); both montages are suitable to measure near-field responses generated by local structures receiving SPES-induced propagation. Unlike Laplacian or average montages, bipolar montage per se may not tell us which of a pair of contacts is responsible for a given neuronal response of interest. Laplacian montage does not allow us to measure neuronal responses at the end of depth electrodes accurately. The computation of Laplacian reference is different between the depth (based on two adjacent contacts) and subdural recordings (based on four adjacent contacts).

4.3. CCEPs or CCSRs?

Our study was not designed to determine whether CCEPs are more useful than CCSRs, or vice versa, for the depth electrode assessment of SPES-based effective connectivity. CCSRs measure the modulations of iEEG amplitudes phase-locked and unlocked to the SPES onset and are agnostic of the polarity of SPES-related neuronal responses (Crone et al., 2001; Sugiura et al., 2020). Conversely, CCEPs measure phase-locked neuronal responses alone (Figs. 3B-3D, 4B-4D, and 8B-8C). The location of a contact showing a reversal of phase of CCEPs may help clinicians in localizing the boundary between gray and white matter, if the MRI-electrode coregistration image is unavailable.

4.4. Methodological considerations

We still don't know whether the significance thresholds optimally distinguishing contacts at the gray matter from those outside the brain in our sEEG cohort are universally applicable to different cohorts of patients. The sample size of our sEEG patients was small in the present study. We analyzed a total of 91 SPES stimulus trials recorded with a total of 347 sEEG electrodes derived from three patients. These patients took different combinations of oral antiepileptic drugs, each of which might have an impact on neuronal propagations (Ziemann et al., 1996; Chen et al., 1997).

Why did multiple electrode contacts outside the brain exhibit apparent sEEG signal deflections on average montage in the present study? We attribute this observation to several methodological issues, some of which may have been specific to our sEEG recording protocol. We suspect that the total number of depth electrode contacts may not have been large enough to make the average reference to be silent at a practical level. The present study computed the average reference voltage by excluding all of the iEEG signals within 3 cm from the midpoint of the SPES sites. sEEG and subdural iEEG recordings had different sampling density in different dimensions. Adjacent contacts within a given sEEG depth electrode may have shared neuronal responses with a common phase. In contrast, the phases of neuronal responses at different electrode sites may be more variable on subdural iEEG recording with a center-to-center electrode distance of 10 mm (Sugiura et al., 2020).

The present study does not clarify what area is the optimal location for the reference electrode. We did not assume that our system reference was utterly silent (Wennberg and Lozano, 2003; Mercier et al., 2017); thus, we re-referenced iEEG signals to the average reference (Crone et al., 2001; Lesser et al., 2010; Nariai et al., 2011). Conversely, some investigators treat an extra- or intra-cranial electrode distant from the SPES site as the original reference (Yamao et al., 2014; Shimada et al., 2017). The benefit of an extracranial reference electrode includes a smaller probability of the reference contaminated by SPES-related neuronal responses. In contrast, the limitation consists of higher susceptibility to movement-related artifacts. An intracranial or subgaleal electrode facing the bone may serve as a more resilient reference. However, even such an intracranial electrode is not entirely silent (Nune et al., 2011), and the placement of such a reference electrode would require additional skin incision.

4.5. Impact of the stimulation site on CCEPs/CCSRs

The present study demonstrated that subcortical SPES elicited significantly greater CCEP/CCSR amplitudes. The proportion of contacts showing significant CCSRs was 28% higher when contacts at the white matter were stimulated compared to at the gray matter. These observations are consistent with a previous SPES study using sEEG recordings that white matter stimulation has a higher probability (by 61%) to show CCEP-based effective connectivity than gray matter stimulation (Trebaul et al., 2018). Investigators previously suggested that white matter stimulation may directly activate neural fibers and elicit both orthodromic and antidromic propagations to connected regions (Yamao et al., 2014; Enatsu et al., 2016; Trebaul et al., 2018). It is also plausible to hypothesize that some of the subcortical contacts may have been attached to the white matter fibers derived not only from the overlying cortex but also from the distant cortex.

Our novel findings include that intracortical stimulation via depth electrodes, compared to cortical stimulation using overlying subdural electrodes, elicited significantly greater CCSR amplitudes. Thereby, the intensity (5 mA) and pulse width (300 μs) remained constant across stimuli. Our observation can be attributed to the proximity between electrode contacts and white matter. It is also possible that structures between the cortex and subdural electrodes (e.g., pia mater) may have reduced or dispersed the excitatory effect of SPES on the cortex. Our findings might be useful for investigators who titrate the SPES intensity based on the neuronal responses observed on an individual basis. Our study suggests that depth electrodes, compared to subdural ones, may require less intensity of SPES to activate the underlying axons. Previous studies reported that 50-Hz electrical stimulation mapping with depth electrodes required about 2-mA smaller intensity to induce a clinical symptom compared to that with subdural electrodes (Zea Vera et al., 2017; Arya et al., 2020).

Supplementary Material

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4
5
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6

Highlights.

  • We measured neuronal responses to single-pulse electrical stimulation (SPES).

  • Bipolar and Laplacian montages record near-field responses on depth electrodes.

  • Subcortical SPES elicited neuronal responses at large numbers of contacts.

Acknowledgments

We are grateful to Karin Halsey, BS, REEGT. and Jamie MacDougall, RN, BSN, CPN at Children's Hospital of Michigan for the collaboration and assistance in performing the studies described above. This work was supported by NIH grant NS064033 (to E.A.) and JST CREST grant JPMJCR1784 (to T.M.).

Abbreviations

CCEPs

cortico-cortical evoked potentials

CCSRs

cortico-cortical spectral responses

CSF

cerebrospinal fluid

iEEG

intracranial electroencephalography

RMS

root mean square

sEEG

stereo-electroencephalography

SOZ

seizure onset zone

SPES

single-pulse electrical stimulation

Footnotes

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Disclosure

None of the authors have potential conflicts of interest to be disclosed.

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