Ictal connectivity changes induced by pulvinar stimulation correlate with improvement of awareness

Abstract

In patients with epilepsy, alteration of awareness (AOA) during seizures is a disabling feature that can potentially lead to serious consequences such as falls and injuries. Regarding the neural mechanisms underlying AOA in focal seizures, some hypotheses have been put forward. In temporal lobe epilepsy, AOA has been related to the extension of the discharge to subcortical structures and to subsequent widespread inhibition [[1]Blumenfeld H. Taylor J. Why do seizures cause loss of consciousness?.Neuroscientist. 2003; 9: 301-310Crossref PubMed Scopus (141) Google Scholar] or disturbed synchrony process [[2]Bartolomei F. Naccache L. The global workspace (GW) theory of consciousness and epilepsy.Behav Neurol. 2011; 24: 67-74Crossref PubMed Google Scholar] of the fronto-parietal association cortices.Thalamic stimulation was shown to be effective in reducing AOA [[3]Gummadavelli A. Motelow J.E. Smith N. Zhan Q. Schiff N.D. Blumenfeld H. Thalamic stimulation to improve level of consciousness after seizures: evaluation of electrophysiology and behavior.Epilepsia. 2015; 56: 114-124Crossref PubMed Scopus (49) Google Scholar]. The medial pulvinar (PuM) is a thalamic nucleus often involved in focal seizures in different type of epilepsy [[4]Pizzo F. Roehri N. Giusiano B. Lagarde S. Carron R. Scavarda D. et al.The ictal signature of thalamus and basal ganglia in focal epilepsy: an SEEG study.Neurology. 2021 Jan; 96: e280-e293https://doi.org/10.1212/WNL.0000000000011003Crossref PubMed Scopus (15) Google Scholar]. In a recent work [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar], we observed that high frequency stimulation of the PuM during temporal lobe seizures could lead to improvement of awareness. Data from intracranial recordings in epileptic patients suggested that transition between conscious and non-conscious states during seizures was due to an excessive synchrony between the thalamus and associative cortices [[2]Bartolomei F. Naccache L. The global workspace (GW) theory of consciousness and epilepsy.Behav Neurol. 2011; 24: 67-74Crossref PubMed Google Scholar,[6]Arthuis M. Valton L. Rgis J. Chauvel P. Wendling F. Naccache L. et al.Impaired consciousness during temporal lobe seizures is related to increased long-distance corticalsubcortical synchronization.Brain. 2009; 132: 2091-2101Crossref PubMed Scopus (151) Google Scholar].We thus hypothesized that pulvinar stimulation, when effective in reducing AOA, may act by reducing global synchrony.To test this hypothesis, we performed functional connectivity analysis during seizures in patients receiving ictal pulvinar stimulation (from the cohort described in Ref. [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar] ) and we compared patients with improvement of awareness (responders) to patients without improvement (non-responders).We investigated 9 consecutive patients with pharmaco-resistant temporal lobe epilepsy studied by stereoelectroencephalography (SEEG), in whom a seizure was triggered by hippocampal stimulation and was immediately followed by the application of a medial pulvinar stimulation (condition “pulvstim”). Seizures obtained in the same patients by hippocampal stimulation but without pulvinar stimulation (condition “nopulvstim”) were used as controls to test for the effect of pulvstim. Functional connectivity analysis was done during seizures by computing nonlinear correlation (h2) in broad band (1–45 Hz) between temporal and extratemporal regions [[7]Wendling F. Bartolomei F. Bellanger J.J. Chauvel P. Interpretation of interdependencies in epileptic signals using a macroscopic physiological model of the EEG.Clin Neurophysiol. 2001; 112: 1201-1218Crossref PubMed Scopus (138) Google Scholar].Total connectivity strength was computed as the sum of h2 from all links comprising a given SEEG channel [[8]Courtens S. Colombet B. Trébuchon A. Brovelli A. Bartolomei F. Bénar C.G. Graph measures of node strength for characterizing preictal synchrony in partial epilepsy.Brain Connect. 