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. 2016 Oct 6;37(11):3767–3778. doi: 10.1002/hbm.23274

Cortico‐cortical and motor evoked potentials to single and paired‐pulse stimuli: An exploratory transcranial magnetic and intracranial electric brain stimulation study

Sébastien Boulogne 1,2,3,✉, Nathalie Andre‐Obadia 1, Vasilios K Kimiskidis 4, Philippe Ryvlin 1,2,3,5, Sylvain Rheims 1,2,3
PMCID: PMC6867359  PMID: 27312488

Abstract

Background

Paired‐pulse (PP) paradigms are commonly employed to assess in vivo cortical excitability using transcranial magnetic stimulation (TMS) to stimulate the primary motor cortex and modulate the induced motor evoked potential (MEP). Single‐pulse cortical direct electrical stimulation (DES) during intracerebral EEG monitoring allows the investigation of brain connectivity by eliciting cortico‐cortical evoked potentials (CCEPs). However, PP paradigm using intracerebral DES has rarely been reported and has never been previously compared with TMS.

Objective

The work was intended (i) to verify that the well‐established modulations of MEPs following PP TMS remain similar using DES in the motor cortex, and (ii) to evaluate if a similar pattern could be observed in distant cortico‐cortical connections through modulations of CCEP.

Methods

Three patients undergoing intracerebral EEG monitoring with electrodes implanted in the central region were studied. Single‐pulse DES (1–3 mA, 1 ms, 0.2 Hz) and PP DES using six interstimulus intervals (5, 15, 30, 50, 100, and 200 ms) in the motor cortex with concomitant recording of CCEPs and MEPs in contralateral muscles were performed. Finally, a navigated PP TMS session targeted the intracranial stimulation site to record TMS‐induced MEPs in two patients.

Results

MEP modulations elicited by PP intracerebral DES proved similar among the three patients and to those obtained by PP TMS. CCEP modulations elicited by PP intracerebral DES usually showed a pattern comparable to that of MEP, although a different pattern could be observed occasionally.

Conclusion

PP intracerebral DES seems to involve excitatory and inhibitory mechanisms similar to PP TMS and allows the recording of intracortical inhibition and facilitation modulation on cortico‐cortical connections. Hum Brain Mapp 37:3767–3778, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: paired‐pulse, epilepsy, cortical excitability, motor evoked potentials, transcranial magnetic stimulation, cortico‐cortical evoked potentials, motor cortex

Abbreviations

CCEP

cortico‐cortical evoked potential

CS

conditioning stimulus

DES

direct electrical stimulation

ICI

intracortical inhibition

ICF

intracortical facilitation

ISI

interstimulus interval

icEEG

intracerebral EEG;

MEP

motor evoked potential

PP

paired‐pulse

SP

single‐pulse

TMS

transcranial magnetic stimulation

TS

test stimulus

INTRODUCTION

Paired‐pulse (PP) paradigms are commonly employed to assess in vivo the excitability of intracortical circuits using transcranial magnetic stimulation (TMS) of the primary motor cortex [Badawy et al., 2014; Hamer, 2005; Rossini et al., 2015]. This approach involves the delivery of a conditioning stimulus (CS) at various interstimulus intervals (ISIs) prior to a test stimulus (TS), resulting in a decrease or increase of the conditioned MEP amplitude, respectively, termed intracortical inhibition (ICI) and intracortical facilitation (ICF). However, using MEPs as an output measure is not relevant for the investigation of non‐motor cortices.

Recently, an alternative approach has been developed where TMS is combined with EEG allowing recordings of TMS‐evoked EEG potentials (TEPs) at the cortical level [Ferreri and Rossini, 2013; Ilmoniemi et al., 1997]. Using a PP paradigm, a limited number of TMS‐EEG studies recorded long‐interval ICI in the motor cortex [Premoli et al., 2014; Rogasch et al., 2013] as well as in prefrontal [Daskalakis et al., 2008] and parietal regions [Fitzgerald et al., 2009]. However, several issues are still unresolved. The physiological substrates of TMS‐induced EEG responses are incompletely understood [Ferreri and Rossini, 2013]. Furthermore, TMS as well as scalp EEG are characterized by a fairly low spatial resolution and therefore, are suboptimal for studying interactions between spatially restricted cortical structures [Rossini et al., 2015].

