We are delighted to present the Emerging Trends in Neuromodulatory Interventions 2021 article collection. This collection showcases the high-quality work of internationally recognized researchers in the early to mid-stages of their research careers. These rising star researchers have been recognized by the Frontiers in Pain Research Editors for their potential to influence the future directions in their respective fields. The work presented here highlights the diversity of research performed across the entire breadth of neuromodulatory interventions and presents advances in theory, experimental techniques and methodology along with their application. New articles will be added to this collection as they are published.

Baylor College of Medicine

University of Texas Southwestern Medical Center

Division of Gastroenterology and Hepatology, University of Michigan

University of Arizona

Frontiers in Pain Research

Neuromodulatory Interventions

Emerging Trends in Neuromodulatory Interventions

Epilepsy is a neurological disorder that affects more than 70 million people globally. A considerable proportion of epilepsy is resistant to anti-epileptic drugs (AED). For patients with drug-resistant epilepsy (DRE), who are not eligible for resective or ablative surgery, neuromodulation has been a palliative option. Since the approval of vagus nerve stimulation (VNS) in 1997, expansion to include other modalities, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), has led to improved seizure control in this population. In this article, we discuss the current updates and emerging trends on neuromodulation for epilepsy.

Epilepsy is a neurological disorder that affects more than 70 million people globally. A considerable proportion of epilepsy is resistant to anti-epileptic drugs (AED). For patients with drug-resistant epilepsy (DRE), who are not eligible for resective or ablative surgery, neuromodulation has been a palliative option. Since the approval of vagus nerve stimulation (VNS) in 1997, expansion to include other modalities, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), has led to improved seizure control in this population. In this article, we discuss the current updates and emerging trends on neuromodulation for epilepsy.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

IntroductionTrigeminal ganglion stimulation is a neuromodulatory surgical procedure utilized to treat trigeminal neuropathic pain. This technique involves the placement of a stimulating electrode adjacent to the trigeminal ganglion and can be trialed before permanent implantation. Wider adoption by surgical practitioners is currently limited by complications such as lead migration from the trigeminal ganglion, which can result in loss of therapy and cannot be rectified without repeat surgery. We describe a novel surgical modification that successfully anchors the trigeminal ganglion electrode long-term.</sec>ObjectiveTo describe a novel surgical technique for the anchoring of trigeminal ganglion stimulation electrodes and a case report of a patient with post-herpetic trigeminal neuropathic pain treated with this approach.</sec>MethodsAn electrode was inserted percutaneously through the foramen ovale into Meckel's cave, adjacent to the trigeminal ganglion. The lead was anchored using a modification of an existing anchoring device, which was inserted into the buccal incision. The lead was connected to a generator for therapeutic stimulation. The location of the lead was followed radiographically using serial lateral skull radiographs.</sec>ResultsA 74-year-old male with post-herpetic trigeminal neuropathic pain, who had failed prior surgical therapies, underwent trigeminal ganglion stimulation. The trial lead was anchored using standard techniques and migrated outward within 7 days, rendering the trial electrode ineffective. The permanent lead was anchored using the described novel technique and remained in position without clinically significant outward migration nor loss in targeted stimulation until the last follow-up at 6 months.</sec>ConclusionTrigeminal ganglion stimulation is an effective therapeutic option for medically refractory trigeminal neuropathic pain. The novel surgical adaptation described prevents the outward migration of the lead and enables stable long-term lead placement.</sec>

Introduction: Trigeminal ganglion stimulation is a neuromodulatory surgical procedure utilized to treat trigeminal neuropathic pain. This technique involves the placement of a stimulating electrode adjacent to the trigeminal ganglion and can be trialed before permanent implantation. Wider adoption by surgical practitioners is currently limited by complications such as lead migration from the trigeminal ganglion, which can result in loss of therapy and cannot be rectified without repeat surgery. We describe a novel surgical modification that successfully anchors the trigeminal ganglion electrode long-term.Objective: To describe a novel surgical technique for the anchoring of trigeminal ganglion stimulation electrodes and a case report of a patient with post-herpetic trigeminal neuropathic pain treated with this approach.Methods: An electrode was inserted percutaneously through the foramen ovale into Meckel's cave, adjacent to the trigeminal ganglion. The lead was anchored using a modification of an existing anchoring device, which was inserted into the buccal incision. The lead was connected to a generator for therapeutic stimulation. The location of the lead was followed radiographically using serial lateral skull radiographs.Results: A 74-year-old male with post-herpetic trigeminal neuropathic pain, who had failed prior surgical therapies, underwent trigeminal ganglion stimulation. The trial lead was anchored using standard techniques and migrated outward within 7 days, rendering the trial electrode ineffective. The permanent lead was anchored using the described novel technique and remained in position without clinically significant outward migration nor loss in targeted stimulation until the last follow-up at 6 months.Conclusion: Trigeminal ganglion stimulation is an effective therapeutic option for medically refractory trigeminal neuropathic pain. The novel surgical adaptation described prevents the outward migration of the lead and enables stable long-term lead placement.