2016; 6: 530-539Crossref PubMed Scopus (24) Google Scholar]. Statistical analysis was conducted to compare connectivity strength between pulvstim and nopulvstim seizures and between temporal and extratemporal regions. We then compared the differences in functional connectivity between responders and non-responders (see Ref. [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar] for detail about clinical assessment).Data analysis was performed with the R software [[9]R Core Teamwww.R-project.orgDate: 2018Google Scholar]. We described the data with univariate statistics (confidence interval 95%, t-test, Kruskal-Wallis test), boxplots and parallel coordinates chart (R packages ggplot2). Then we analyzed the relations between connectivity strength and factors with possible effect ((1) pulvinar stimulation response: responders/non-responders, (2) location: temporal/extratemporal, (3) condition: pulvstim/nopulvstim) thanks to a linear mixed model of regression with repeated measures (R package lme4). Then we did post-hoc comparison t-tests with Bonferroni correction for multiple tests (R package emmeans).Results are summarized in Fig. 1. A total of 152 nodes were considered in the calculations with a fairly balanced distribution for each factor of interest. Fig. 1(a–d) shows the values of connectivity strength during all seizures analyzed across patients (1a) and according to the conditions of interest (1b-d). Fig. 1a reveals great heterogeneity across patients and Fig. 1b demonstrates higher values of connectivity strength in responder patients (R) compared to non-responders (NR). This effect is significant at p < 0.05 in the mixed regression model (supp. Table 1). Connectivity strength is lower in the pulvstim condition (Fig. 1c) - but this is not significant at the whole group level (supp. Table 1) - and appears higher for the temporal regions compared to extratemporal regions (Fig. 1d), which proves significant in the mixed model regression (supp. Table 1). Multivariate analysis showed a significant effect on the global connectivity strength of the interaction between the factor condition (pulvstim/nopulvstim) and the factor response (responder/non-responder) as showed in Fig. 1 (e). This is the main result of the study: functional connectivity strength was shown to be significantly modified by medial pulvinar stimulation (pulvstim vs nopulvstim condition) only in responders. Post-hoc comparison t-tests (supp. Table 2), demonstrate that this modification is evident in temporal (p < 0.001) and in extratemporal regions (p < 0.001) only in responders and that there are no statistically significant results in temporal (p > 0.15) and extratemporal (p > 0.15) regions in non-responders. In the nopulvstim condition, moreover, connectivity strength is significantly higher in responders than non-responders (respectively 0.22 and 0.16, t-test p < 0.0001, Fig. 1e), which suggests a possible predicting value for the response to pulvinar stimulation.To summarize, our results show that pulvinar stimulation during seizures can modify connectivity values, lowering the level of synchrony, only in patients that experienced a clinical improvement in awareness level. This finding is in line with previous evidences from the literature and with the hypothesis that AOA is linked to high synchrony value [[6]Arthuis M. Valton L. Rgis J. Chauvel P. Wendling F. Naccache L. et al.Impaired consciousness during temporal lobe seizures is related to increased long-distance corticalsubcortical synchronization.Brain. 2009; 132: 2091-2101Crossref PubMed Scopus (151) Google Scholar]. Decreased synchrony has also been shown as an effective way to reduce seizure severity in patients with VNS stimulation during seizures [[10]Ravan M. Investigating the correlation between short-term effectiveness of VNS Therapy in reducing the severity of seizures and long-term responsiveness.Epilepsy Res. 2017; 133: 46-53Crossref PubMed Scopus (12) Google Scholar]. Moreover, the state of synchrony (more elevated in responder patients) might be a predictive marker of the potential response to pulvinar stimulation. In patients with epilepsy, alteration of awareness (AOA) during seizures is a disabling feature that can potentially lead to serious consequences such as falls and injuries. Regarding the neural mechanisms underlying AOA in focal seizures, some hypotheses have been put forward. In temporal lobe epilepsy, AOA has been related to the extension of the discharge to subcortical structures and to subsequent widespread inhibition [[1]Blumenfeld H. Taylor J. Why do seizures cause loss of consciousness?.Neuroscientist. 