Low frequency direct electrical stimulation (DES) performed during intracerebral EEG (icEEG) recordings in patients with drug‐resistant focal epilepsy allows the investigation of cortico‐cortical evoked potentials (CCEPs) with a high temporal and spatial resolution [Keller et al., 2014]. CCEPs can be used to study cerebral connectivity but might also show differences in the morphology and amplitude of the evoked responses between epileptogenic and non‐epileptogenic cortical regions [Enatsu et al., 2012; Iwasaki et al., 2010]. Investigating the modulations of CCEPs with a PP paradigm might thus represent a useful tool to investigate cortical excitability, especially between distant‐connected cortical areas. A limited number of studies applied PP intracranial DES and showed that DES‐induced MEPs [Ashby et al., 1999; Matsunaga et al., 2002] or loco‐regional CCEPs [Matsumoto et al., 2005; Wilson et al., 1998] could be complexly modulated. However, none of them compared both types of responses within the same subjects and the impact of PP DES on distant cortico‐cortical connections has never been investigated. Furthermore, the measurement and interpretation of CCEPs elicited by PP stimuli raised methodological issues, primarily related to the potential overlap between the late phases of the CS response with the TS response [Premoli et al., 2014; Wilson et al., 1998].

In order to investigate whether PP intracranial DES could be used to assess the excitability of functional cortico‐cortical connections, we conducted a study in three patients who underwent icEEG recordings. Our primary objectives were (i) to confirm that the well‐established modulations of MEPs following PP paradigms using TMS remain similar using DES in the primary motor cortex, and (ii) to evaluate if a similar pattern could be observed in distant cortico‐cortical connections through modulations of CCEPs.

MATERIAL AND METHODS

Patients

We recruited three patients (all male, age 19–29 years) with drug‐resistant focal epilepsy who underwent icEEG recordings during presurgical evaluation (Table 1) and fulfilled the following inclusion criteria: (1) presence of at least one electrode within the primary motor cortex allowing reproducible and visually detectable DES‐induced myoclonus in one contralateral limb, (2) primary motor cortex not part of the epileptogenic zone, and (3) written informed consent from the patient to participate to the study that was approved by ethics committee (CPP Sud‐Est IV n° 14/048) and competent authority (ANSM n° B140705‐31).

Table 1.

Patients characteristics

Age Seizures semiology MRI Antiepileptic medication Number of implanted electrodes (number or recording leads) Lobes investigated Epileptogenic zone as determined after icEEG exploration
Patient #1 26 yo Déjà‐vécu experience, right ear buzz followed by loss of contact, right dystonia, head rotating toward the right side. Bilateralization were frequent. Normal Lacosamide, levetiracetam, oxcarbazepine, clobazam 16 (172) Temporal, Frontal, Parietal, Occipital, Insula (left) Left superior temporal gyrus
Patient #2 29 yo Right dystonia without loss of contact. Left parieto‐occipital surgery cavity (type IIB cortical dysplasia cortectomy) Eslicarbazepine, phenobarbital, carbamazepine 8 (102) Frontal, Parietal, Occipital (left) Anterior part of the residual cavity (left parietal lobe)
Patient #3 19 yo Loss of contact, pain, choking feelings, left limb and facial clonism Normal Carbamazepine, topiramate, lacosamide 14 (164) Temporal, Frontal, Parietal, Occipital, Insula (right) Right frontal opercular cortex
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Brain MRI was normal in patient #1 and #3. Patient #2 had previously undergone left parieto‐occipital cortical resection targeting a type IIB focal cortical dysplasia. However, the resection of the dysplasia was not complete and seizures recurred few months after surgery. After a follow‐up of 5 years, icEEG was planned in order to investigate if a second cortical resection could be proposed.

Intracerebral EEG Procedure

IcEEG was performed according to the method described by Talairach and Bancaud [Bancaud et al., 1970] and routinely used in our department [Guenot et al., 2001]. The brain regions to be investigated were determined for each patient, based on individual presurgical data, and most likely origin of seizure onset. In general, about one third of the electrodes target the most likely zone of seizure onset, whereas the remaining electrodes probe alternative but less likely hypotheses, or help to define the borders of the epileptogenic zone.

