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Abstract Background Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain. Methods (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0–10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS. Results (1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI − 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen’s D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia. Conclusions Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 μs pulse width, 50 μs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11–17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal–Wallis: P < 0.05). However, stimulated CIA rats (n = 5–6) had significantly decreased inflammatory scores and ankle swelling (Kruskal–Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.

Vast scientific effort in recent years have been focused on the search for effective and safe treatments for cognitive decline. In this regard, non-invasive neuromodulation has gained increasing attention for its reported effectiveness in promoting the recovery of multiple cognitive domains after central nervous system damage. In this short review, we discuss the available evidence supporting a possible cognitive effect of trigeminal nerve stimulation (TNS). In particular, we ask that, while TNS has been widely and successfully used in the treatment of various neuropsychiatric conditions, as far as research in the cognitive field is concerned, where does TNS stand? The trigeminal nerve is the largest cranial nerve, conveying the sensory information from the face to the trigeminal sensory nuclei, and from there to the thalamus and up to the somatosensory cortex. On these bases, a bottom-up mechanism has been proposed, positing that TNS-induced modulation of the brainstem noradrenergic system may affect the function of the brain networks involved in cognition. Nevertheless, despite the promising theories, to date, the use of TNS for cognitive empowering and/or cognitive decline treatment has several challenges ahead of it, mainly due to little uniformity of the stimulation protocols. However, as the field continues to grow, standardization of practice will allow for data comparisons across studies, leading to optimized protocols targeting specific brain circuitries, which may, in turn, influence cognition in a designed manner.

Background: Most external peripheral nerve stimulation devices designed to alter mood states use electrical energy, but mechanical stimulation for activation of somatosensory pathways may be harnessed for potential therapeutic neuromodulation. A novel investigational device for Mechanical Affective Touch Therapy (MATT) was created to stimulate C-tactile fibers through gentle vibrations delivered by piezoelectric actuators on the bilateral mastoid processes. Methods: 22 adults with anxiety disorders and at least moderate anxiety symptom severity enrolled in an open-label pilot trial that involved MATT self-administration using a simple headset at home at least twice per day for 4 weeks. Resting EEG data were acquired before and after a baseline MATT session and again before the final MATT session. Self-report measures of mood and anxiety were collected at baseline, week 2, and week 4, while interoception was assessed pre- and post-treatment. Results: Anxiety and depressive symptoms improved significantly from baseline to endpoint, and mindfulness was enhanced. EEG metrics confirmed an association between acute MATT stimulation and oscillatory power in alpha and theta bands; symptom changes correlated with changes in some metrics. Conclusion: Open-label data suggest MATT is a promising non-invasive therapeutic approach to anxiety disorders that warrants further development. [ABSTRACT FROM AUTHOR]

Introduction: Current external peripheral nerve stimulation devices stimulate only one nerve. This prospective, randomized, double-blind, sham-controlled trial assessed efficacy, safety, and tolerability of a novel external combined occipital and trigeminal neurostimulation (eCOT-NS) device as a self-administered home treatment for migraine (Relivion®MG, Neurolief Ltd; Netanya, Israel). Methods: Episodic and chronic migraine subjects (N = 55) were randomized to receive active (n = 27) or sham (n = 28) treatment. Subjects received eCOT-NS devices and performed 60 ± 20-min home treatments within 45 min of migraine episode onset. The primary endpoint was relative (percent) change in mean baseline VAS pain scores 1 h after treatment initiation. Treatment outcomes assessed at 1-, 2-, and 24-h post-treatment initiation were pain reduction and proportion of pain-free subjects and treatment responders, defined as ≥ 50% pain reduction. Categorical pain ratings (none, mild, moderate, and severe pain) were also analyzed. Results: Active stimulation was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%), 2 h (52% vs. 17%), and 24 h (71% vs. 34%). Pain-free ratings were greater for the active treatment arm at 1 h (29.2% vs. 16%), 2 h (41.7% vs. 20%), and 24 h (65.2% vs. 40%). The number of subjects with baseline moderate or severe migraine pain who were pain-free at 2 h was significantly greater among active treatment subjects (43% vs. 10.5%). The responder rate was significantly higher among the active treatment group at 1 h (67% vs. 20%), 2 h (66.7% vs. 32%,), and 24 h (78.3% vs. 48%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (76% vs. 31.6%). Mild adverse events, reported by a minority of subjects, resolved spontaneously. Conclusions: eCOT-NS provides superior clinically meaningful relief and freedom from migraine pain, offering an effective and safe therapy for acute treatment of migraine. Trial registration: ClinicalTrials.gov Identifier NCT03398668. Plain Language Summary: As current external nerve stimulation devices stimulate only one nerve, this study assessed the effectiveness, safety, and tolerability of a new external nerve stimulation device that stimulates two nerves (occipital and trigeminal) as a self-administered home treatment for migraine (Relivion®MG, Neurolief Ltd; Netanya, Israel). Fifty-five subjects with episodic and chronic migraine were randomly assigned to active (n = 27) or sham (dummy) treatment (n = 28). Subjects performed a 60-min home treatment within 45 min of migraine onset. The primary endpoint was the change in pain intensity 1 h after treatment initiation. Active treatment was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%) and 2 h (52% vs. 17%). Pain-free ratings were also greater for the active treatment arm at 1 h (29.2% vs. 16%) and 2 h (41.7% vs. 20%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (66.7% vs. 32%). Mild, transient side effects reported by a few subjects resolved without treatment. This new external concurrent occipital and trigeminal neurostimulation (eCOT-NS) device provides superior and meaningful relief and freedom from migraine pain compared to sham treatment. [ABSTRACT FROM AUTHOR]

Background: Wireless percutaneous nerve stimulation (PNS) for chronic pain is rapidly evolving in the ever expanding neuromodulation paradigm. Safety and lower risks with a potential of long-term analgesia cannot be over emphasised especially with the ongoing opioid pandemic. PNS with an implanted pulse generator (IPG) has also been shown to provide good benefit, without often unpleasant widespread paraesthesia from conventional spinal cord stimulators. Aim and Methods: We retrospectively extracted data on all wireless PNS implants in our highly specialised pain neuromodulation centre since initiation of wireless PNS service in August 2019. Patient demographics, pain history, analgesic intake and details on implant follow-up data within 1 year post-implant including pain relief, EuroQol-5 Dimension (EQ-5D) and Patients' Global Impression of Change (PGIC) scores were extracted. The cases are presented in a narrative format. Result: A total of five patients were implanted with wireless (Stimwave®) PNS from August 2019 to February 2020. Neuropathic pain was the most common presenting diagnosis. All patients showed >50% pain relief at 3 months. EQ-5D and PGIC did not show any improvement in the subjects. Two of the patients managed to decrease their analgesics after implantation. Similar sustained benefits could not be demonstrated after 1 year. Discussion: PNS can provide analgesia in appropriately selected cases. Naivety of the technique and procedure might cause some degree of uncertainty. External pulse generator with wireless transmission avoids IPG and tunnelling related side effects, but requires individualised special wearable technology to power the lead. Minimally invasive nature of the technique might be attractive and preferable for patients with complex medical issues, nickel allergy and poor general health who may otherwise be unsuitable for Spinal Cord Stimulation (SCS) with conventional hardware. Robust prospective controlled studies and RCTs in future might provide further insights on utility in other neuropathic pain diagnosis, long-term outcomes and acceptability compared to conventional SCS. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition in patients who have received chemotherapy. The role of neuromodulation therapy in treating pain and improving neurological function in CIPN remains unclear and warrants evidence appraisal. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review to assess change in pain intensity and neurological function after implementation of any neuromodulation intervention for CIPN. Neuromodulation interventions consisted of dorsal column spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), or peripheral nerve stimulation (PNS). In total, 15 studies utilized SCS (16 participants), 7 studies utilized DRG-S (7 participants), and 1 study utilized PNS (50 participants). Per the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria, there was very low-quality GRADE evidence supporting that dorsal column SCS, DRG-S, and PNS are associated with a reduction in pain severity from CIPN. Results on changes in neurological function remained equivocal due to mixed study findings on thermal sensory thresholds and touch sensation or discrimination. Future prospective, well-powered, and comparative studies assessing neuromodulation for CIPN are warranted. [ABSTRACT FROM AUTHOR]