Case Report: Novel Anchoring Technique and Surgical Nuances for Trigeminal Ganglion Stimulation in the Treatment of Post-Herpetic Trigeminal Neuropathic Facial Pain

IntroductionSpinal cord stimulation is emerging as a minimally invasive technique for treatment of persistent spinal pain syndrome (PSPS).</sec>MethodsWe describe a case series of 25 individuals with PSPS who underwent implantation of a spinal cord stimulator device between 2017 and 2021.</sec>ResultsThere was a significant reduction in mean visual analog scale pain scores in the immediate postoperative phase, (8.61 vs. 2.3, p < 0.001). There were twelve patients who consumed pre-operative opioid, and 75% showed reduction of use with a significantly lower average daily dose (66.8 vs. 26.9 meq/D, p < 0.05). There was a significant reduction in the Oswestry Disability Index during postoperative follow-up visits (p < 0.001). There were no major perioperative or long-term complications from the procedure in follow-up.</sec>ConclusionThe analysis of this cohort suggests successful long-term treatment of a diverse set of patients with PSPS who underwent spinal cord stimulation (SCS) and had meaningful improvement in quality of life and reduction in opioid consumption.</sec>

Introduction: Spinal cord stimulation is emerging as a minimally invasive technique for treatment of persistent spinal pain syndrome (PSPS).Methods: We describe a case series of 25 individuals with PSPS who underwent implantation of a spinal cord stimulator device between 2017 and 2021.Results: There was a significant reduction in mean visual analog scale pain scores in the immediate postoperative phase, (8.61 vs. 2.3, p &lt; 0.001). There were twelve patients who consumed pre-operative opioid, and 75% showed reduction of use with a significantly lower average daily dose (66.8 vs. 26.9 meq/D, p &lt; 0.05). There was a significant reduction in the Oswestry Disability Index during postoperative follow-up visits (p &lt; 0.001). There were no major perioperative or long-term complications from the procedure in follow-up.Conclusion: The analysis of this cohort suggests successful long-term treatment of a diverse set of patients with PSPS who underwent spinal cord stimulation (SCS) and had meaningful improvement in quality of life and reduction in opioid consumption.

Spinal Cord Stimulation as an Alternative to Opioid for Axial Neck and Back Pain: A Case Series

Introduction: Migraine is a chronic neurological disease that is the primary cause of years lived with disability in people under the age of 50. Remote electrical neuromodulation (REN) is a novel drug-free acute treatment of migraine, that is FDA cleared for episodic and chronic migraine. As a prescribed digital therapeutic, REN enables large-scale post-marketing research, thus providing real-world information on the use of the intervention in a wide range of populations, environments, and situations.Methods: The REN device (®Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 h post-treatment. Real-world data on REN treatments were collected via the app from patients across the United States who used Nerivio between October 1st, 2019, and May 24th, 2021. Data analysis focused on four metrics: 1. Per-treatment patterns of REN use as a standalone treatment vs. in combination with medications. 2. Per-user intra-individual efficacy across multiple treatments. 3. Distribution of treatment intensity among users (the electroceutical equivalent to treatment dose). 4. Prevalence and severity of adverse events.Results: 1. Out of 23,151 treatments, in 66.5% of treatments REN was used as a standalone treatment, in 12.9% it was followed by over-the-counter medications, and in 20.6% followed by prescription medications. 2. Out of 2,514 patients, response in at least 50% of treatments was achieved in 66.5% of cases for pain relief, and in 22.6% for pain freedom. 3. Out of 117,583 treatments, in 80% of cases intensity levels were between 18 and 55% of the stimulator's range. The mean intensity was 34.3% of the stimulator's output (±16.6%). 4. Out of 12,368 users (121,947 treatments), there were 59 users (0.48%) who reported device related adverse events, 56 (0.45%) of which were mild, three (0.03%) were moderate, and none were severe.Conclusions: The current analysis of real-world clinical data indicates that REN provides an efficacious, stable, and safe treatment option for acute treatment of migraine in real-world settings, both as a standalone replacement of pharmaceuticals, as well as an adjunct to medications.