Electrodes were 0.8 mm in diameter and included 5–18 recording leads 2 mm in length, 1.5 mm apart (Dixi Medical, Besançon, France). They were implanted stereotactically, perpendicular to the mid‐sagittal plane. The exact location of each electrode and recording lead was verified on a post‐implantation MRI.

A total of 8, 14, and 16 electrodes were implanted in patient #1, #2, and #3, respectively, including 1 electrode targeting the primary motor cortex in each of them. No morbidity was related to electrodes implantation or icEEG recordings. However, patient #3 suffered from intracerebral hematoma that developed a few days after electrodes removal and required craniotomy because of intracranial hypertension. He demonstrated left hemiparesis in the post‐operative period that progressively improved. After a follow‐up of 6 months, the neurological exam only showed mild left facial palsy.

The results of icEEG exploration, together with that of non‐invasive investigations, indicated that the epileptogenic zone was located within the left superior temporal gyrus in patient #1, the left superior parietal lobule (margins of the first surgery cavity) in patient #2, and within the right frontal opercular cortex in patient #3.

Intracerebral Stimulation

Stimulation protocol

DES was performed at least 9 hours apart from an epileptic seizure and icEEG activity was similar to their habitual interictal activity; patients were resting lying in bed. The stimulated dipoles were all located in the mesial and superior part of the central region, parallel to the cortical columns (Fig. 1), where DES induced myoclonus in contralateral upper and proximal lower limbs. The stimulation of two to four consecutive pairs of electrode leads in this region could induce a myoclonus, the dipole that induced the most reproducible myocloni were chosen for the DES session.

Figure 1.

Figure 1

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Intracranial stimulation sites. Transversal FLAIR‐weighted MRI scans of the three patients showing that the stimulated electrode leads (red dot) were all located in the inner and upper part of the central region. [Color figure can be viewed at http://wileyonlinelibrary.com.]

After an exploratory phase, surface EMG electrodes were placed on the muscles where the MEPs were of highest amplitude. IcEEG and EMG were concomitantly recorded using a video‐EEG monitoring system (Micromed, Treviso, Italy) at a sampling rate of 1,024 Hz. The EMG signal was amplified, filtered with a 20–200 Hz band‐pass filter and stored for off‐line analysis.

DES were produced by a current‐regulated neurostimulator (Micromed, Treviso, Italy). Square pulses of current were applied between two adjacent contacts (bipolar stimulation). We used monophasic pulses of 1 ms duration with a 0.2 Hz stimulation rate. Such stimulation is known to deliver current within 5 mm around the stimulated dipole [Nathan et al., 1993]. The 0.2 Hz frequency, commonly used in TMS and intracranial DES protocols, does not induce habituation during repetitive stimulations. All the parameters used during the study ensured a charge density below the maximal safety limit of 60 μC/cm2/phase, in order to avoid tissue damage [Gordon et al., 1990].

Two stimulation protocols were successively applied in each patient: (i) single‐pulse stimulations (SP) in order to acquire baseline unconditioned MEPs and CCEPs and assess which cortical regions were functionally connected with the primary motor cortex, as reported in previous studies [Almashaikhi et al., 2013, 2014; Catenoix et al., 2005, 2011; Rosenberg et al., 2009]; (ii) PP stimulations in order to study if modulation of cortical excitability could be detected at the MEP and/or the CCEP level.

Single‐pulse stimulation

The SP stimulation protocol was similar to that used in previous studies [Almashaikhi et al., 2013, 2014; Catenoix et al., 2005, 2011; Rosenberg et al., 2009]. Two blocks of 10 SP stimulations were performed for each stimulated dipole. The intensity was determined as the lowest intensity providing reproducible MEPs, in order to minimize the patient's discomfort related to the triggered myoclonus.

Paired‐pulse stimulation

Six blocks of 10 PP stimulations were performed using 5, 15, 30, 50, 100, and 200 ms ISI. Stimulation intensity was identical to the SP stimulation sets’.