2003; 9: 301-310Crossref PubMed Scopus (141) Google Scholar] or disturbed synchrony process [[2]Bartolomei F. Naccache L. The global workspace (GW) theory of consciousness and epilepsy.Behav Neurol. 2011; 24: 67-74Crossref PubMed Google Scholar] of the fronto-parietal association cortices. Thalamic stimulation was shown to be effective in reducing AOA [[3]Gummadavelli A. Motelow J.E. Smith N. Zhan Q. Schiff N.D. Blumenfeld H. Thalamic stimulation to improve level of consciousness after seizures: evaluation of electrophysiology and behavior.Epilepsia. 2015; 56: 114-124Crossref PubMed Scopus (49) Google Scholar]. The medial pulvinar (PuM) is a thalamic nucleus often involved in focal seizures in different type of epilepsy [[4]Pizzo F. Roehri N. Giusiano B. Lagarde S. Carron R. Scavarda D. et al.The ictal signature of thalamus and basal ganglia in focal epilepsy: an SEEG study.Neurology. 2021 Jan; 96: e280-e293https://doi.org/10.1212/WNL.0000000000011003Crossref PubMed Scopus (15) Google Scholar]. In a recent work [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar], we observed that high frequency stimulation of the PuM during temporal lobe seizures could lead to improvement of awareness. Data from intracranial recordings in epileptic patients suggested that transition between conscious and non-conscious states during seizures was due to an excessive synchrony between the thalamus and associative cortices [[2]Bartolomei F. Naccache L. The global workspace (GW) theory of consciousness and epilepsy.Behav Neurol. 2011; 24: 67-74Crossref PubMed Google Scholar,[6]Arthuis M. Valton L. Rgis J. Chauvel P. Wendling F. Naccache L. et al.Impaired consciousness during temporal lobe seizures is related to increased long-distance corticalsubcortical synchronization.Brain. 2009; 132: 2091-2101Crossref PubMed Scopus (151) Google Scholar]. We thus hypothesized that pulvinar stimulation, when effective in reducing AOA, may act by reducing global synchrony. To test this hypothesis, we performed functional connectivity analysis during seizures in patients receiving ictal pulvinar stimulation (from the cohort described in Ref. [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar] ) and we compared patients with improvement of awareness (responders) to patients without improvement (non-responders). We investigated 9 consecutive patients with pharmaco-resistant temporal lobe epilepsy studied by stereoelectroencephalography (SEEG), in whom a seizure was triggered by hippocampal stimulation and was immediately followed by the application of a medial pulvinar stimulation (condition “pulvstim”). Seizures obtained in the same patients by hippocampal stimulation but without pulvinar stimulation (condition “nopulvstim”) were used as controls to test for the effect of pulvstim. Functional connectivity analysis was done during seizures by computing nonlinear correlation (h2) in broad band (1–45 Hz) between temporal and extratemporal regions [[7]Wendling F. Bartolomei F. Bellanger J.J. Chauvel P. Interpretation of interdependencies in epileptic signals using a macroscopic physiological model of the EEG.Clin Neurophysiol. 2001; 112: 1201-1218Crossref PubMed Scopus (138) Google Scholar]. Total connectivity strength was computed as the sum of h2 from all links comprising a given SEEG channel [[8]Courtens S. Colombet B. Trébuchon A. Brovelli A. Bartolomei F. Bénar C.G. Graph measures of node strength for characterizing preictal synchrony in partial epilepsy.Brain Connect. 2016; 6: 530-539Crossref PubMed Scopus (24) Google Scholar]. Statistical analysis was conducted to compare connectivity strength between pulvstim and nopulvstim seizures and between temporal and extratemporal regions. We then compared the differences in functional connectivity between responders and non-responders (see Ref. [[5]Filipescu C. Lagarde S. Lambert I. Pizzo F. Trebuchon A. McGonigal A. et al.The effect of medial pulvinar stimulation on temporal lobe seizures.Epilepsia. 