Neurostimulation for Epilepsy: Advances, Applications and Opportunities

Neurostimulation for Epilepsy: Advances, Applications, and Opportunities comprehensively reviews the diverse array of neurostimulation technologies currently in use and in development for the treatment of epilepsy. The book covers basic mechanisms of neurostimulation, technical characteristics of approved and investigational neurostimulation devices, clinical applications and programming considerations of these devices, and progress toward next-generation device technology. Leading experts in the field provide a contemporary appraisal of neurostimulation in epilepsy, one that highlights recent advances, outlines unanswered questions, and proposes future directions.

Neurostimulation for Epilepsy: Advances, Applications, and Opportunities will be of high interest to clinical, basic, and translational researchers seeking to understand leading-edge applications of neurostimulation in epilepsy and to clinicians managing patients with epilepsy who are treated with implanted and external neurostimulation devices. This book will also be of interest to trainees, to physicians in other areas of neurology where neurostimulation is employed, such as Pain and Movement Disorders, and to general medical practitioners, neurobiologists, and engineers.

• Explains fundamental principles of neurostimulation in accessible terms
• Details technical characteristics and engineering considerations of neurostimulation devices
• Describes strengths and limitations of approved and investigational neurostimulation devices
• Overviews clinical applications of neurostimulation, including device selection and programming
• Highlights the patient experience with neurostimulation, with an emphasis on quality of life
• Provides a roadmap for the development of next-generation devices

• Language: English
• Publisher: Academic Press
• Release date: Apr 11, 2023
• ISBN: 9780323985642

Book preview

Chapter 1: Principles of neurostimulation

Andreas Schulze-Bonhage    Epilepsy Center, University Medical Center, University of Freiburg, Freiburg, Germany

Abstract

Neurostimulation has been applied for the treatment of epilepsy for 50 years now. Despite the presence of clinical applications with different stimulation sites and target groups, open questions have remained as to best stimulation sites and stimulus parameters, including frequency, amplitude, and pattern. This chapter provides an overview of basic principles underlying brain stimulation for the treatment of epilepsy, mechanisms involved and evidence for efficacy in animal models, modeling and human applications, considering the present landscape of clinically available technologies.

Keywords

Neurostimulation; High-frequency stimulation; Low-frequency stimulation; Focus stimulation; Network hub; DC stimulation

Introduction

Epilepsy is a disorder characterized by hyperexcitability, manifesting as transient periods of abnormally synchronized discharges, which—when involving eloquent brain regions—clinically manifest as seizures. Traditionally, treatment involves application of pharmaceutical drugs which decrease high-frequency neuronal discharges (e.g., sodium channel blockers), decrease postsynaptic responses to excitatory neurotransmitters (e.g., glutamate receptor blockers), or increase the presynaptic amount or the postsynaptic response to the inhibitory neurotransmitter, GABA (e.g., inhibitors of presynaptic GABA metabolism or reuptake, and agonists at postsynaptic GABA receptors).

At first glance, a treatment applying additional electrical stimulation to a hyperexcitable brain may appear counterintuitive, even more so as electrical stimulation can acutely induce seizures (e.g., electroconvulsive therapy¹) and as chronic electrical stimulation is an established method to kindle an epileptic focus.² Using electrical stimulation as a therapeutic approach thus requires a careful consideration of appropriate stimulus intensities and forms, and of target regions and their connectivity within the complex brain network. Knowledge of basic concepts of the effects of electrical stimulation thus is a prerequisite to design neurostimulation approaches exerting antiepileptic or antiseizure effects.

Such basic concepts include:

•the imprinting of electrical fields on neurons relevant for seizure generation or propagation, decreasing their responsiveness to epileptic patterns

•modulation of synaptic transfer function, particularly in the form of long-term depression of excitatory neurotransmission

•activating inhibitory brain networks from brain nuclei with widespread neuromodulatory functions mediated by noradrenaline, serotonin, or dopamine.

Using such neuromodulatory approaches opens up windows for treatments with good tolerability, as local brain networks involved in seizure generation, propagation, or control can be specifically targeted. Neurostimulation cannot only be targeted in space but also in time: electrical fields applied exert immediate effects within milliseconds and enable closed-loop approaches, e.g., during pro-ictal phases or during seizures, in contrast to the slow onset of action of systemically applied pharmaceutical agents.

Identification of the optimal stimulation parameters is more difficult in epilepsy compared, for example, to movement disorders, as observed effects are often not immediately apparent but can be assessed only with the observation of prolonged time periods, depending on the baseline frequency of seizures in a given patient.