Data analysis

Single‐pulse stimulation

Data were analyzed with BrainVision Analyzer version 2.0.4.368 (Brain Products, Gilching, Germany). We first performed an automatic detection of the pulse artifact generated on the stimulated contacts, and verified visually the accuracy of the trigger markers. These markers were then used for averaging each block of consecutive stimulations. Noisy trials containing artifacts or epileptiform discharges were excluded. Analysis was performed on the average of each stimulation block. CCEPs were searched on all the recorded cortical regions using a bipolar montage of adjacent contacts. The first 10 ms after each electrical pulse were not evaluated due to the presence of the stimulation artifact. CCEPs consisted of an early bi‐ or polyphasic component (10–50 ms) generally followed by a slow wave (50–500 ms) [Lacruz et al., 2007; Matsumoto, 2004] (Fig. 2 and Supporting Information Fig. S1). CCEPs were considered significant when reproducible on the two SP series with amplitude at least twice superior that of background activity [Catenoix et al., 2005]. When a CCEP was recorded on several adjacent dipoles within the same brain structures, the dipole with maximal amplitude was selected for analysis.

Figure 2.

Figure 2

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Cortico‐cortical evoked potentials induced by direct electrical stimulation of the primary motor cortex in patient #1. Transversal FLAIR‐weighted MRI scans of patient #1 showing the location of the stimulated dipole (red dot) and of some responding regions (green dot) with their corresponding CCEP in the superior frontal gyrus, the posterior cingulate and the lateral parietal cortex [Color figure can be viewed at http://wileyonlinelibrary.com.]

Peak‐to‐peak amplitude and delay until return to baseline were measured for all MEPs and CCEPs. The latency was set at the first peak for CCEPs and at the beginning of the MEP waveform.

Paired‐pulse stimulation

The impact of PP stimulation was evaluated for each ISI by comparing the peak‐to‐peak amplitude of the conditioned and the unconditioned response. The peak‐to‐peak amplitude of the conditioned response was expressed as a percentage of the unconditioned response amplitude. When the percentage was below 80%, CS was considered to have induced ICI; when above 120%, CS was considered to have induced ICF; when TS amplitude was between 80% and 120%, CS was considered as having no effect.

CCEPs may have different amplitude, morphology and duration across the recorded cortical regions and return to baseline may take over 300 ms for some connections. These properties implied that in most PP stimulation blocks, TS was delivered before return to baseline. In order to correct the overlap of CS and TS responses and to be able to estimate the response specific to the TS, we used two different methods:

  • Method #1 corresponded to that used in a recent PP TMS‐EEG study [Premoli et al., 2014]. For each PP stimulation block, we subtracted the average unconditioned response from the conditioned response, aligned to the time of the CS, in order to estimate the response specific to the TS, without the residual CS activity (Fig. 3C).

    Figure 3.

    Figure 3

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    Methodological approaches to study paired‐pulse cortico‐cortical evoked potential modulation. Each vertical red line represents the stimulation delivery: test stimulus (TS) alone for the single‐pulse waveform; conditioning (CS) and TS separated by an interstimulus interval (ISI), here 100 ms, for the paired‐pulse waveforms. (A) Single‐pulse stimulation induced a CCEP, which may last several hundreds of milliseconds before return to baseline is reached. (B) During paired‐pulse stimulation, the TS response and the CS residual activity coalesced into a single waveform, which prevented its direct comparison to the single‐pulse potential. To circumvent this issue, two approaches were employed: the “subtraction approach” (C) consisted in subtracting the average single‐pulse potential to the paired‐pulse waveform in order to compare the corrected conditioned response to the unconditioned response. An alternative “theoretical approach” (D) consisted in adding an identical unconditioned response after the ISI duration to create a waveform estimating what would be recorded if the CS had no influence on the TS response: the observed TS potential (dashed line) could then be compared with the theoretical TS response. [Color figure can be viewed at http://wileyonlinelibrary.com.]

  • In method #2, we used “theoretical PP potentials” similarly to other PP TMS‐EEG studies [Ferreri et al., 2011]. These theoretical responses were produced by adding a second identical SP waveform after the ISI duration. Thus, theoretical PP potentials showed what would be observed if the CS had no effect on the TS response (Fig. 3D). Observed and theoretical TS potentials could then be compared, which offered the advantage to verify whether the observed response presented additional or missing components.

As shown in Supporting Information Figure S2, the CCEP modulations obtained with method #2 were similar to those observed with method #1 and presented in Figure 7. In this context, all further data will be presented using method #1.

Figure 7.