Spinal cord stimulation (SCS) is effective for the treatment of chronic intractable pain of the trunk and limbs. The mechanism of action may be based, at least in part, upon the gate control theory; however, new waveforms may suggest other mechanisms. Although benefits of the SCS technology generally outweigh the complications associated with SCS, some complications such as infection and skin erosion over the implant can result in device removal. Additional reasons for device removal, such as pocket pain and battery depletion, have driven technological innovations including battery‐free implants and device miniaturization. The neurostimulation system described here was specifically designed to address complications commonly associated with implantable batteries and/or larger implantable devices. The benefits of the small size are further augmented by a minimally invasive implant procedure. Usability data show that patients found this novel neurostimulation system to be easy to use and comfortable to wear. What is more, clinical data demonstrate that the use of this system provides statistically significant reduction in pain scores with responder rates (defined as ≥50% reduction in pain) of 78% in the low back and 83% in the leg(s). Advances in miniaturization technology arose from the considerable shrinkage of the integrated circuit, with an increase in performance, according to Moore's law (1965). However, commensurate improvements in battery technology have not maintained a similar pace. This has prompted some manufacturers to place the battery outside, against the skin, thereby allowing a massive reduction in the implant volume, with the hopes of fewer device‐related complications. [ABSTRACT FROM AUTHOR]

The article presents a case of a 45 year old woman with C5-C7 fusion who was rushed to a clinic due to chronic left sided shoulder pain reflective of surgeries and interventional pain procedures like cervical spinal cord stimulation to discuss the unexpected motor response of peripheral nerve stimulation (PNS) in a patient with chronic shoulder pain. Other topics include the abnormal motor response to neurostimulation.

Chronic pain affects about 100 million adults in the US and is primarily treated with drugs, which can have significant side effects. A promising alternative therapy is electrical peripheral nerve stimulation (PNS) treatment. However, it has been associated with suboptimal efficacy since its modulation mechanisms are unclear, and the current therapies are primarily open-loop (i.e. manually adjusting the stimulation parameters). Critical to advancing PNS treatment is a deeper understanding of pain processing, but the pain system is difficult to probe experimentally and analyze via mathematical models. Previously, mechanistic models of pain transmission have been developed to investigate modulation mechanisms but are nonlinear and high-dimensional. In this work, we construct linear phenomenological models of spinal cord activity in chronic pain and healthy conditions derived from state-of-the-art electrophysiological recordings from rats. We can then accurately predict the neural responses to electrical stimulation of the peripheral nerve in both conditions. We then apply H ∞ control systems techniques to drive the dynamics of the chronic pain model into normal ranges of physiological pain by using closed-loop control of the PNS. This proof-of-concept computational framework will guide the development of new closed-loop PNS therapies for chronic pain, one of the most prevalent diseases on earth. [ABSTRACT FROM AUTHOR]

Peripheral nerve stimulation (PNS) is rapidly increasing in use. This interventional pain treatment modality involves modulating peripheral nerves for a variety of chronic pain conditions. This review evaluated its use specifically in the context of chronic lower extremity pain. Studies continue to elucidate the utility of PNS and better define indications, contraindications, as well as short- and long-term benefits of the procedure for the lower extremity. While large, prospective evidence is still lacking, the best available evidence suggests that improvements may be seen in pain scores, functionality, and opioid consumption. Overall, evidence synthesis suggests that PNS for the lower extremities may be a viable option for patients with chronic lower extremity pain. [ABSTRACT FROM AUTHOR]

BackgroundPeripheral nerve stimulation has been used for decades to treat chronic pain but has not been used for postoperative analgesia due to multiple limitations, beginning with invasive electrode placement. With the development of small-diameter/gauge leads enabling percutaneous insertion, ultrasound guidance for accurate introduction, and stimulators small enough to be adhered to the skin, neurostimulation may now be provided in a similar manner to continuous peripheral nerve blocks. Here, we report on the use of ultrasound-guided percutaneous peripheral nerve stimulation to treat postoperative pain.Materials and methodsSubjects within 60 days of a total knee arthroplasty with pain insufficiently treated with oral analgesics had a 0.2-mm-diameter electrical lead (pre-loaded into a 20 gauge needle) introduced percutaneously using ultrasound guidance with the tip located approximately 0.5-1.0 cm from the femoral nerve (a second lead was inserted approximately 1.0-3.0 cm from the sciatic nerve for posterior knee pain). An external stimulator delivered current. Endpoints were assessed before and after lead insertion and the leads subsequently removed. Due to the small sample size for this pilot/feasibility study, no statistics were applied to the data.ResultsLeads were inserted in subjects (n = 5) 8-58 days postoperatively. Percutaneous peripheral nerve stimulation decreased pain an average of 93% at rest (from a mean of 5.0 to 0.2 on a 0-10 numeric rating scale), with 4 of 5 subjects experiencing complete resolution of pain. During passive and active knee motion pain decreased an average of 27 and 30%, respectively. Neither maximum passive nor active knee range-of-motion was consistently affected.ConclusionsUltrasound-guided percutaneous peripheral nerve stimulation may be a practical modality for the treatment of postoperative pain following orthopedic surgical procedures, and further investigation appears warranted.

