Ninety-Hz Spinal Cord Stimulation-Induced Analgesia Is Dependent on Active Charge Balance and Is Nonlinearly Related to Amplitude: A Sham-Controlled Behavioral Study in a Rodent Model of Chronic Neuropathic Pain.

Background: Ninety-Hz active-recharge spinal cord stimulation (SCS) applied at below sensory-threshold intensity, as used with fast-acting subperception therapy spinal cord stimulation, has been shown clinically to produce significant analgesia, but additional characterization is required to better understand the therapy. This preclinical study investigates the behavioral effect of multiple 90-Hz SCS variants in a rodent model of neuropathic pain, focusing on charge balance and the relationship between 90-Hz efficacy and stimulation intensity.

Materials And Methods: Rats (n = 24) received a unilateral partial sciatic nerve ligation to induce neuropathic pain and were implanted with a quadripolar lead at T13.

Absence of paresthesia during high-rate spinal cord stimulation reveals importance of synchrony for sensations evoked by electrical stimulation.

Electrically activating mechanoreceptive afferents inhibits pain. However, paresthesia evoked by spinal cord stimulation (SCS) at 40-60 Hz becomes uncomfortable at high pulse amplitudes, limiting SCS "dosage." Kilohertz-frequency SCS produces analgesia without paresthesia and is thought, therefore, not to activate afferent axons.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aβ-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aβ-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons.

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation.

Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk.

In Vivo Measurements Reveal that Both Low- and High-frequency Spinal Cord Stimulation Heterogeneously Modulate Superficial Dorsal Horn Neurons.

Current sub-perception spinal cord stimulation (SCS) is characterized by the use of high-frequency pulses to achieve paresthesia-free analgesic effects. High-frequency SCS demonstrates distinctive properties from paresthesia-based SCS, such as a longer time course to response, implying the existence of alternative mechanism(s) of action beyond gate control theory. We quantified the responses to SCS of single neurons within the superficial dorsal horn (SDH), a structure in close proximity to SCS electrodes, to investigate the mechanisms underlying high-frequency SCS in 62 urethane-anesthetized male rats.

Surround Inhibition Mediates Pain Relief by Low Amplitude Spinal Cord Stimulation: Modeling and Measurement.

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds-minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH).

Evaluating optimized temporal patterns of spinal cord stimulation (SCS).

Background: Temporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain.

Objective: We hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation.

Methods: Using a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation.

Spinal Cord Stimulation Attenuates Mechanical Allodynia and Increases Central Resolvin D1 Levels in Rats With Spared Nerve Injury.

Mounting evidence from animal models of inflammatory and neuropathic pain suggests that inflammation regulates the resolution of pain by producing specialized pro-resolving mediators (SPMs), such as resolvin D1 (RvD1). However, it remains unclear how SPMs are induced in the central nervous system and whether these mechanisms can be reconciled with outcomes of neuromodulation therapies for pain, such as spinal cord stimulation. Here, we show that in a male rat model of neuropathic pain produced by spared nerve injury (SNI), 1 kHz spinal cord stimulation (1 kHz SCS) alone was sufficient to reduce mechanical allodynia and increase RvD1 in the cerebrospinal fluid (CSF).

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

Objective: Understanding the acute effects of responsive stimulation (AERS) based on intracranial EEG (iEEG) recordings in ambulatory patients with drug-resistant partial epilepsy, and correlating these with changes in clinical seizure frequency, may help clinicians more efficiently optimize responsive stimulation settings.

Methods: In patients implanted with the NeuroPace® RNS® System, acute changes in iEEG spectral power following active and sham stimulation periods were quantified and compared within individual iEEG channels. Additionally, acute stimulation-induced acute iEEG changes were compared within iEEG channels before and after patients experienced substantial reductions in clinical seizure frequency.

Limited Sensitivity of Hippocampal Synaptic Function or Network Oscillations to Unmodulated Kilohertz Electric Fields.

Understanding the cellular mechanisms of kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation including forms of transcranial electrical stimulation, interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in respond to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most studied systems in neuroscience and exhaustively characterized in screening the effects of electrical stimulation.

Time-dynamic pulse modulation of spinal cord stimulation reduces mechanical hypersensitivity and spontaneous pain in rats.

Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design.

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons.

Electrophysiology equipment for reliable study of kHz electrical stimulation.

Characterizing the cellular targets of kHz (1-10 kHz) electrical stimulation remains a pressing topic in neuromodulation because expanding interest in clinical application of kHz stimulation has surpassed mechanistic understanding. The presumed cellular targets of brain stimulation do not respond to kHz frequencies according to conventional electrophysiology theory. Specifically, the low-pass characteristics of cell membranes are predicted to render kHz stimulation inert, especially given the use of limited-duty-cycle biphasic pulses.