Figure 7

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Paired‐pulse modulation of the amplitude ratio across the 10 cortico‐cortical evoked potentials. Each line represents one of the 10 CCEPs among the three patients. Each dot represents, for a given interstimulus interval, the amplitude ratio between the conditioned potential, corrected with the subtraction approach, and the unconditioned potential. Ratios below 0.8 corresponded to an intracortical inhibition (ICI) and ratios above 1.2 to an intracortical facilitation (ICF). For ratios between 0.8 and 1.2 CS was considered as having no effect. CCEPs that behaved differently than the others are marked with a star. [Color figure can be viewed at http://wileyonlinelibrary.com.]

Concerning MEPs, this overlap issue was only relevant for the shortest ISI (5 ms). In this case, the unconditioned potential was subtracted from the conditioned potential so as to reveal the true size of the response to the TS: the resulting waveform was then compared with the unconditioned response amplitude [Kujirai et al., 1993].

Similarly to CCEP, the peak‐to‐peak amplitude of the conditioned MEP was expressed as a percentage of the unconditioned response MEP.

Transcranial Magnetic Stimulation

Stimulation protocol

In order to assess whether the MEPs modulations observed with PP‐DES were similar with those obtained using PP‐TMS, a stimulation session using PP‐TMS‐EMG was performed a few weeks after icEEG recordings in patients #1 and #2. This procedure could not be performed in patient #3 due to the intracerebral hematoma that developed few days after electrodes removal.

TMS was performed using a magnetic stimulator (Mag‐Pro X100, Medtronic, Minneapolis, Minnesota) inducing biphasic pulses via a butterfly coil.

Before the TMS experiment, three‐dimensional (3D) T1‐weighted MRIs were obtained to allow its coregistration with the TMS neuronavigation system. The coil was positioned to target the region where the DES were delivered during icEEG and fixed using an adjustable arm; the TMS foci remained less than 2 cm away from the intracranial stimulation site. MEPs were recorded using a standard EMG machine and surface electrodes. Resting motor threshold (rMT) was determined using a relative frequency method [Rossini et al., 2015; Rothwell, 1999]. Briefly, starting from a stimulus intensity of 40% maximal stimulator output (MSO) intensity was gradually increased in steps of 5% MSO until MEPs of greater than 50 μV were consistently elicited. Thereafter, stimulus intensity was decreased in steps of 1% MSO until the lowest intensity that elicited MEPs of greater than 50 μV in 5 out of 10 stimuli was reached. The intensity used for all the stimulations (SP, CS, and TS) was set at 120% of the rMT to reproduce the supra‐motor intensity of the intracerebral stimulations. TMS pulses were applied during muscular rest in blocks of 10, approximately every 5 s. We investigated the same ISIs as those tested during the intracerebral protocol.

Data analysis

Analysis was performed on the average of each stimulation block with the same methodology used for intracerebral PP stimulation.

RESULTS

Single‐Pulse Intracranial Stimulation

MEPs were recorded in the deltoid and psoas muscles in the three patients, at 3 mA in patients #1 and #2 and at 1 mA in patient #3.

A total of 90 cortico‐cortical connections between the primary motor cortex and other recorded brain areas were tested in the three patients, 10 of which (11%) gave rise to significant CCEPs: 5 in patient #1, 3 in patient #2, and 2 in patient #3 (Supporting Information Fig. S1). Recorded CCEPs typically corresponded to biphasic early responses, with an average ± SD latency of the first peak of 27 ± 23 ms (range 11–89 ms). Return to baseline was observed after an average ± SD latency of 240 ± 94 ms (range 120–390 ms). Five of the 10 connections were regional, involving the post‐central gyrus and the paracentral lobule. The other five involved the superior frontal gyrus, the lateral parietal cortex and the anterior and posterior cingulate cortex. None of these connections were included in the epileptogenic zone (Table 1).

Paired‐Pulse Stimulation

Motor evoked potentials

In patients #1 and #2, the MEPs modulation pattern elicited by PP intracranial DES and TMS was highly similar (Figs. 4 and 5). Spearman's rank correlation coefficient between the TMS and DES data were significant (P < 0.05) for both patients. ICF was recorded for all stimulation blocks using ISI from 5 to 50 ms; MEPs’ amplitude was always greater for ISI 15, 30, and 50 ms than for ISI 5 ms. ICI was observed for ISI 100 and 200 ms; MEPs’ amplitude was always lower for 100 than for 200 ms.