To simultaneously treat phantom limb pain (PLP) and restore somatic sensations using peripheral nerve stimulation (PNS), two bilateral transradial amputees were implanted with stimulating electrodes in the proximity of the medial, ulnar and radial nerves. Application of PNS evoked tactile and proprioceptive sensations in the phantom hand. Both patients learned to determine the shape of invisible objects by scanning a computer tablet with a stylus while receiving feedback based on PNS or transcutaneous electrical nerve stimulation (TENS). Оne patient learned to use PNS as feedback from the prosthetic hand that grasped objects of different sizes. PNS abolished PLP completely in one patient and reduced it by 40–70% in the other. We suggest incorporating PNS and/or TENS in active tasks to reduce PLP and restore sensations in amputees. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain (NP) is characterized by abnormal activation of pain conducting pathways and manifests as mechanical allodynia and thermal hypersensitivity. Peripheral nerve stimulation is used for treatment of medically refractory chronic NP and has been shown to reduce neuroinflammation. However, whether sciatic nerve stimulation (SNS) is of therapeutic benefit to NP remains unclear. Moreover, the optimal frequency for SNS is unknown. To address this research gap, we investigated the effect of SNS in an acute NP rodent model.Methods: Rats with right L5 nerve root ligation (NRL) or Sham surgery were used. Ipsilateral SNS was performed at 2 Hz, 20 Hz, and 60 Hz frequencies. Behavioral tests were performed to assess pain and thermal hypersensitivity before and after NRL and SNS. Expression of inflammatory proteins in the L5 spinal cord and the immunohistochemical alterations of spinal cord astrocytes and microglia were examined on post-injury day 7 (PID7) following NRL and SNS. The involvement of the descending pain modulatory pathway was also investigated.Results: Following NRL, the rats showed a decreased pain threshold and latency on the von Frey and Hargreaves tests. The immunofluorescence results indicated hyperactivation of superficial spinal cord dorsal horn (SCDH) neurons. Both 2-Hz and 20-Hz SNS alleviated pain behavior and hyperactivation of SCDH neurons. On PID7, NRL resulted in elevated expression of spinal cord inflammatory proteins including NF-κB, TNF-α, IL-1β, and IL-6, which was mitigated by 2-Hz and 20-Hz SNS. Furthermore, 2-Hz and 20-Hz SNS suppressed the activation of spinal cord astrocytes and microglia following NRL on PID7. Activity of the descending serotoninergic pain modulation pathway showed an increase early on PID1 following 2-Hz and 20-Hz SNS.Conclusions: Our results support that both 2-Hz and 20-Hz SNS can alleviate NP behaviors and hyperactivation of pain conducting pathways. We showed that SNS regulates neuroinflammation and reduces inflammatory protein expression, astrocytic gliosis, and microglia activation. During the early post-injury period, SNS also facilitates the descending pain modulatory pathway. Taken together, these findings support the therapeutic potential of SNS for acute NP. [ABSTRACT FROM AUTHOR]

Aim: Novel minimally invasive short‐term and long‐term peripheral nerve stimulation (PNS) systems have revolutionized targeted treatment of chronic neuropathic pain. We present an international survey of PNS‐implanting pain physicians to assess what factors they consider when offering permanent PNS. Methods: This cross‐sectional study consisted of a survey (Qualtrics) that was distributed to PNS‐implanting physicians in a device supplier's entire email database on November 13, 2020, with 3 weeks of response time. Physicians' contact information in the form of their email addresses had been previously collected by the supplier upon device distribution with permission to use survey responses for research. Results: Of 2032 database physicians, 40 physicians representing 37 institutions responded to the survey. The most common application of PNS was mononeuropathic pain (57%). The most frequently targeted nerve was the suprascapular nerve (29%). 14% of physicians reported 81–100% of their implants were dual‐lead. The representative physicians ranged broadly in their most frequently targeted nerves. Although mononeuropathic pain was the most common indication for PNS, there was still varied response regarding other indications such as CRPS and post‐surgical chronic pain. Conclusion: In context of a low response rate, identifying such factors can help update the prevailing treatment algorithm for interventional therapies, assist pain physicians in better identifying which patients are the best candidates for PNS, and inform future clinical trial design on PNS efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Repeated sprint ability is an integral component of team sports. This study aimed to evaluate fatigability development and its aetiology during and immediately after a cycle repeated sprint exercise performed until a given fatigability threshold. Methods: On an innovative cycle ergometer, 16 healthy males completed an RSE (10-s sprint/28-s recovery) until task failure (TF): a 30% decrease in sprint mean power (Pmean). Isometric maximum voluntary contraction of the quadriceps (IMVC), central alterations [voluntary activation (VA)], and peripheral alterations [twitch (Pt)] were evaluated before (pre), immediately after each sprint (post), at TF and 3 min after. Sprints were expressed as a percentage of the total number of sprints to TF (TSTF). Individual data were extrapolated at 20, 40, 60, and 80% TSTF. Results: Participants completed 9.7 ± 4.2 sprints before reaching a 30% decrease in Pmean. Post-sprint IMVCs were decreased from pre to 60% TSTF and then plateaued (pre: 345 ± 56 N, 60% 247 ± 55 N, TF: 233 ± 57 N, p < 0.001). Pt decreased from 20% and plateaued after 40% TSTF (p < 0.001, pre-TF = − 45 ± 13%). VA was not significantly affected by repeated sprints until 60% TSTF (pre-TF = − 6.5 ± 8.2%, p = 0.036). Unlike peripheral parameters, VA recovered within 3 min (p = 0.042). Conclusion: During an RSE, Pmean and IMVC decreases were first concomitant to peripheral alterations up to 40% TSTF and central alterations was only observed in the second part of the test, while peripheral alterations plateaued. The distinct recovery kinetics in central versus peripheral components of fatigability further confirm the necessity to reduce traditional delays in neuromuscular fatigue assessment post-exercise. [ABSTRACT FROM AUTHOR]

Purpose: The use of high‐performance gradient systems (i.e., high gradient strength and/or high slew rate) for human MRI is limited by physiological effects (including the elicitation of magnetophosphenes and peripheral nerve stimulation (PNS)). These effects, in turn, depend on the interaction between time‐varying magnetic fields and the body, and thus on the participant's position with respect to the scanner's isocenter. This study investigated the occurrence of magnetophosphenes and PNS when scanning participants on a high‐gradient (300 mT/m) system, for different gradient amplitudes, ramp times, and participant positions. Methods: Using a whole‐body 300 mT/m gradient MRI system, a cohort of participants was scanned with the head, heart, and prostate at magnet isocenter and a train of trapezoidal bipolar gradient pulses, with ramp times from 0.88 to 4.20 ms and gradient amplitudes from 60 to 300 mT/m. Reports of magnetophosphenes and incidental reports of PNS were obtained. A questionnaire was used to record any additional subjective effects. Results: Magnetophosphenes were strongly dependent on participant position in the scanner. 87% of participants reported the effect with the heart at isocenter, 33% with the head at isocenter, and only 7% with the prostate at isocenter. PNS was most widely reported by participants for the vertical gradient axis (67% of participants), and was the dominant physiological effect for ramp times below 2 ms. Conclusion: This study evaluates the probability of eliciting magnetophosphenes during whole‐body imaging using an ultra‐strong gradient MRI system. It provides empirical guidance on the use of high‐performance gradient systems for whole‐body human MRI. [ABSTRACT FROM AUTHOR]

Chronic shoulder pain not relieved by either conservative or surgical management is referred to as chronic refractory shoulder pain. This is a retrospective case series where chronic refractory shoulder pain patients were treated either with peripheral nerve stimulation (PNS) or with pulsed radiofrequency (p-RF) therapy to the suprascapular nerve. Both patients receiving PNS reported 100% pain relief for the first month. At the 3- and 6-month follow-ups, one patient continued to experience 100% relief while the other reported 90% relief. One patient undergoing p-RF experienced about 90% pain relief at both 1- and 3-month intervals and 0% relief at the 6-month interval. The other patient with p-RF experienced 33% relief at 1-month and 0% relief thereafter. No patient reported any complications. The results of previous randomized controlled trials evaluating the efficacy of p-RF administered to the suprascapular nerve were mixed, and there is a lack of published studies on PNS effects. Neuromodulation of the suprascapular nerve can be effective for chronic refractory shoulder pain patients. Larger scale randomized controlled trials comparing PNS and p-RF are needed to better understand their respective therapeutic capacity.