In this chapter, basic concepts of electrical stimulation for the treatment of epilepsy, in particular stimulus forms and targets for neurostimulation, are discussed in general terms and in exemplified clinical applications, which are elaborated more comprehensively in other chapters of this textbook.

Technical and biophysical background of neurostimulation

Electrical stimulators apply electrical fields to the brain via extracellularly placed electrodes. In direct current (DC) stimulation, electrodes are predefined as anodes (positive) or cathode (negative), whereas in alternate current (AC) stimulation, polarity of electrodes changes over time at a chosen frequency. To avoid polarization and corrosion of electrodes, equilibrated pulses are applied either with symmetrical alternating pulses (e.g., rectangular pulses) or with pulses with different amplitudes and duration for compensation (Fig. 1.1).

Fig. 1.1

Fig. 1.1 Symmetrical pulses vs asymmetrical stimulation with a predominant active polarity and a low-amplitude equilibration pulse assumed to have little neuronal effect.

Implantable neurostimulators usually consist of an internal battery or a rechargeable accumulator, a signal processor to steer stimulation and to communicate with a programming device or a device to trigger stimulations externally, and one or several leads with electrodes for local brain stimulation and recording of brain signals.

Electrical fields applied via electrodes usually primarily exert effects on axons given their lower threshold for action potential generation, with larger and more branched axons being preferentially activated. Effects on axons and neuronal somata critically depend on their orientation in relation to the external electrical field, with stronger effects when fields are oriented in the direction of the axon or along the axis of the apical dendrite to the axon hillock in pyramidal neurons. Negative external fields applied over the apical dendrite cause a local depolarization of the transmembrane potential, yet hyperpolarization at the soma and axon hillock reduces the neuronal propensity to generate action potentials; in contrast, positive external fields applied over the apical dendrite induce local hyperpolarization and somatic depolarization, favoring action potential generation (Fig. 1.2). Field strength declines at a power law and fields will mostly be effective only in a volume with a diameter of 2–5 mm from the electrode surface.³

Fig. 1.2

Fig. 1.2 Schematic effect of applied polarizing (DC) pulses from the brain surface.

Note that resulting effects depend critically on a polar neuronal structure and on the parallel arrangement of neuronal populations with homogeneous arrangement in relation to the applied field.

For neurostimulation in the human, peak voltages of up to 10 mV or electrical currents up to 5 mA are typically used, AC stimulation frequencies of 0.1–200 Hz, and pulse widths of 90–1000 μs. Duty cycles, time periods when stimulation is active, range from less than 10 min per day in responsive neurostimulation (RNS) to 4 h per day (17%) or even continuous stimulation with open-loop stimulation approaches (Fig. 1.3).

Fig. 1.3

Fig. 1.3 Multidimensional parameter space with some relevant stimulus parameters which add to qualitative parameters like topographical electrode positioning, pulse form, and timing of stimulation and duty cycles.

Unlike with pharmacological treatment, where dosage and frequency of dosing are the only parameters modified for treatment optimization, brain stimulation can be modified in a wide and multidimensional parameter space, which, in combination with the latency of antiepileptic efficacy, renders it difficult to perform systematical clinical assessments to optimize stimulation paradigms.

Narrowing down of the parameter space thus requires in vitro and in vivo experimental studies in animal models of epilepsy and modeling of stimulation effects on brain networks. To model the spatial effect of brain stimulation, tissue conductivity plays a critical role. The white matter (myelinated axons) is highly anisotropic with about 10× higher conductivity parallel to the direction of tracts. Individual neurons are typically represented by a conductance, representing ion channels in the neuronal membrane, and a parallel capacitance of the membrane, neuronal ensembles interconnected resistively. Modern computational models encompass modeling of anatomy, electrical fields, and neural activation.⁴,⁵

Safety aspects of neurostimulation are related to the process of implantation of a specific device, to tissue effects of electrical pulses, and to the neuromodulatory effects on brain excitability. Safety of the intensity of stimuli to which brain tissue is exposed has been studied in chronic applications over days and weeks, and relevant limits have been reviewed accordingly.⁶ Notably, these data do not reflect toxic changes of individual short stimulation pulses, and stimuli applied by the devices are considered to be far from a neurotoxic range and are lower than used in diagnostic settings, like cortical mapping in a presurgical context. Clinically relevant safety concerns can arise depending on specific stimulation settings, however, depending on chosen stimulation settings, e.g., when applying stimulation frequencies in the range of 10–80 Hz, when applying anodal stimuli, or when applying high stimulus amplitudes, which have individually been considered pro-ictal with stimulation of the anterior nucleus of the thalamus.⁷

Targets for neurostimulation in epilepsy

The advantage of neurostimulation to offer a spatially targeted therapy also implies the definition of a promising target (Fig. 1.4). This clearly differs depending on the mechanism of action of neurostimulation:

•In focal epilepsy, the epileptogenic zone is a target to modulate epileptogenicity, ictal and interictal epileptic discharges at their origin. This requires an adequate delineation of the epileptogenic area, and a selection of proper sites for stimulation electrodes to exert modulatory activity.