Figure 4.

Figure 4

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Motor evoked potentials elicited in the psoas muscle by intracranial direct electrical stimulation and by MRI‐navigated transcranial magnetic stimulation of the primary motor cortex in patient #2. Each vertical red line represents the stimulation delivery for the conditioning (CS) and test stimulation (TS). Six conditions are shown: single‐pulse, paired‐pulse using interstimulus intervals (ISIs) ranging from 5 to 200 ms. Intracortical facilitation (ICF) was observed for ISI below 50 ms, with a maximum for the ISI 15 ms, and inhibition (ICI) for ISI above 100 ms. [Color figure can be viewed at http://wileyonlinelibrary.com.]

Figure 5.

Figure 5

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Paired‐pulse modulation of the amplitude ratio across of the motor evoked potentials recorded in the psoas muscle during the magnetic and intracranial electrical stimulation sessions across the three patients. Each line represents one of the 10 CCEPs among the three patients. Each dot represents, for a given interstimulus interval, the amplitude ratio between the conditioned potential and the unconditioned potential. [Color figure can be viewed at http://wileyonlinelibrary.com.]

In patient #3, who only undertook the intracerebral DES session, MEPs’ modulation was similar to that described in the two other patients.

Cortico‐cortical evoked potentials

The 10 significant CCEPs were modulated by PP stimulations (Figs. 6 and 7). We did not find cortico‐cortical connections that were not observed during the SP session. Across the six ISIs tested over the 10 significant CCEPs (i.e., 60 blocks), 14 blocks showed an ICI (23%), 17 an ICF (28%), while the reminder 29 (49%) failed to demonstrate a significant change in CCEPs (Table 2).

Figure 6.

Figure 6

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Modulation of cortico‐cortical evoked potentials induced by paired‐pulse intracranial direct electrical stimulation recorded in the superior frontal gyrus in patient #3. The paired‐pulse waveforms were corrected using the subtraction approach allowing the comparison of the conditioned to the unconditioned response. In this connection, inhibition (ICI) was observed with the ISIs 5 and 100 ms and facilitation (ICF) with the ISI 30 ms. [Color figure can be viewed at http://wileyonlinelibrary.com.]

Table 2.

Modulation observed for each interstimulus interval across the 10 cortico‐cortical evoked potentials, using the subtraction approach (Blue cells represent the most representative effect for the given ISI) [Color figure can be viewed at http://wileyonlinelibrary.com.]

ISI (ms) 5 15 30 50 100 200 TOTAL
ICF 10% 20% 60% 40% 40% 0% 28%
No effect 40% 50% 40% 60% 10% 90% 49%
ICI 50% 30% 0% 0% 50% 10% 23%
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A similar pattern as the one observed for MEPs was noted for 6 of the 10 cortico‐cortical connections (60%) with a progressive switch from ICI to ICF then ICI before return to baseline (Table 2 and Fig. 7). The four remaining connections, marked with a star in Figure 7, behaved differently: in patient #2, two connections only showed ICI and in patient #1, one connection only showed ICF and one showed ICI at the ISI 15 ms and ICF at the ISI 100 ms.

Within a same patient, CCEP modulation could vary across cortico‐cortical connections for a same ISI and could also differ from the concomitant MEP modulation. For instance at ISI 15 ms, a clear‐cut ICF was recorded on MEPs in all patients whereas ICF was seen in 2/10 CCEPs. Similarly at ISI 100 ms, ICI was prominent on MEPs while 4/10 CCEPs presented ICF. We did not observe differences between loco‐regional and distant cortico‐cortical connections.

DISCUSSION

While PP paradigms are routinely used in TMS studies in order to investigate cortical excitability in vivo, its applicability through DES in patients undergoing icEEG remains largely unknown. A limited number of studies previously applied PP paradigms trough DES [Ashby et al., 1999; Matsumoto et al., 2005; Matsunaga et al., 2002; Wilson et al., 1998] but their differences in terms of stimulation protocols and methods of analysis limited comparisons and general conclusions. The primary objective of the present study was to reassess the feasibility of intra‐cranial PP stimulations and specifically to address methodological issues. Focusing on PP stimulations within the primary motor cortex in order to compare DES with TMS at individual patient level, we showed that (i) a PP paradigm applied with intracerebral DES can elicit cortical excitability changes, reflected in MEPs as well as loco‐regional and distant CCEPs modulation, (ii) MEPs modulation was similar between TMS and intracerebral DES when using comparable stimulation parameters, and (iii) the most frequent CCEP modulation pattern was similar to those observed with MEPs, though differences were also observed.