Timothy R Deer,1 Sam Eldabe,2 Steven M Falowski,3 Marc A Huntoon,4 Peter S Staats,5 Isaac R Cassar,6 Nathan D Crosby,6 Joseph W Boggs6 1The Spine and Nerve Center of the Virginias, Charleston, WV, USA; 2Department of Pain Medicine, The James Cook University Hospital, Middlesbrough, UK; 3Department of Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 4Anesthesiology, Virginia Commonwealth University Medical Center, Richmond, VA, USA; 5Premier Pain Centers, Shrewsbury, NJ, USA; 6SPR Therapeutics, Cleveland, OH, USACorrespondence: Timothy R DeerThe Spine and Nerve Center of the Virginias, 400 Court Street, Suite 100, Charleston, WV, 25301, USATel +1 304/347-6141Fax +1 304/347-6855Email doctdeer@aol.comAbstract: Peripheral nerve stimulation (PNS) is an effective tool for the treatment of chronic pain, although its efficacy and utilization have previously been significantly limited by technology. In recent years, purpose-built percutaneous PNS devices have been developed to overcome the limitations of conventional permanently implanted neurostimulation devices. Recent clinical evidence suggests clinically significant and sustained reductions in pain can persist well beyond the PNS treatment period, outcomes that have not previously been observed with conventional permanently implanted neurostimulation devices. This narrative review summarizes mechanistic processes that contribute to chronic pain, and the potential mechanisms by which selective large diameter afferent fiber activation may reverse these changes to induce a prolonged reduction in pain. The interplay of these mechanisms, supported by data in chronic pain states that have been effectively treated with percutaneous PNS, will also be discussed in support of a new theory of pain management in neuromodulation: Peripherally Induced Reconditioning of the Central Nervous System (CNS).Keywords: chronic pain, neuromodulation, peripheral nerve stimulation, cortical plasticity, peripherally induced reconditioning, mechanism of action

Abstract Background Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. Methods We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. Results Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p

Objectives: Earlier studies have shown how chronic spinal cord injury (SCI) patients have benefitted from paired associative stimulation (PAS), consisting of high-frequency peripheral nerve stimulation (PNS) and high-intensity transcranial magnetic stimulation (TMS). Since high-frequency PNS is poorly characterized, its therapeutic effect without TMS should be evaluated. We tested the effect of PNS combined with motor imagery in chronic SCI patients using the same parameters of PNS as in earlier PAS-based studies that also used TMS. Methods: Five patients with chronic incomplete SCI and tetraplegia received a 6-week treatment of PNS combined with motor imagery to the weaker upper limb. Patients were evaluated with Manual Muscle Testing (MMT), hand function tests (Box and block, grip and pinch strength dynamometry), and spasticity. Results: There was no significant change in hand function tests or spasticity. MMT values improved significantly immediately after the PNS period (0.59 ± 0.17, p = 0.043) and in the 1-month follow-up visit (0.87 ± 0.18, p = 0.043). However, improvement of MMT values was weaker than in chronic tetraplegic patients in a corresponding PAS study that used identical PNS stimulation but also included the TMS component omitted here (Tolmacheva et al., 2019a, Clin Neurophysiol Pract). Conclusions: The lack of effect on functional hand tests with the protocol presented here suggests that the synergistic effect of PNS and TMS components is essential for the full therapeutic effect previously observed with PAS intervention. The moderate improvement of the MMT score suggests the possible usefulness of PNS and motor imagery for some of those tetraplegic SCI patients who have contraindications to TMS. Significance: These results add to the understanding of the PAS therapeutic mechanism by highlighting the importance of dual stimulation for achieving the full therapeutic effect of long-term PAS with a high-frequency PNS component.

Haptic perception is a vital part of the human experience that enriches our engagement with the world, but the ability to provide haptic information in virtual reality (VR) environments is limited. Neurostimulation-based sensory feedback has the potential to enhance the immersive experience within VR environments by supplying relevant and intuitive haptic feedback related to interactions with virtual objects. Such feedback may contribute to an increase in the sense of presence and realism in VR and may contribute to the improvement of virtual reality simulations for future VR applications. This work developed and evaluated xTouch, a neuro-haptic platform that extends the sense of touch to virtual environments. xTouch is capable of tracking a user’s grasp and manipulation interactions with virtual objects and delivering haptic feedback based on the resulting grasp forces. Seven study participants received haptic feedback delivered via multi-channel transcutaneous electrical stimulation of the median nerve at the wrist to receive the haptic feedback. xTouch delivered different percept intensity profiles designed to emulate grasp forces during manipulation of objects of different sizes and compliance. The results of a virtual object classification task showed that the participants were able to use the active haptic feedback to discriminate the size and compliance of six virtual objects with success rates significantly better than the chance of guessing it correctly (63.9 ± 11.5%, chance = 16.7%, p < 0.001). We demonstrate that the platform can reliably convey interpretable information about the physical characteristics of virtual objects without the use of hand-mounted devices that would restrict finger mobility. Thus, by offering an immersive virtual experience, xTouch may facilitate a greater sense of belonging in virtual worlds.

Implantable electrical nerve stimulation (ENS) can be used to treat neuropathic pain caused by herpes zoster. However, little is known about the cortical mechanism underlying neuromodulation therapy. Here, we recorded a 16-channel resting-state electroencephalogram after the application of spinal cord stimulation (n = 5) or peripheral nerve stimulation (n = 3). The neuromodulatory effect was compared between specific conditions (active ENS versus rest). To capture the cortical responses of ENS, spectral power and coherence analysis were performed. ENS therapy achieved satisfactory relief from pain with a mean visual analog scale score reduction of 5.9 ± 1.1. The spectral analysis indicated that theta and alpha oscillations increased significantly during active neuromodulation compared with the resting state. Furthermore, ENS administration significantly increased frontal-frontal coherence in the alpha band. Our findings demonstrate that, despite methodological differences, both spinal cord and peripheral nerve stimulation can induce cortical alpha oscillation changes in patients with zoster-related pain. The dynamic change may, in part, mediate the analgesic effect of ENS on herpes zoster–related pain.