Introduction: Migraine is a chronic neurological disease that is the primary cause of years lived with disability in people under the age of 50. Remote electrical neuromodulation (REN) is a novel drug-free acute treatment of migraine, that is FDA cleared for episodic and chronic migraine. As a prescribed digital therapeutic, REN enables large-scale post-marketing research, thus providing real-world information on the use of the intervention in a wide range of populations, environments, and situations.Methods: The REN device (®Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 h post-treatment. Real-world data on REN treatments were collected via the app from patients across the United States who used Nerivio between October 1st, 2019, and May 24th, 2021. Data analysis focused on four metrics: 1. Per-treatment patterns of REN use as a standalone treatment vs. in combination with medications. 2. Per-user intra-individual efficacy across multiple treatments. 3. Distribution of treatment intensity among users (the electroceutical equivalent to treatment dose). 4. Prevalence and severity of adverse events.Results: 1. Out of 23,151 treatments, in 66.5% of treatments REN was used as a standalone treatment, in 12.9% it was followed by over-the-counter medications, and in 20.6% followed by prescription medications. 2. Out of 2,514 patients, response in at least 50% of treatments was achieved in 66.5% of cases for pain relief, and in 22.6% for pain freedom. 3. Out of 117,583 treatments, in 80% of cases intensity levels were between 18 and 55% of the stimulator's range. The mean intensity was 34.3% of the stimulator's output (±16.6%). 4. Out of 12,368 users (121,947 treatments), there were 59 users (0.48%) who reported device related adverse events, 56 (0.45%) of which were mild, three (0.03%) were moderate, and none were severe.Conclusions: The current analysis of real-world clinical data indicates that REN provides an efficacious, stable, and safe treatment option for acute treatment of migraine in real-world settings, both as a standalone replacement of pharmaceuticals, as well as an adjunct to medications.

Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine

Over 50% of the 34 million people who suffer from diabetes mellitus (DM) are affected by diabetic neuropathy. Painful diabetic neuropathy (PDN) impacts 40–50% of that group (8.5 million patients) and is associated with a significant source of disability and economic burden. Though new neuromodulation options have been successful in recent clinical trials (NCT03228420), still there are many barriers that restrict patients from access to these therapies. We seek to examine our tertiary care center (Albany Medical Center, NY, USA) experience with PDN management by leveraging our clinical database to assess patient referral patterns and utilization of neuromodulation. We identified all patients with a diagnosis of diabetes type 1 (CODE: E10.xx) or diabetes type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE: G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4) who saw endocrinology, neurology, and/or neurosurgery from January 1, 2019, to December 31, 2019. We then determined which patients had received pain medications and/or neuromodulation to divide the cohort into three groups: no treatment, conservative treatment, and neuromodulation treatment. The cohorts were compared with chi-square or one-way ANOVA with multiple comparisons to analyze the differences. A total of 2,635 PDN patients were identified, of which 700 received no treatment for PDN, 1,906 received medication(s), and 29 received neuromodulation (intrathecal therapy, spinal cord stimulation, or dorsal root ganglion stimulation). The patients who received pain medications for PDN visited neurology more often than the pain specialists. Of the patients that received neuromodulation, 24 had seen neurology, 6 neurology pain, and 3 anesthesia pain. They averaged 2.78 pain medications prior to implant. Approximately 41% of the patients in the conservative management group were prescribed three or more medications. Of the 1,935 treated patients, only 1.5% of the patients received neuromodulation. The patients on three or more pain medications without symptomatic relief may be potential candidates for neuromodulation. An opportunity, therefore, exists to educate providers on the benefits of neuromodulation procedures.

Over 50% of the 34 million people who suffer from diabetes mellitus (DM) are affected by diabetic neuropathy. Painful diabetic neuropathy (PDN) impacts 40&#x2013;50% of that group (8.5 million patients) and is associated with a significant source of disability and economic burden. Though new neuromodulation options have been successful in recent clinical trials (NCT03228420), still there are many barriers that restrict patients from access to these therapies. We seek to examine our tertiary care center (Albany Medical Center, NY, USA) experience with PDN management by leveraging our clinical database to assess patient referral patterns and utilization of neuromodulation. We identified all patients with a diagnosis of diabetes type 1 (CODE: E10.xx) or diabetes type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE: G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4) who saw endocrinology, neurology, and/or neurosurgery from January 1, 2019, to December 31, 2019. We then determined which patients had received pain medications and/or neuromodulation to divide the cohort into three groups: no treatment, conservative treatment, and neuromodulation treatment. The cohorts were compared with chi-square or one-way ANOVA with multiple comparisons to analyze the differences. A total of 2,635 PDN patients were identified, of which 700 received no treatment for PDN, 1,906 received medication(s), and 29 received neuromodulation (intrathecal therapy, spinal cord stimulation, or dorsal root ganglion stimulation). The patients who received pain medications for PDN visited neurology more often than the pain specialists. Of the patients that received neuromodulation, 24 had seen neurology, 6 neurology pain, and 3 anesthesia pain. They averaged 2.78 pain medications prior to implant. Approximately 41% of the patients in the conservative management group were prescribed three or more medications. Of the 1,935 treated patients, only 1.5% of the patients received neuromodulation. The patients on three or more pain medications without symptomatic relief may be potential candidates for neuromodulation. An opportunity, therefore, exists to educate providers on the benefits of neuromodulation procedures.