In the two patients of the present study who underwent both TMS and DES, PP stimulation of the primary motor cortex induced a similar MEPs modulation, which resulted in a ternary pattern (Fig. 4), highly consistent with TMS literature in healthy volunteers [Kujirai et al., 1993; Rossini et al., 2015; Tokimura et al., 1996; Valls‐Solé et al., 1992]. These studies indicated that regardless of CS intensity, ISI from 10 to 50 ms elicit ICF and that ISI above 100 ms elicit ICI, followed by Late Cortical Disinhibition [Rossini et al., 2015]. For ISI below 6 ms or between 60 and 90 ms, modulation is markedly influenced by CS intensity: ICI is recorded when CS is infra‐motor threshold while ICF could be recorded when CS is at‐threshold or low supra‐threshold intensities for some ISIs. Similar results were also reported in the two studies that investigated the characteristics of MEPs induced by DES of the primary motor cortex and their modulation by PP paradigm [Ashby et al., 1999; Matsunaga et al., 2002]. Both studies recorded ICI with ISI 1–5 ms and ICF with ISI 10–30 ms, using infra‐motor threshold CS intensity and they recorded ICI with ISI 50–300 ms, using supra‐motor threshold CS. However, none of the investigated patients included in these latter studies underwent both PP‐DES and PP‐TMS.

One can underline that ICF seems to be stronger in DES than in TMS (Figs. 4 and 5). This could be explained by the fact that the stimulated parenchyma volume was different between TMS and DES but also by the difference of stimulation directionality: TMS being mainly perpendicular to cortical columns in a gyrus and parallel to columns in a sulcus while in our three patients, the stimulated dipole for DES was oriented parallel to the cortical columns. MEP amplitudes were smaller with DES and consequently the resting motor threshold, CS and TS intensities could not be assessed as precisely using DES then with TMS.

Modulation of CCEPs using PP intracranial DES has been evaluated in few studies. Wilson et al. reported PP stimulation of mesio‐temporal structures in patients with refractory mesio‐temporal epilepsy investigated with bilateral depth electrodes, using supra‐threshold CS and ISI from 20 to 800 ms [Wilson et al., 1998]. PP stimulation mainly resulted in ICI of local responses whereas ICF was rarely observed and generally recorded at ISI 50 ms. In contrast, Matsumoto et al. reported PP stimulation of the primary motor cortex, applied during electrocorticography in a single patient with a focal cortical dysplasia located in the foot area of the left motor cortex [Matsumoto et al., 2005]. The authors used subthreshold CS intensity and observed ICI of local CCEPs with ISI 1–2 ms and ICF with ISI 20 ms. These two studies therefore indicated, as the present study, that CCEPs modulation induced by PP‐DES might follow a pattern similar to the one observed for MEPs. It should however be noted that they only investigated loco‐regional connections.

