Acute effects of brain-responsive neurostimulation in drug-resistant partial onset epilepsy

Rønborg, Søren Nicolaj; Esteller, Rosana; Tcheng, Thomas K.; Greene, David; Morrell, Martha J.; Kjær, Troels W.; Desai, Sharanya Arcot

doi:10.1016/j.clinph.2021.03.013

Cited by 18 publications

(11 citation statements)

References 26 publications

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“…Delayed stimulation is a drawback of current closed-loop DBS, because this is based on detection of abnormal brain activity within a sliding window, using complex signal processing methods [57, 58]. To enable real-time feedback operation of the bridge, early detection of interictal events is here achieved with a simple amplitude threshold-crossing approach, and triggers the stimulation within one sampling interval (see online methods).…”

Section: Resultsmentioning

confidence: 99%

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Caron¹,

Buccelli

Canal-Alonso³

et al. 2023

Preprint

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Objective. The compromise of the hippocampal loop is a hallmark of mesial temporal lobe epilepsy (MTLE); particularly, the hippocampal output to the parahippocampal cortex is disrupted by damage of the CA1. While closed-loop deep brain stimulation (DBS) is the latest frontier to improve drug-refractory MTLE, current approaches do not restore the hippocampal loop, are designed by trial-and-error and heavily rely on seizure detection or prediction algorithms. The objective of this study is to evaluate the efficacy and robustness of bridging hippocampus and cortex via closed-loop stimulation to achieve the functional restoration of the hippocampal loop and control limbic seizures. Approach. In hippocampus-cortex slices treated with 4-aminopyridine and in which the Schaffer Collaterals are severed, we used interictal discharges originating in the CA3 to trigger stimulation in the subiculum and re-establish the hippocampus output to the cortex. Combining tools from information theory with quantification of ictal activity, we addressed the efficacy of the bridge in restoring the functional connectivity of the hippocampal loop and controlling ictogenesis. Main results. Bridging hippocampus and cortex recovered the functional connectivity of the hippocampal loop, controlled ictogenesis and proved robust to failure mimicking the functional impairment of the CA3 seen in MTLE rodent models and patients. The efficacy and robustness of the bridge stem in mirroring the adaptive properties of the CA3, which acts as biological neuromodulator. Significance. A DBS device that does not depend on seizure detection/prediction algorithms but relies on endogenous interictal patterns presents the key to advance the conceptual design of current DBS paradigms for epilepsy treatment.

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Section: Resultsmentioning

confidence: 99%

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Caron¹,

Buccelli

Canal-Alonso³

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…However, it still relies on arbitrary settings defined by trial-and-error, and it is primarily designed to halt rather than prevent seizures. In addition, delayed stimulation is a drawback of current closed-loop DBS, because this is based on detection of abnormal brain activity within a sliding window, using complex signal processing methods [37,38]. As a result, the median seizure reduction rate reported by follow-up evaluations is a remarkable yet improvable 51%-70% [9].…”

Section: Discussionmentioning

confidence: 99%

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

et al. 2023

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Objective. The compromise of the hippocampal loop is a hallmark of mesial temporal lobe epilepsy (MTLE), the most frequent epileptic syndrome in the adult population and the most often refractory to medical therapy. Hippocampal sclerosis is found in >50% of drug-refractory MTLE patients and primarily involves the CA1, consequently disrupting the hippocampal output to the entorhinal cortex (EC). Closed-loop deep brain stimulation (DBS) is the latest frontier to improve drug-refractory MTLE; however, current approaches do not restore the functional connectivity of the hippocampal loop, they are designed by trial-and-error and heavily rely on seizure detection or prediction algorithms. The objective of this study is to evaluate the anti-ictogenic efficacy and robustness of an artificial bridge restoring the dialog between hippocampus and EC. Approach. In mouse hippocampus-EC slices treated with 4-aminopyridine and in which the Schaffer Collaterals are severed, we established an artificial bridge between hippocampus and EC wherein interictal discharges originating in the CA3 triggered stimulation of the subiculum so to entrain EC networks. Combining quantification of ictal activity with tools from information theory, we addressed the efficacy of the bridge in controlling ictogenesis and in restoring the functional connectivity of the hippocampal loop.Main results. The bridge significantly decreased or even prevented ictal activity and proved robust to failure; when operating at 100% of its efficiency (i.e., delivering a pulse upon each interictal event), it recovered the functional connectivity of the hippocampal loop to a degree similar to what measured in the intact circuitry. The efficacy and robustness of the bridge stem in mirroring the adaptive properties of the CA3, which acts as biological neuromodulator.Significance. This work is the first stepping stone toward a paradigm shift in the conceptual design of stimulation devices for epilepsy treatment, from function control to functional restoration of the salient brain circuits.