Fig. 1.4

Fig. 1.4 Targets for neurostimulation.

Such targets may be well definable, as with circumscribed lesions, like hippocampal sclerosis, focal cortical dysplasias of type II, or heterotopias. In patients with extended lesions or unclear borders of the epileptogenic structures, options for focal cortical stimulation may be limited, or a modulatory effect extending well beyond the directly excited brain area must be assumed. Responsive neurostimulation using a hippocampal depth and a temporo-basal strip electrode is one approach to such a situation. Preliminary results from transcranial focal cortex stimulation similarly suggest efficacy even if epileptogenic zones are well below the primarily targeted gyral crowns.⁸

Even in patients with circumscribed epileptogenic zones like the hippocampus, it has been suggested that a better modulation may be obtained using afferent or efferent tracts, such as the fornix, to retrogradely modulate the activity of large neuronal populations.⁹–¹¹

•Aside from areas where epileptic activity is primarily generated, network hubs critical for the propagation of epileptic discharges and particularly of ictal activity are an interesting target. Modeling suggests that the ‘hubness’ of target areas, e.g., nodes with high eigenvector centrality values, has the greatest likelihood of modulating epileptic discharges.¹² Thalamic nuclei are examples of targets which are key hubs in networks involved in the propagation of epileptic activity, even if they are not assumed to participate in seizure generation. Prevention of the spread of ictal seizure patterns, but also retrograde and anterograde modulation of the network involved, may contribute to the efficacy of stimulating these targets, and even effects of neurogenesis have been discussed.¹³ Stimulation of network hubs may also exert effects on widespread seizure propagation; for example, stimulation of the centromedian thalamic nuclei has been found to be effective in primarily generalized epilepsy.

•Even more indirect network effects of neurostimulation are involved when extracortical target areas with widespread efferents are selected, like with the activation of noradrenergic and serotoninergic brainstem nuclei with vagus nerve stimulation, or with activation of dopaminergic networks when stimulating subthalamic nuclei.

The activation of nucleus coeruleus and dorsal raphe nuclei by peripheral stimulation of the vagus nerve induces widespread alterations in the metabolism of thalamus, hypothalamus, hippocampus, amygdala, cingulum, insular and postcentral cortex.¹⁴,¹⁵ Similarly, with deep brain stimulation of subthalamic nuclei, activity patterns in internal pallidum, thalamus, cerebellum, as well as the primary motor cortex and putamen are modulated.¹⁶

Antiepileptic effects of specific stimulus forms

High-frequency stimulation (HFS)

In the context of neurostimulation, the application of electrical stimuli at frequencies of 80–200 Hz is frequently considered as high-frequency stimulation. HFS is the most common type of neurostimulation applied for the treatment of neurological disorders.¹⁷,¹⁸ In epileptology, it is applied at various targets (epileptic focus, network hubs, modulatory regions) in the setting of open-loop stimulation, independent of information on the state of brain dynamics and of closed-loop stimulation triggered based on biomarkers of brain states.

Various modes of action of HFS on neuronal activity have been considered to contribute to its antiepileptic effects¹⁹:

•Local depolarization blockade²⁰,²¹

•Synaptic depression due to neurotransmitter depletion²²,²³

•Preferential activation of GABA-ergic interneurons capable of discharging at high firing rates compared to excitatory glutamatergic principal neurons, leading to predominant synaptic inhibition²⁴

•Disruption/desynchronization of abnormal rhythmic network activity ²⁵,²⁶

•Reduced recruitability of neurons for epileptic rhythms¹⁹

•Long-term neuroplasticity in hypersynchronous networks.¹³

HFS exerts antiseizure effects in both experimental models²⁷,²⁸ and in the human.²⁹,³⁰ In particular, evidence for an acute terminating effect of ictal activity was found when interrupting stimulation-induced afterdischarges during extraoperative cortical mapping using 50-Hz stimulation by Lesser.³¹,³² Immediate efficacy of HFS renders it particularly useful for closed-loop applications as realized with RNS³³ and transcranial focal cortical stimulation (FCS),⁸,³⁴,³⁵ and for the treatment of status epilepticus.³⁶

In addition to the local and immediate effects HFS exerts on the stimulated area, remote network effects are attracting increased attention.¹³ Beyond long-term changes in synaptic efficacy and release of trophic factors, structural changes in connectivity and induction of neurogenesis have been considered to contribute to network neuroplasticity and to long-term increases in the efficacy of HFS.³⁷

Optimal frequencies for an antiseizure effect of neurostimulation are practically difficult to establish.³⁸ On the one hand, multiple factors contribute, like the topology of electrode positions to the targeted neuronal tissue and differential neuronal arrangement in brain nuclei, hippocampus, and cortex; on the other hand, unlike in movement disorders, effects are not immediate but can often only be assessed with observation over long time periods.

