A Definition of Neuromodulation and Classification of Implantable Electrical Modulation for Chronic Pain.

OBJECTIVES: Neuromodulation therapies use a variety of treatment modalities (eg, electrical stimulation) to treat chronic pain. These therapies have experienced rapid growth that has coincided with escalating confusion regarding the nomenclature surrounding these neuromodulation technologies. Furthermore, studies are often published without a complete description of the effective stimulation dose, making it impossible to replicate the findings. To improve clinical care and facilitate dissemination among the public, payors, research groups, and regulatory bodies, there is a clear need for a standardization of terms. APPROACH: We formed an international group of authors comprising basic scientists, anesthesiologists, neurosurgeons, and engineers with expertise in neuromodulation. Because the field of neuromodulation is extensive, we chose to focus on creating a taxonomy and standardized definitions for implantable electrical modulation of chronic pain. RESULTS: We first present a consensus definition of neuromodulation. We then describe a classification scheme based on the 1) intended use (the site of modulation and its indications) and 2) physical properties (waveforms and dose) of a neuromodulation therapy. CONCLUSIONS: This framework will help guide future high-quality studies of implantable neuromodulatory treatments and improve reporting of their findings. Standardization with this classification scheme and clear definitions will help physicians, researchers, payors, and patients better understand the applications of implantable electrical modulation for pain and guide informed treatment decisions.

Neurotechnology for Pain.

Neurotechnologies for treating pain rely on electrical stimulation of the central or peripheral nervous system to disrupt or block pain signaling and have been commercialized to treat a variety of pain conditions. While their adoption is accelerating, neurotechnologies are still frequently viewed as a last resort, after many other treatment options have been explored. We review the pain conditions commonly treated with electrical stimulation, as well as the specific neurotechnologies used for treating those conditions. We identify barriers to adoption, including a limited understanding of mechanisms of action, inconsistent efficacy across patients, and challenges related to selectivity of stimulation and off-target side effects. We describe design improvements that have recently been implemented, as well as some cutting-edge technologies that may address the limitations of existing neurotechnologies. Addressing these challenges will accelerate adoption and change neurotechnologies from last-line to first-line treatments for people living with chronic pain.

Dorsal Root Ganglion Stimulation for Chronic Pain: Hypothesized Mechanisms of Action.

Dorsal root ganglion stimulation (DRGS) is a neuromodulation therapy for chronic pain that is refractory to conventional medical management. Currently, the mechanisms of action of DRGS-induced pain relief are unknown, precluding both our understanding of why DRGS fails to provide pain relief to some patients and the design of neurostimulation technologies that directly target these mechanisms to maximize pain relief in all patients. Due to the heterogeneity of sensory neurons in the dorsal root ganglion (DRG), the analgesic mechanisms could be attributed to the modulation of one or many cell types within the DRG and the numerous brain regions that process sensory information. Here, we summarize the leading hypotheses of the mechanisms of DRGS-induced analgesia, and propose areas of future study that will be vital to improving the clinical implementation of DRGS. PERSPECTIVE: This article synthesizes the evidence supporting the current hypotheses of the mechanisms of action of DRGS for chronic pain and suggests avenues for future interdisciplinary research which will be critical to fully elucidate the analgesic mechanisms of the therapy.

Distinct perceptive pathways selected with tonic and bursting patterns of thalamic stimulation.

BACKGROUND: Novel patterns of electrical stimulation of the brain and spinal cord hold tremendous promise to improve neuromodulation therapies for diverse disorders, including tremor and pain. To date, there are limited numbers of experimental studies in human subjects to help explain how stimulation patterns impact the clinical response, especially with deep brain stimulation. We propose using novel stimulation patterns during electrical stimulation of somatosensory thalamus in awake deep brain stimulation surgeries and hypothesize that stimulation patterns will influence the sensory percept without moving the electrode. METHODS: In this study of 15 fully awake patients, the threshold of perception as well as perceptual characteristics were compared for tonic (trains of regularly-repeated pulses) and bursting stimulation patterns. RESULTS: In a majority of subjects, tonic and burst percepts were located in separate, non-overlapping body regions (i.e., face vs. hand) without moving the stimulating electrode (p < 0.001; binomial test). The qualitative features of burst percepts also differed from those of tonic-evoked percepts as burst patterns were less likely to evoke percepts described as tingling (p = 0.013; Fisher's exact test). CONCLUSIONS: Because somatosensory thalamus is somatotopically organized, percept location can be related to anatomic thalamocortical pathways. Thus, stimulation pattern may provide a mechanism to select for different thalamocortical pathways. This added control could lead to improvements in neuromodulation - such as improved efficacy and side effect attenuation - and may also improve localization for sensory prostheses.

Central neuromodulation for refractory pain.

Chronic neuropathic pain affects 8.2% of adults, extrapolated to roughly 18 million people every year in the United States. Patients who have pain that cannot be controlled with pharmacologic management or less invasive techniques can be considered for deep brain stimulation or motor cortex stimulation. These techniques are not currently approved by the Food and Drug Administration for chronic pain and are, thus, considered off-label use of medical devices for this patient population. Conclusive effectiveness studies are still needed to demonstrate the best targets as well as the reliability of the results with these approaches.

In vivo impedance spectroscopy of deep brain stimulation electrodes.

Deep brain stimulation (DBS) represents a powerful clinical technology, but a systematic characterization of the electrical interactions between the electrode and the brain is lacking. The goal of this study was to examine the in vivo changes in the DBS electrode impedance that occur after implantation and during clinically relevant stimulation. Clinical DBS devices typically apply high-frequency voltage-controlled stimulation, and as a result, the injected current is directly regulated by the impedance of the electrode-tissue interface. We monitored the impedance of scaled-down clinical DBS electrodes implanted in the thalamus and subthalamic nucleus of a rhesus macaque using electrode impedance spectroscopy (EIS) measurements ranging from 0.5 Hz to 10 kHz. To further characterize our measurements, equivalent circuit models of the electrode-tissue interface were used to quantify the role of various interface components in producing the observed electrode impedance. Following implantation, the DBS electrode impedance increased and a semicircular arc was observed in the high-frequency range of the EIS measurements, commonly referred to as the tissue component of the impedance. Clinically relevant stimulation produced a rapid decrease in electrode impedance with extensive changes in the tissue component. These post-operative and stimulation-induced changes in impedance could play an important role in the observed functional effects of voltage-controlled DBS and should be considered during clinical stimulation parameter selection and chronic animal research studies.

Experimental and theoretical characterization of the voltage distribution generated by deep brain stimulation.

Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease and shows great promise for numerous other disorders. While the fundamental purpose of DBS is to modulate neural activity with electric fields, little is known about the actual voltage distribution generated in the brain by DBS electrodes and as a result it is difficult to accurately predict which brain areas are directly affected by the stimulation. The goal of this study was to characterize the spatial and temporal characteristics of the voltage distribution generated by DBS electrodes. We experimentally recorded voltages around active DBS electrodes in either a saline bath or implanted in the brain of a non-human primate. Recordings were made during voltage-controlled and current-controlled stimulation. The experimental findings were compared to volume conductor electric field models of DBS parameterized to match the different experiments. Three factors directly affected the experimental and theoretical voltage measurements: 1) DBS electrode impedance, primarily dictated by a voltage drop at the electrode-electrolyte interface and the conductivity of the tissue medium, 2) capacitive modulation of the stimulus waveform, and 3) inhomogeneity and anisotropy of the tissue medium. While the voltage distribution does not directly predict the neural response to DBS, the results of this study do provide foundational building blocks for understanding the electrical parameters of DBS and characterizing its effects on the nervous system.