2019; 1–6Google Scholar] for detail about clinical assessment). Data analysis was performed with the R software [[9]R Core Teamwww.R-project.orgDate: 2018Google Scholar]. We described the data with univariate statistics (confidence interval 95%, t-test, Kruskal-Wallis test), boxplots and parallel coordinates chart (R packages ggplot2). Then we analyzed the relations between connectivity strength and factors with possible effect ((1) pulvinar stimulation response: responders/non-responders, (2) location: temporal/extratemporal, (3) condition: pulvstim/nopulvstim) thanks to a linear mixed model of regression with repeated measures (R package lme4). Then we did post-hoc comparison t-tests with Bonferroni correction for multiple tests (R package emmeans). Results are summarized in Fig. 1. A total of 152 nodes were considered in the calculations with a fairly balanced distribution for each factor of interest. Fig. 1(a–d) shows the values of connectivity strength during all seizures analyzed across patients (1a) and according to the conditions of interest (1b-d). Fig. 1a reveals great heterogeneity across patients and Fig. 1b demonstrates higher values of connectivity strength in responder patients (R) compared to non-responders (NR). This effect is significant at p < 0.05 in the mixed regression model (supp. Table 1). Connectivity strength is lower in the pulvstim condition (Fig. 1c) - but this is not significant at the whole group level (supp. Table 1) - and appears higher for the temporal regions compared to extratemporal regions (Fig. 1d), which proves significant in the mixed model regression (supp. Table 1). Multivariate analysis showed a significant effect on the global connectivity strength of the interaction between the factor condition (pulvstim/nopulvstim) and the factor response (responder/non-responder) as showed in Fig. 1 (e). This is the main result of the study: functional connectivity strength was shown to be significantly modified by medial pulvinar stimulation (pulvstim vs nopulvstim condition) only in responders. Post-hoc comparison t-tests (supp. Table 2), demonstrate that this modification is evident in temporal (p < 0.001) and in extratemporal regions (p < 0.001) only in responders and that there are no statistically significant results in temporal (p > 0.15) and extratemporal (p > 0.15) regions in non-responders. In the nopulvstim condition, moreover, connectivity strength is significantly higher in responders than non-responders (respectively 0.22 and 0.16, t-test p < 0.0001, Fig. 1e), which suggests a possible predicting value for the response to pulvinar stimulation. To summarize, our results show that pulvinar stimulation during seizures can modify connectivity values, lowering the level of synchrony, only in patients that experienced a clinical improvement in awareness level. This finding is in line with previous evidences from the literature and with the hypothesis that AOA is linked to high synchrony value [[6]Arthuis M. Valton L. Rgis J. Chauvel P. Wendling F. Naccache L. et al.Impaired consciousness during temporal lobe seizures is related to increased long-distance corticalsubcortical synchronization.Brain. 2009; 132: 2091-2101Crossref PubMed Scopus (151) Google Scholar]. Decreased synchrony has also been shown as an effective way to reduce seizure severity in patients with VNS stimulation during seizures [[10]Ravan M. Investigating the correlation between short-term effectiveness of VNS Therapy in reducing the severity of seizures and long-term responsiveness.Epilepsy Res. 2017; 133: 46-53Crossref PubMed Scopus (12) Google Scholar]. Moreover, the state of synchrony (more elevated in responder patients) might be a predictive marker of the potential response to pulvinar stimulation. None. The study was in part financially supported by grant GAČR 21-25953S , Grant Agency of the Czech Republic . Appendix A. Supplementary dataThe following is the Supplementary data to this article: Download .docx (.02 MB) Help with docx files Multimedia component 1 The following is the Supplementary data to this article: Download .docx (.02 MB) Help with docx files Multimedia component 1

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