BackgroundMost external peripheral nerve stimulation devices designed to alter mood states use electrical energy, but mechanical stimulation for activation of somatosensory pathways may be harnessed for potential therapeutic neuromodulation. A novel investigational device for Mechanical Affective Touch Therapy (MATT) was created to stimulate C-tactile fibers through gentle vibrations delivered by piezoelectric actuators on the bilateral mastoid processes.Methods22 adults with anxiety disorders and at least moderate anxiety symptom severity enrolled in an open-label pilot trial that involved MATT self-administration using a simple headset at home at least twice per day for 4 weeks. Resting EEG data were acquired before and after a baseline MATT session and again before the final MATT session. Self-report measures of mood and anxiety were collected at baseline, week 2, and week 4, while interoception was assessed pre- and post-treatment.ResultsAnxiety and depressive symptoms improved significantly from baseline to endpoint, and mindfulness was enhanced. EEG metrics confirmed an association between acute MATT stimulation and oscillatory power in alpha and theta bands; symptom changes correlated with changes in some metrics.ConclusionOpen-label data suggest MATT is a promising non-invasive therapeutic approach to anxiety disorders that warrants further development.

The article presents the discussion on Occipital neuralgia (ON) also known as C2 neuralgia or Arnold's neuralgia. Topics include characterized as unilateral or bilateral paroxysmal shooting or stabbing pain in the posterior part of the scalp; and use of coiled, smaller-gauge, flexible leads associated with significantly fewer infections.

Purpose of Review: Despite the rapid advance in anti-cancer treatment in recent years, the treatment to cancer-related pain remains largely unchanged. One systemic review has shown that approximately 32% of patient with cancer-related pain were undertreated. While in patients responding to strong opioids, long-term use of opioids will lead to many undesired side effects such as constipation, tolerance, and addiction. The goals of this review are to re visit the current algorism of cancer pain management and bring attention to the emerging interventional pain management techniques. Recent Findings: Peripheral nerve stimulation (PNS) has been successfully used to treat certain types of chronic non-cancer pain with long-term analgesic effect. PNS has also brought some promising results in treating localized cancer-related pain in a pilot study. Summary: More studies are needed to advance the novel and safe treatment of cancer-related pain. Incorporating interventional techniques such as PNS properly can optimize the current treatment strategy and improve outcomes. [ABSTRACT FROM AUTHOR]

Purpose: A novel silent imaging method is proposed that combines a gradient insert oscillating at the inaudible frequency 20 kHz with slew rate‐limited gradient waveforms to form a silent gradient axis that enable quiet and fast imaging. Methods: The gradient insert consisted of a plug‐and‐play (45 kg) single axis z‐gradient, which operated as an additional fourth gradient axis. This insert was made resonant using capacitors and combined with an audio amplifier to allow for operation at 20 kHz. The gradient field was characterized using field measurements and the physiological effects of operating a gradient field at 20 kHz were explored using peripheral nerve stimulation experiments, tissue heating simulations and sound measurements. The imaging sequence consisted of a modified gradient‐echo sequence which fills k‐space in readout lanes with a width proportional to the oscillating gradient amplitude. The feasibility of the method was demonstrated in‐vivo using 2D and 3D gradient echo (GRE) sequences which were reconstructed using a conjugate‐gradient SENSE reconstruction. Results: Field measurements yielded a maximum gradient amplitude and slew rate of 40.8 mT/m and 5178T/m/s at 20 kHz. Physiological effects such as peripheral nerve stimulation and tissue heating were found not to be limiting at this amplitude and slew rate. For a 3D GRE sequence, a maximum sound level of 85 db(A) was measured during scanning. Imaging experiments using the silent gradient axis produced artifact free images while also featuring a 5.3‐fold shorter scan time than a fully sampled acquisition. Conclusion: A silent gradient axis provides a novel pathway to fast and quiet brain imaging. [ABSTRACT FROM AUTHOR]

Background: There is growing recognition of peripheral stimulation techniques for controlling arm symptoms in essential tremor (ET). Recently, the FDA gave clearance to the Cala system, a device worn around the wrist to treat arm tremors. The Cala system stimulates the sensory afferents of the peripheral nerves with high-frequency pulses. These pulses are delivered to the median and radial nerves alternately at the tremor frequency of the individual patient. Methods: The PubMed database was searched using the terms ("Essential Tremor"[Mesh] OR "essential tremor" [Title/Abstract] OR "tremor" [Title/Abstract]) AND ("peripheral arm stimulation" [Title/Abstract] OR "Cala device" [Title/Abstract] OR "sensory afferent stimulation" [Title/Abstract] OR "afferent stimulation" [Title/Abstract] OR "arm stimulation" [Title/Abstract] OR "peripheral nerve stimulation" [Title/Abstract]). Results: The search yielded 54 articles. Many studies discussed the rationale and various strategies for peripheral modulation of tremor. While the Cala system was found to be safe and well-tolerated in ET, data on efficacy revealed mixed findings. In a large randomized, blinded trial (n = 77), the primary outcome evaluated with spiral drawing task did not improve but the secondary outcomes reflected by the arm tremor severity and the activities of the daily living score revealed 20-25% improvements. A subsequent trial (n = 323) found that the in-home use of the Cala device led to improvements of similar magnitude lasting for at least three months but the clinical assessments were open-labeled. Discussion: Peripheral stimulation techniques are promising therapeutic modalities for treating ET symptoms. Stimulation of sensory afferent nerve fibers at the wrist can potentially modulate the peripheral and central components of the tremor network. Although the Cala system is user-friendly, safe, and well-tolerated, the current clinical evidence on the efficacy is inconsistent and insufficient. Thus, more data is warranted for implementing peripheral nerve stimulation as a standard of care for ET. [ABSTRACT FROM AUTHOR]

Purpose: Peripheral nerve stimulation (PNS) modeling has a potential role in designing and operating MRI gradient coils but requires computationally demanding simulations of electromagnetic fields and neural responses. We demonstrate compression of an electromagnetic and neurodynamic model into a single versatile PNS matrix (P‐matrix) defined on an intermediary Huygens' surface to allow fast PNS characterization of arbitrary coil geometries and body positions. Methods: The Huygens' surface approach divides PNS prediction into an extensive pre‐computation phase of the electromagnetic and neurodynamic responses, which is independent of coil geometry and patient position, and a fast coil‐specific linear projection step connecting this information to a specific coil geometry. We validate the Huygens' approach by performing PNS characterizations for 21 body and head gradients and comparing them with full electromagnetic‐neurodynamic modeling. We demonstrate the value of Huygens' surface‐based PNS modeling by characterizing PNS‐optimized coil windings for a wide range of patient positions and poses in two body models. Results: The PNS prediction using the Huygens' P‐matrix takes less than a minute (instead of hours to days) without compromising numerical accuracy (error ≤ 0.1%) compared to the full simulation. Using this tool, we demonstrate that coils optimized for PNS at the brain landmark using a male model can also improve PNS for other imaging applications (cardiac, abdominal, pelvic, and knee imaging) in both male and female models. Conclusion: Representing PNS information on a Huygens' surface extended the approach's ability to assess PNS across body positions and models and test the robustness of PNS optimization in gradient design. [ABSTRACT FROM AUTHOR]