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“…As more patients with insular epilepsy are implanted with the NeuroPace RNS system, it might be possible to study acute as well as long-term insular stimulation-induced icEEG changes and correlate them with long-term outcomes. In a recent retrospective study, Rønborg and colleagues found that patients with drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation showed an acute stimulation-related reduction in iEEG spectral power, which was associated with reductions in clinical seizure frequency [ 30 ]; however, because most patients had mesial temporal lobe epilepsy, it is unlikely that the insula was stimulated in a significant number of patients in the aforementioned study.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of High-Frequency Insular Stimulation on Interictal Epileptiform Discharge Rates in Patients with Refractory Epilepsy

et al. 2022

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Rationale: Deep brain stimulation (DBS) of several sites, such as the thalamus, has been shown to reduce seizure frequency and interictal epileptiform activity in patients with refractory epilepsy. Recent findings have demonstrated that the insula is part of the ‘rich club’ of highly connected brain regions. This pilot study investigated short-term effects of high-frequency (HF) insular DBS on interictal epileptiform discharge (IED) rate in patients with refractory epilepsy. Methods: Six patients with drug-resistant epilepsy undergoing an intracranial electroencephalographic study received two sets of 10 min continuous 150 Hz HF-DBS of the insula. For each patient, epileptiform activity was analyzed for a total of 80 min, starting 20 min prior to stimulation set 1 (S1), and ending 20 min after stimulation set 2 (S2). All IEDs were identified and classified according to their anatomic localization by a board-certified epileptologist. The IED rate during the 20 min preceding S1 served as a baseline for comparison with IED rate during S1, S2 and post-stimulation periods. Results: HF-DBS of the anterior insula (aINS) was performed in a patient with an aINS epileptic focus (patient 1). HF-DBS of the posterior insula (pINS) was performed in two patients with a pINS epileptic focus (patients 2 and 4), in one patient with an aINS focus (patient 3), and in two non-insular patients (patients 5 and 6). The total IED (irrespective of their location) rate significantly decreased (p < 0.01) in two patients (patients 1 and 2) during the stimulation period, whereas it significantly increased (p < 0.01) in one patient (patient 6); there was no change in the other three patients. Looking at subsets of spike localization, HF-DBS of the aINS significantly reduced aINS and orbitofrontal IEDs in patient 1 (p < 0.01), while HF-DBS of the pINS had an effect on pINS IEDs (p < 0.01) in both patients with a pINS focus; there was no significant effect of HF-DBS of the insula on IEDs in temporal or other frontal regions. Conclusion: Short-term HF-DBS of the insula had heterogeneous effects on the IED rate. Further work is required to examine factors underlying these heterogeneous effects, such as stimulation frequency, location of IEDs and subregions of the insula stimulated.

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Acute effects of brain-responsive neurostimulation in drug-resistant partial onset epilepsy

Cited by 18 publications

References 26 publications

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Acute Effects of High-Frequency Insular Stimulation on Interictal Epileptiform Discharge Rates in Patients with Refractory Epilepsy

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