Most importantly, previous studies using PP intracranial DES did not consider the potential impact of the late phase of the response to CS on the TS, and CS and TS responses were directly compared without correction [Wilson et al., 1998]. Management of the potential overlap between the late phases of the response to the CS with the TS response is, however, one of the major issues of PP paradigms. TS delivered before return to baseline activity after CS might significantly modify the morphology of the response, especially for short ISIs, resulting in misinterpretation of the direction of the modulation (i.e., ICI or ICF). In TMS‐EMG studies, the muscular response is brief and usually biphasic. Return to baseline is reached between 50 and 100 ms. In contrast, CCEPs are long and polyphasic responses, and return to baseline is observed after 300 ms [Komssi et al., 2004], properties similar to those reported for TMS‐evoked EEG potentials [Lioumis et al., 2009]. In TMS‐EMG approaches, the most widely used protocols for ISIs below 100ms consist in applying infra‐motor CS intensities that do not induce myoclonus (usually set at 80% of the rMT), which circumvent MEPs’ superposition [Rossini et al., 2015; Valls‐Solé et al., 1992]. The conditioned response is then compared with an unconditioned response acquired separately [Badawy et al., 2014; Rossini et al., 2015]. A less common PP protocol, named “short‐interval ICF,” uses supra‐motor intensities for both stimuli with ISI under 5 ms [Kujirai et al., 1993; Tokimura et al., 1996]. Here, conditioned responses are considered facilitated if their amplitudes are at least twice the amplitude of the unconditioned potential. In our study, lowering the intensity of the CS was not appropriate because, as reported in TMS‐EEG studies [Lioumis et al., 2009], the use of stimuli below motor threshold still elicits clear‐cut evoked EEG responses in some regions. Furthermore, the intensity threshold to elicit a CCEP can be different from one cortico‐cortical connection to another [Enatsu et al., 2012]. In addition, TMS‐EEG studies over the primary motor cortex showed that early and late TMS‐evoked EEG potentials were differentially modulated by alteration of stimulation intensities [Rogasch et al., 2013], reinforcing the view that using the same intensity for both CS and TS might limit risk of bias. Accordingly, we used two alternative approaches similar to that developed in TMS‐EEG studies that used “long‐interval ICI” protocols to record primary motor and dorso‐lateral prefrontal cortices responses [Daskalakis et al., 2008; Farzan et al., 2010; Premoli et al., 2014]. They applied supra‐motor threshold CS and TS with 100 ms ISI. In order to avoid responses overlap during analysis, they subtracted the unconditioned average potentials persisting after 100 ms to the conditioned TS response [Premoli et al., 2014].

Several limitations of our study need to be acknowledged. First, this study was essentially exploratory and the number of patients as well as the number of tested connections remained limited. Although we did not observe differences between loco‐regional and distant cortico‐cortical connections, we could not exclude that modulation might differ across brain regions. In addition, stimulation was restricted to the primary motor cortex. Whether or not our paradigm and/or method of analysis might be applied in other brain areas remains to be investigated. A second issue relates to the fact that icEEG‐based studies of functional connectivity are necessarily performed in patients with epilepsy whose brain connections and excitability might be altered. The 10 connections investigated in the current study were not included in the seizure onset zone. These efferent connections were consistent with the motor system organization [Rizzolatti et al., 1998] and other electrocorticographic studies [Enatsu et al., 2013; Matsumoto et al., 2005] in which primary motor cortex stimulation elicited large CCEPs in adjacent pre‐ and post‐central electrodes, and smaller CCEPs in premotor, lateral parietal, supplementary motor areas, and in cingulate gyrus. However, we cannot exclude the possibility that the modulation pattern observed was impacted by epilepsy or the use of antiepileptic drugs.

In fact, the potential differences of modulation patterns between the brain areas located outside and within the epileptogenic zone represent an important open question. Previous studies reported that SP stimulations can induce late epileptiform responses [Valentín et al., 2002, 2005] or high frequency oscillations [van't Klooster et al., 2011] that might help localizing the epileptogenic zone during presurgical evaluation. Furthermore, some PP‐TMS‐EMG studies in drug‐naïve focal epilepsy patients showed a significant reduction of ICI, predominant on the hemisphere containing the epileptogenic zone [Badawy et al., 2007; Varrasi et al., 2004]. In this context, one might hypothesize that intracranial PP stimulation might be used to study the epileptogenic zone's excitability mechanisms and delineation. As a matter of fact, Matsumoto et al. [2005] as well as Wilson et al. [1998] found complex but significant differences of PP modulation between epileptogenic and non‐epileptogenic loco‐regional connections. It might, therefore, be interesting to evaluate in future studies if the stimulation paradigm and method of analysis reported here might improve the epileptogenic zone evaluation.

CONCLUSIONS

PP intracranial DES seems to involve similar excitatory and inhibitory mechanisms to PP‐TMS and allows recording ICI and ICF modulation on cortico‐cortical connections. However, their interpretation is complex and might differ across the cortical regions explored.

Supporting information

Supporting Information

Click here for additional data file. (6.5MB, tiff)

Supporting Information

Click here for additional data file. (1MB, tiff)

ACKNOWLEDGMENTS

Thanks to Taïssia LELOKOV‐BOISSARD for her precious help during the TMS recordings.

The authors have no disclosure to declare regarding the present study.

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Supporting Information

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