Francis Houde, 1– 3 Marie-Philippe Harvey, 1, 3 Pierre-François Tremblay Labrecque, 1, 3 Francis Lamarche, 1, 3 Alexandra Lefebvre, 1, 3 Leonard Guillaume 1, 3 1Research Center on Aging, CIUSSS de l’Estrie - CHUS, Université de Sherbrooke, Sherbrooke, Québec, Canada; 2Research Center of the Centre hospitalier universitaire de Sherbrooke (CHUS), CIUSSS de l’Estrie – CHUS, Université de Sherbrooke, Sherbrooke, Québec, Canada; 3Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, CanadaCorrespondence: Leonard GuillaumeCentre de recherche sur le vieillissement, CIUSSS de l’Estrie - CHUS, 1036, rue Belvédère Sud, Sherbrooke, Québec J1H 4C4, CanadaTel +1 (819) 829-7131 ext. 45246Fax +1 (819) 820-6864Email guillaume.leonard2@usherbrooke.caPurpose: Complex regional pain syndrome (CRPS) is a rare neuropathic pain condition characterized by sensory, motor and autonomic alterations. Previous investigations have shown that transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) can alleviate pain in various populations, and that a combination of these treatments could provide greater hypoalgesic effects. In the present case report, we describe the effect of tDCS and TENS treatment on pain intensity and unpleasantness in a patient suffering from chronic CRPS.Results: The patient was a 37-year-old woman, suffering from left lower limb CRPS (type I) for more than 5 years. Despite medication (pregabalin, tapentadol, duloxetine), rehabilitation treatments (sensorimotor retraining, graded motor imagery) and spinal cord stimulation (SCS), the participant reported moderate to severe pain. Treatments of tDCS alone (performed with SCS turned off during tDCS application, 1 session/day, for 5 consecutive days) did not significantly decrease pain. Combining tDCS with TENS (SCS temporarily turned off during tDCS, 1 session/day, for 5 consecutive days) slightly reduced pain intensity and unpleasantness.Discussion: Our results suggest that combining tDCS and TENS could be a therapeutic strategy worth investigating further to relieve pain in chronic CRPS patients. Future studies should examine the efficacy of combined tDCS and TENS treatments in CRPS patients, and other chronic pain conditions, with special attention to the cumulative and long-term effects and its effect on function and quality of life.Keywords: chronic pain, neuropathic pain, electrotherapy, peripheral electrical stimulation, peripheral nerve stimulation, non-invasive brain stimulation

Chronic low back pain remains highly prevalent, costly, and the leading cause of disability worldwide. Symptoms are complex and treatment involves an interdisciplinary approach. Due to diverse anatomical etiologies, treatment outcomes with interventional options are highly variable. A novel approach to treating chronic axial low back pain entails the use of peripheral nerve stimulation to the lumbar medial branch nerve, and this review examines the clinical data of the two different, commercially available, non-spinal neuromodulation systems. This review provides the clinician a succinct narrative that presents up-to-date data objectively. Our review found ten clinical studies, including one report of two cases, six prospective studies, and three randomized clinical trials published to date. Currently, there are different proposed mechanisms of action to address chronic axial low back pain with different implantation techniques. Evidence suggests that peripheral nerve stimulation of the lumbar medial branch nerve may be effective in improving pain and function in patients with chronic axial low back pain symptoms at short and long term follow up, with good safety profiles. Further long-term data is needed to consider this intervention earlier in the pain treatment algorithm, but initial data are promising.

Background: Peripheral neuropathy is estimated to be prevalent in up to 12% of the population, increasing to 30% in older demographics. This makes peripheral neuropathy one of the most common neurological diseases in the United States., Objectives: This retrospective study aims to report on the efficacy and safety of peripheral nerve stimulation (PNS) on the treatment of peripheral neuropathy in a commercial setting., Study Design: This was a retrospective study. A chart review was conducted for all eligible study patients., Setting: This study was conducted at the Advanced Spine and Pain Center in San Antonio, a center focused on physical medicine and rehabilitation, pain management and advanced interventional procedures that effectively ease pain., Methods: From September 2018 through July 2022, a total of 63 consecutive patients with peripheral neuropathy who presented with chronic pain symptoms originating from the shoulder, hip, knee, ankle, and groin were trialed in this study. All patients were required to be at least 18 years old. These patients underwent PNS therapy via implantation of the Freedom® PNS System (Curonix LLC) in order to treat their chronic pain related to or due to peripheral neuropathy from various peripheral nerve origins., Results: The mean Numeric Rating Scale (NRS-11) score of 63 patients at baseline was 7.24 (SD, 1.80). At 2-3 weeks postimplantation, the mean NRS-11 score decreased to 3.43 (SD, 2.38). A total of 53 out of the 63 patients reported a reduction in their NRS-11 score at the 2-3 week follow-up. A total of 24 patients completed a long-term follow-up. The mean follow-up time was 763.13 days (SD, 428.42); all patients had their PNS system permanently implanted for at least 8 months (range, 255-1,592 days)., Limitations: This was a retrospective study investigating the efficacy and safety of the Freedom® PNS System in patients with peripheral neuropathy. We were limited to the data available in the patient charts., Conclusion: PNS effectively treats chronic pain due to peripheral neuropathy for patients who have failed other conservative treatments.

Introduction: We recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS)., Methods: We explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz., Results: Suprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50-1000 Hz stimulation and C-fibers blocked by 10-50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS., Discussion: The current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (<100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders., Competing Interests: BF is the co-founder and President of C.F. Neuromedics Inc., a start-up company working on neural devices for treating pain. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Chen, Ladez, Seferge, Liu and Feng.)