Temperature increases by kilohertz frequency spinal cord stimulation.

Introduction: Kilohertz frequency spinal cord stimulation (kHz-SCS) deposits significantly more power in tissue compared to SCS at conventional frequencies, reflecting increased duty cycle (pulse compression). We hypothesize kHz-SCS increases local tissue temperature by joule heat, which may influence the clinical outcomes.

Methods: To establish the role of tissue heating in KHZ-SCS, a decisive first step is to characterize the range of temperature changes expected during conventional and KHZ-SCS protocols.

Automated detection of mesial temporal and temporoperisylvian seizures in the anterior thalamic nucleus.

Background And Purpose: Focal seizures can arise from coordinated activity across large-scale epileptic networks and propagate to regions that are not functionally altered but are recruited by epileptiform discharges. In preclinical models of focal epilepsy, the thalamus is recruited by cortical onset seizures, but it remains to be demonstrated in clinical studies. In this pilot study, the authors investigate whether seizures with onset within and outside the mesial temporal structures are detected in the anterior thalamus (ATN).

Seizure Detection and Network Dynamics of Generalized Convulsive Seizures: Towards Rational Designing of Closed-Loop Neuromodulation.

Objective: Studies have demonstrated the utility of closed-loop neuromodulation in treating focal onset seizures. There is an utmost need of neurostimulation therapy for generalized tonic-clonic seizures. The study goals are to map the thalamocortical network dynamics during the generalized convulsive seizures and identify targets for reliable seizure detection.

Artifactual hyperpolarization during extracellular electrical stimulation: Proposed mechanism of high-rate neuromodulation disproved.

Background: Kilohertz-frequency electric field stimulation (kEFS) applied to the spinal cord can reduce chronic pain without causing the buzzing sensation (paresthesia) associated with activation of dorsal column fibers. This suggests that high-rate spinal cord stimulation (SCS) has a mode of action distinct from conventional, parasthesia-based SCS. A recent study reported that kEFS hyperpolarizes spinal neurons, yet this potentially transformative mode of action contradicts previous evidence that kEFS induces depolarization and was based on patch clamp recordings whose accuracy in the presence of kEFS has not been verified.

Sensitivity of quantitative EEG for seizure identification in the intensive care unit.

Objective: To evaluate the sensitivity of quantitative EEG (QEEG) for electrographic seizure identification in the intensive care unit (ICU).

Methods: Six-hour EEG epochs chosen from 15 patients underwent transformation into QEEG displays. Each epoch was reviewed in 3 formats: raw EEG, QEEG + raw, and QEEG-only.

Continuous energy variation during the seizure cycle: towards an on-line accumulated energy.

Objective: Increases in accumulated energy on intracranial EEG are associated with oncoming seizures in retrospective studies, supporting the idea that seizures are generated over time. Published seizure prediction methods require comparison to 'baseline' data, sleep staging, and selecting seizures that are not clustered closely in time. In this study, we attempt to remove these constraints by using a continuously adapting energy threshold, and to identify stereotyped energy variations through the seizure cycle (inter-, pre-, post- and ictal periods).

A multi-feature and multi-channel univariate selection process for seizure prediction.

Objective: To develop a prospective method for optimizing seizure prediction, given an array of implanted electrodes and a set of candidate quantitative features computed at each contact location.

Methods: The method employs a genetic-based selection process, and then tunes a probabilistic neural network classifier to predict seizures within a 10 min prediction horizon. Initial seizure and interictal data were used for training, and the remaining IEEG data were used for testing.

Epileptic seizure prediction using hybrid feature selection over multiple intracranial EEG electrode contacts: a report of four patients.

Epileptic seizure prediction has steadily evolved from its conception in the 1970s, to proof-of-principle experiments in the late 1980s and 1990s, to its current place as an area of vigorous, clinical and laboratory investigation. As a step toward practical implementation of this technology in humans, we present an individualized method for selecting electroencephalogram (EEG) features and electrode locations for seizure prediction focused on precursors that occur within ten minutes of electrographic seizure onset. This method applies an intelligent genetic search process to EEG signals simultaneously collected from multiple intracranial electrode contacts and multiple quantitative features derived from these signals.

Detection of seizure precursors from depth-EEG using a sign periodogram transform.

Brief bursts of focal, low amplitude rhythmic activity have been observed on depth electroencephalogram (EEG) in the minutes before electrographic onset of seizures in human mesial temporal lobe epilepsy. We have found these periods to contain discrete, individualized synchronized activity in patient-specific frequency bands ranging from 20 to 40 Hz. We present a method for detecting and displaying these events using a periodogram of the sign-limited temporal derivative of the EEG signal, denoted joint sign periodogram event characterization transform (JSPECT).