Correlations between ictal propagation and response to electrical cortical stimulation: A cortico-cortical evoked potential study

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Summary

Objective

To better understand the process of ictal propagation in epilepsy by using cortico-cortical evoked potential (CCEP), which reveals the brain networks.

Methods

Intracranial EEG recordings of 11 seizures from 11 patients with pharmacoresistant focal epilepsy were studied to identify the propagation sites and times. Six patients had a history of secondary generalization (Gen (+) group) and five patients did not (Gen (−) group). Thereafter repetitive 1 Hz bipolar electrical stimuli were applied to the ictal onset zones and CCEPs were recorded by averaging electrocorticograms.

Results

The propagation of contiguous spread was significantly faster than non-contiguous spread (p = 0.033). In four patients, CCEP amplitudes were significantly larger in the ictal propagation area than out of the propagation area. However, the distribution of CCEP responses was not necessarily consistent with the ictal propagation area as a whole. Furthermore, the ictal propagation areas out of CCEP-positive areas were significantly broader in Gen (+) group than Gen (−) group (p = 0.017).

Conclusion

The present findings suggest that contiguous spread is faster than non-contiguous spread, which can be explained by the enhancement of excitability around the ictal onset area. Furthermore, there is a group of fibers that is “closed” during the seizures and secondary generalization might be more associated with the impairment of cortical inhibition over the broad cortical area rather than direct connection.

Introduction

The ictal onset zone, as determined by electrocorticography plays an important role in localization of the epileptogenic zone in patients who undergo an invasive evaluation (Carreno and Luders, 2001). Long-term intracranial electrode recording has superior time resolution and offers a unique opportunity to study seizure propagation in humans. Focal seizures often arise from a limited area of the cerebral cortex. They then propagate to larger areas of the cerebral cortex and subcortical structures. Early signs and symptoms of seizures might be produced by the cortex in the area of seizure onset, or the area propagated by seizure activity (So, 2006). Although Penfield and Jasper (1954) accurately reported the relationships between seizure semiology and the sites of epileptic discharge, such semiology in some patients may reflect the site of seizure propagation rather than origin (Rosenow and Luders, 2001). Both normal cerebral connectivity and neuronal pathways developed in the process of epileptogenesis participate in seizure spread (Blume, 2009). Seizure activity involves a brain network and the extent of this network changes over time. Knowledge of the propagation routes would be important for the interpretation of clinical phenomena and increase our understanding of the mechanisms of seizure spread.

Electrical stimulation in vivo human was recently introduced to track the various brain networks (Greenlee et al., 2007, Lacruz et al., 2007, Oya et al., 2007, Rosenberg et al., 2009, Keller et al., 2011), evaluate the cortical epileptogenicity (Valentin et al., 2002, Valentin et al., 2005a, Valentin et al., 2005b, Flanagan et al., 2009) and investigate the mechanisms of human memory in the hippocampus (Lacruz et al., 2010). Electrical stimulation produces responses via fiber projection by excitation of cortico-cortical projecting neurons and cortico-cortical evoked potentials (CCEPs) are obtained by averaging responses time-locked to electrical stimuli. CCEPs provide an opportunity to track connectivity among various functional areas that can be defined by cortical electrical stimulation and MRI-electrode co-registration (Matsumoto et al., 2004a, Matsumoto et al., 2004b, Matsumoto et al., 2007, Matsumoto et al., in press, Terada et al., 2008, Terada et al., 2012, Umeoka et al., 2009, Conner et al., 2011, Kikuchi et al., 2012, Koubeissi et al., in press).

We hypothesized that electrical stimuli produce CCEPs at an adjacent or distant cortex via both normal fiber projection and developed neuronal pathways related to epileptogenesis. Ictal propagations and CCEP results were correlated in patients to identify the seizure spread pathway: the ictal spread area via direct connection and indirect pathway which is secondary spread from outside the ictal onset zone.

Thereafter, based on CCEP responses, we evaluated two aspects of ictal propagation; contiguity of cortical spread and secondary generalization. First, the propagation time is estimated in contiguous spread and non-contiguous spread. Contiguous spread is ictal spread to adjacent cortical regions, and non-contiguous spread is propagation to distant sites of the cortex leaving areas in between unaffected. These propagation patterns are reported to be associated with surgical outcome (Kutsy et al., 1999). Understanding the characteristics of these propagation patterns is useful to interpret clinical and electrophysiological phenomena in patients with epilepsy.

Second, propagated areas via direct and indirect pathways were compared between patients with a history of secondary generalization and patients without it to elucidate which pathway is more associated with secondary generalization. Secondary generalization is the most dangerous seizure type of focal epilepsy. The identification of the factors causing secondary generalization would be crucial to better understand the mechanisms of seizure generalization and to develop better treatments for this seizure type.

The purpose of this study was to track the process of ictal propagation and to elucidate the factors affecting the propagation area and secondary generalization.

Section snippets

Patients

Thirteen patients with medically intractable focal epilepsy, who underwent presurgical evaluation with extraoperative invasive recordings with subdural grids or depth electrodes between October 2008 and December 2009 at our center, were included in the study. We included only those patients who had a focal ictal onset identified on the intracranial recordings. Two patients were excluded from this study because the ictal onset zone identified in our review was different from previous monitor

Waveform configuration of CCEP

The typical CCEP response was composed of a prominent negative peak component (Fig. 1). N1 peaks were present at the latency of 9–199 ms (median 60 ms) in 10–43 electrodes of each patient (median 28 electrodes). Stimulus intensities were inconsistent between patients (Table 1) and the amplitudes of CCEP responses were different between patients. N1 amplitude at maximum intensity ranged from 42 to 965 μV.

As shown in Fig. 1(a), most prominent CCEP responses were detected around the stimulus sites.

Discussion

This is the first study to correlate CCEP responses and ictal propagation. Our study reveals a discrepancy between CCEP responses and the ictal propagation areas. These results are useful to understand the propagation pathway.

We expected that CCEP could track seizure propagation patterns; however, the correlation between CCEP results and ictal propagation indicated that CCEP distribution is not necessarily correlated with the ictal propagation area. Based on the hypothesis that CCEP reflect

Conflicts of interest

None of the authors has any conflicts of interest in relation to this work to disclose.

Acknowledgement

We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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