Modeling and experimental studies using in vivo models of epilepsy are best suited to assess the large parameter space available for neurostimulation and to suggest stimulation parameters to be tested in clinical trials. Some such studies found the best acute antiseizure effects with similar stimulation frequencies as used to modulate extrapyramidal networks in movement disorders (130 Hz),³⁹ aside from frequencies below 2 Hz.¹⁹ In presently available neurostimulation devices, default settings for neurostimulation are 100 Hz (FCS), 145 Hz (DBS of the ANT), and 200 Hz (responsive neurostimulation), yet a range is being used in practice.⁴⁰

Low-Frequency Stimulation (LFS)

The application of electrical stimuli to the brain at frequencies of below 10 Hz is usually considered as low-frequency stimulation. Whereas neuronal stimulation at frequencies of 10 Hz and above results in long-term potentiation of synaptic transmission⁴¹ and may contribute to kindling of epileptic foci,⁴² low-frequency stimulation has been shown to induce long-term depression (LTD) of synaptic transmission.⁴³,⁴⁴ Not all studies reporting antiepileptic effects, however, could correlate this with LTD,⁴⁵ leaving open a role of additional mechanisms involved, e.g., GABA-ergic hyperpolarization.⁴⁶

Modeling based thereon has suggested antiepileptic effects particularly with LFS below 2 Hz.¹⁹ Experimental epilepsy models, mostly using hippocampal slices or in vivo models, demonstrated antiepileptic effects of LFS in vitro⁴⁵,⁴⁷ as well as in vivo.⁴⁸,⁴⁹ A slower onset but longer duration of antiepileptic efficacy of electrical LFS compared to HFS has been suggested by Albensi⁴⁷ and was shown in vivo over several weeks by Paschen.⁴⁸ Recently, optogenetic variants of LFS have been shown to have antiepileptic effects in vivo⁴⁸; for a review of the studies using LFS in epilepsy, refer to Han et al.⁵⁰ A reduction in cortical excitability following LFS of the seizure onset zone has also been shown in the human.⁵¹

Clinical studies have been performed only in relatively small patient cohorts. However, antiseizure effects were reported with stimulation in the hippocampus⁴⁹,⁵²,⁵³ (see, however, Boex et al.⁵⁴), fornix,¹⁰,⁵⁵ neocortex,⁵⁶,⁵⁷ thalamus,⁵⁸ and mixed hippocampal and neocortical structures.⁵⁹ Recently, LFS at 7 Hz has also been reported as effective—and even superior to standard responsive high-frequency burst stimulation—using the RNS device with modified stimulus parameters.⁶⁰ Furthermore, subacute anticonvulsive effects of LFS at centromedian thalamic nuclei have been reported in two patients with status epilepticus: in a refractory generalized status epilepticus using 0.2-Hz stimulation,⁶¹ and in a patient with focal status epilepticus using 6-Hz stimulation.⁵⁸

LFS does not guarantee safety and anticonvulsive efficacy. Indeed, 1-Hz stimulation at high amplitudes routinely used in the context of presurgical evaluation of patients with drug-resistant epilepsy to map connectivity⁶²,⁶³ and epileptogenic brain areas may trigger afterdischarges and clinically manifest seizures when applied within the epileptogenic network.⁶⁴,⁶⁵

DC stimulation

Physiological in vivo effects of the application of polarizing electrical fields over many seconds have been studied extensively more than 50 years ago. In foundational papers, Purpura and McMurtry⁶⁶ and Bindman⁶⁷ established major principles of the mode of action:

•Anodal stimulation applied over the cortical surface exerts an immediate effect in depolarizing underlying pyramidal neurons at the soma and axon hillock and thus facilitating action potential generation.

•Cathodal stimulation applied over the cortical surface exerts an immediate effect in hyperpolarizing underlying pyramidal neurons at the soma and axon hillock, inhibiting action potential generation (see Fig. 1.2).

•Nonpyramidal neurons (e.g., inhibitory interneurons) respond to a lesser degree, and differentially respond depending on their positioning in the cortical layers, with predominant depolarization/activation in the superficial layers and hyperpolarization in lower