Background: Adults with refractory, mechanical chronic low back pain associated with impaired neuromuscular control of the lumbar multifidus muscle have few treatment options that provide long-term clinical benefit. This study hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology., Materials and Methods: In this prospective five-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (N = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic low back pain, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. Low back pain intensity (10-cm visual analog scale [VAS]), disability (Oswestry Disability Index), and quality of life (EuroQol's "EQ-5D-5L" index) were compared with baseline and following the intent-to-treat principle, with a supporting mixed-effects model for repeated measures that accounted for missing data., Results: At five years (n = 126), low back pain VAS had improved from 7.3 to 2.4 cm (-4.9; 95% CI, -5.3 to -4.5 cm; p < 0.0001), and 71.8% of participants had a reduction of ≥50%. The Oswestry Disability Index improved from 39.1 to 16.5 (-22.7; 95% CI, -25.4 to -20.8; p < 0.0001), and 61.1% of participants had reduction of ≥20 points. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95% CI, 0.195-0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a five-year visit, 46% discontinued, and 23% decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed., Conclusion: Over a five-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic low back pain associated with multifidus muscle dysfunction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354; registration date: October 15, 2016; principal investigator: Christopher Gilligan, MD, Brigham and Women's Hospital, Boston, MA, USA. The study was conducted in Australia (Broadmeadow, New South Wales; Noosa Heads, Queensland; Welland, South Australia; Clayton, Victoria), Belgium (Sint-Niklaas; Wilrijk), The Netherlands (Rotterdam), UK (Leeds, London, Middlesbrough), and USA (La Jolla, CA; Santa Monica, CA; Aurora, CO; Carmel, IN; Indianapolis, IN; Kansas City, KS; Boston, MA; Royal Oak, MI; Durham, NC; Winston-Salem, NC; Cleveland, OH; Providence, RI; Spartanburg, SC; Spokane, WA; Charleston, WV)., Competing Interests: Conflict of Interest Christopher Gilligan reports stock options received from Mainstay, personal fees from Mainstay, Saluda, Persica, and Iliad Lifesciences, expert witness testimony personal fees, and serving as editor-in-chief of Pain Practice; Willem Volschenk reports personal fees from Mainstay; Marc Russo reports personal fees from Mainstay; Matthew Green reports personal fees from Mainstay; Christopher Gilmore reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, and Saluda; Vivek Mehta reports grants and honoraria from Mainstay and Abbott, personal fees from Boston Scientific, personal fees and honoraria from Medtronic, patent fees from EEPIN-Executive Education Program in Neuromodulation, and leadership/fiduciary role as Chair, Faculty of Pain Medicine UK; Kris De Smedt reports personal fees from Mainstay; Usman Latif reports personal fees from Hydrocision, Spinal Simplicity, Omnia Medical, SPR Therapeutics, and Vertos, and honoraria and personal fees from Nevro and Nalu; Dawood Sayed reports personal fees from Abbott, Boston Scientific, Flowonix, Medtronic, Nevro, Saluda, and Vertiflex, personal fees and stock options from Mainstay, SPR Therapeutics, PainTEQ, and Vertos, and stock options from Neuralace and Surgentec; Peter Georgius reports personal fees from Boston Scientific and Medtronic, lecture support and personal fees from Tilray, lecture support from CSL Seqirus, patent pending personal fees for Arch Bar Wire Application, and personal fees and data safety monitoring/advisory board membership for Presidio; Jonathan Gentile reports personal fees from Mainstay; Bruce Mitchell reports personal fees from Mainstay; Meredith Langhorst reports personal fees from Mainstay and Vivex; Frank Huygen reports grants, personal fees, and honoraria from Abbott and personal fees and honoraria from Saluda; Ganesan Baranidharan reports a grant from Mainstay, grants and personal fees from Nevro, Abbott, Boston Scientific, and personal fees from Nalu and Stryker; Vivek Patel reports personal fees from Mainstay, grants from Orthofix, Pfizer, Premia Spine, Medicrea, Globus, 3-Spine, and Spinal Kinetics, contracts and grants from Aesculap and Medtronic, contracts from Zimmer Biomet Spine, Inc, J&J Medical Device Business Services, NCS America, Simplify Medical, SI Bone, Orthobond Corp, and Cerapedics, consulting fees from Spine Welding, SI Bone, expert testimony for Ogborn Mihm, LLP—Expert Witness Deposition, and support attending meetings from Ecential Robotics and Johnson & Johnson Medical; Alexios Carayannopolous reports consulting fees from Pain Spine and Rehabilitation Consulting, Inc, royalties from Springer Press, grants from Aspen Medical, National Institutes of Health, Defense Advanced Research Projects Agency, and Medtronic, expert testimony as PSR Consulting, Inc, meeting/travel support from American Society of Regional Anesthesia and Pain Medicine, National Board of Osteopathic Medical Examiners, American Alliance of Orthopaedic Executives (AAOE), and American Orthopedic Association, and leadership/fiduciary roles for AAOE, and Rhode Island Society of Pain Physicians; Salim Hayek reports data safety/advisory board membership as immediate past president of North American Neuromodulation Society; Adish Gulve reports personal fees, honoraria, and data safety/advisory board membership from Medtronic, grants and honoraria from Boston Scientific and Abbott, honoraria from Mainstay Medical, grants, honoraria, and safety/advisory board membership from Nevro, and other services from Medtronic and Abbott; Jean-Pierre Van Buyten reports personal fees from Mainstay and grants and personal fees from Medtronic, Nevro, Boston Scientific, and Abbott; Antoine Tohmeh reports stock ownership and personal fees with two spine companies; Jeffrey Fischgrund reports personal fees from Stryker, Relievant, FzioMed, and Asahi Kasei, expert testimony from multiple sources, and data safety/advisory board personal fees for OssDesign; Shivanand Lad reports personal fees from Mainstay; Farshad Ahadian reports institutional grants from Mainstay Medical, Sollis Therapeutics, Boston Scientific, Semnur Pharma, and SI Bone, consulting fees for PainScan, expert testimony for the US Department of Justice, patent personal fees from US Patent 62/949,876, data safety/advisory board personal fees and institutional grant from SKK, institutional payments for leadership/fiduciary roles with the AAMP as Director at Large, Treasurer, President-Elect, as President; Timothy Deer reports grants from, Boston Scientific, PainTEQ; grants, personal fees, and stock from Saluda, grants, personal fees, and data safety/monitoring board membership from SPR Therapeutics, grants, patent pending, data safety/monitoring board membership, and personal fees from Abbott, personal fees from Boston Scientific, SpineThera, Cornerloc, PainTeq, and Spinal Simplicity, personal and institution fees from Mainstay Medical, data safety monitoring/advisory board and personal fees from Biotronik and Vertos, leadership/fiduciary role with American Society of Pain and Neuroscience, and stock (personal) from SpineThera; William R. Klemme reports personal fees, meeting support, and data safety/advisory board membership with Mainstay Medical and Sollis Therapeutics; Richard Rauck reports grants from SPR, Nalu, and Nevro, personal fees from Presidio, and grants and personal fees from Boston Scientific and Saluda; James Rathmell reports a leadership/fiduciary role on the editorial board from American Society of Anesthesiology; Greg Maislin provides biostatistical consulting services concerning statistical analysis methods and presentation for Mainstay Medical; Jan Pieter Heemels provides full-time executive consultancy receiving monthly retainer and stock options from Mainstay Medical; Sam Eldabe reports personal fees and nonfinancial support from Mainstay, personal fees from Saluda, institutional grants and personal fees from Medtronic, institutional grants from Boston Scientific, leadership/fiduciary roles as chair of European Diploma of Pain Medicine and European Society of Regional Anaesthesia and Pain Therapy, examination faculty, chair of neuromodulation device Expert Working Group at National Health Service England, and chair International Association for the Study of Pain Neuromodulation Special Interest Group. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Neuromodulation represents one of the more advanced tools in the armamentarium of pain physicians. To optimize neuromodulation patient selection and management, an institutional interdisciplinary neuromodulation committee was created at each of two academic medical centers (University of California Davis [UCD] and Stanford University). The committee aims to collaboratively optimize neuromodulation candidates, to assess and minimize medical and psychologic risks, and to select the best device given a patient's pain condition. In this study, we present the methods and outcome data of the Neuromodulation Committee at the two institutions., Materials and Methods: After institutional review board approval, we included all adult patients who were evaluated by the Neuromodulation Committee between 2017 and 2020 at two academic pain clinics. Patients with insufficient data were excluded from the study. A retrospective chart review was completed on 385 UCD and Stanford University patient committee reviews. Data collected from the chart review included demographics (age, sex), committee meeting results (proceed with trial/implant or decline), trial success, and implant rate., Results: Of the 385 patients screened, the committees recommended proceeding with an implantable device (peripheral and neuraxial) in 337 patients (87.5%). Of the 278 patients recommended for neuraxial neuromodulation, 131 underwent trials with percutaneous leads (47.1%). Trials were successful (causing a ≥50% reduction in self-reported pain or improved function) in 108 patients (82.4%). The institutions completed 87 implants of 131 trials, representing a trial-to-permanent ratio of 66.4%., Conclusions: The Neuromodulation Committee aims to identify optimal patients for neuromodulation, address procedural challenges, decrease adverse events, provide educational context for trainees, and improve patient-related outcomes. Patients who were recommended for neuromodulation and subsequently underwent intervention had high trial success rates for dorsal root ganglion stimulation and spinal cord stimulation. The findings indicate that such an approach can lead to neuromodulation success, especially at academic centers, by combining the expertise of both medical and psychologic professionals., Competing Interests: Conflict of Interest Scott G. Pritzlaff has had a financial agreement or affiliation with the following commercial interests in the form of consultant: Bioness, SPR Therapeutics, Nalu Medical, EBT Medical; royalties: Oxford University Press, Wolters Kluwer; and research grants; Medtronic, Nevro Corp, and Abbott. Michael Jung, Naileshni Singh, Juliann Cho, Matthew Skoblar, and Manoj Jagtiani reported no conflicts of interest. Michael S. Leong has had a financial agreement or affiliation with the following commercial interests in the form of consultant: Sorrento Therapeutics, and research: Wex Pharmaceuticals. Ravi Prasad has had a financial agreement or affiliation with the following commercial interests in the form of consultant: Menda Health and Nitto Inc. Vafi Salmasi has had a financial agreement or affiliation with the following commercial interests in the form of consultant: Biotronik, Vertos Medical, and AppliedVR., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Managing abdominal pain can be difficult. This is due to the nonspecific nature of the pain, the multiple etiologies, and the different mechanisms underlying this type of pain. Abdominal wall pain in particular poses its own challenges. Traditionally, chronic abdominal wall pain has been managed with nonopioid analgesics, and in severe cases, opioid therapy has been considered. For patients with chronic abdominal wall pain refractory to medication management, peripheral nerve blocks and spinal cord stimulation also have been trialed with some success. In this study, we present a case series in patients with chronic abdominal wall pain who were treated with a multicontact peripheral nerve stimulation (PNS) system in the transversus abdominis plane (TAP)., Materials and Methods: This was a single-center, retrospective case series. Data were included from adults with chronic abdominal wall pain whose symptoms were refractory to standard medical management and who underwent a multicontact PNS system placement in the TAP., Results: Four patients met the inclusion criteria. All four patients underwent a multicontact PNS trial lead placement in the TAP. One patient reported no benefit from the trial. The remaining three patients underwent a permanent multicontact PNS system placement in the TAP., Conclusions: In patients with chronic abdominal wall pain whose symptoms are refractory to conservative medical management, PNS may be an alternative treatment option. As the use of PNS for chronic abdominal wall pain and other fascial planes continues to develop, additional research is necessary to determine optimal placements and specific stimulation parameters., Competing Interests: Conflict of Interest Amitabh Gulati acts as a consultant for SPR Therapeutics, Nalu Medical, Medtronic, Averitas Medical, Modoscript, Tersera Medical, and Neurovasis, and as a medical advisor for AIS Healthcare and Hingehealth. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Total knee arthroplasty (TKA) is an effective surgery for end-stage knee osteoarthritis, but chronic postoperative pain and reduced function affect up to 20% of patients who undergo such surgery. There are limited treatment options, but percutaneous peripheral nerve stimulation (PNS) is a promising nonopioid treatment option for chronic, persistent postoperative pain. The objective of the present study was to evaluate the effect of a 60-day percutaneous PNS treatment in a multicenter, randomized, double-blind, placebo-controlled trial for treating persistent postoperative pain after TKA., Materials and Methods: Patients with postoperative pain after knee replacement were screened for this postmarket, institutional review board-approved, prospectively registered (NCT04341948) trial. Subjects were randomized to receive either active PNS or placebo (sham) stimulation. Subjects and a designated evaluator were blinded to group assignments. Subjects in both groups underwent ultrasound-guided placement of percutaneous fine-wire coiled leads targeting the femoral and sciatic nerves on the leg with postoperative pain. Leads were indwelling for eight weeks, and the primary efficacy outcome compared the proportion of subjects in each group reporting ≥50% reduction in average pain relative to baseline during weeks five to eight. Functional outcomes (6-minute walk test; 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index) and quality of life (Patient Global Impression of Change) also were evaluated at end of treatment (EOT)., Results: A greater proportion of subjects in the PNS groups (60%; 12/20) than in the placebo (sham) group (24%; 5/21) responded with ≥50% pain relief relative to baseline (p = 0.028) during the primary endpoint (weeks 5-8). Subjects in the PNS group also walked a significantly greater distance at EOT than did those in the placebo (sham) group (6MWT; +47% vs -9% change from baseline; p = 0.048, n = 18 vs n = 20 completed the test, respectively). Prospective follow-up to 12 months is ongoing., Conclusions: This study provides evidence that percutaneous PNS decreases persistent pain, which leads to improved functional outcomes after TKA at EOT., Competing Interests: Conflict of Interest Johnathan H. Goree serves as a consultant to Saluda Medical, Stratus Medical, and Abbott. David M. Dickerson serves as a consultant to Abbott, Vertos, Biotronik, and SPR Therapeutics, and has received honoraria for lectures from Nalu. Yashar Eshraghi serves as a consultant for Saluda Medical and SPR Therapeutics. Ali K. Valimahomed serves as a consultant for SPR Therapeutics, Nalu, Vertos, and Biotronik, and has received honoraria for lectures from the World Academy of Pain Medicine. Jarna R. Shah serves as a consultant for and has received honoraria from SPR Therapeutics. Maged N. Guirguis serves as a consultant for SPR Therapeutics, Nevro, Saluda, Boston Scientific, Abbott, Averitas Pharma, PainTeq, and Avanos. Maxim S. Eckmann serves as a consultant for Avanos and has participated on a data safety monitoring or advisory board for Abbott. Amorn Wongsarnpigoon is an inventor on >40 patents planned, issued, or pending related to peripheral nerve stimulation (PNS) and has stock/stock options with SPR Therapeutics. Joseph W. Boggs is an inventor on >100 patents planned, issued, or pending related to PNS and has stock/stock options with SPR Therapeutics. John E. Gilbert, Amorn Wongsarnpigoon, and Joseph W. Boggs are all employees of SPR Therapeutics as well in case that needs to be included. The remaining authors reported no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to assess whether patient response to targeted diagnostic peripheral nerve block before peripheral nerve stimulator (PNS) device implantation is associated with efficacy after PNS implantation., Materials and Methods: The electronic medical records from the Mayo Clinic Enterprise (three quarternary care medical centers and additional satellite medical centers) were reviewed to identify patients who underwent PNS implantation between January 2014 and January 2023. A primary outcome of interest was to assess whether administration of a preimplant diagnostic peripheral nerve block predicted pain relief at three months and six months after temporary and permanent PNS implantation. Another primary outcome was to investigate whether there was an association between the pain relief from a preimplant diagnostic peripheral nerve block and pain relief after three and six months after temporary or permanent PNS therapy. Linear regression analysis was conducted for outcomes of interest., Results: Of 193 eligible patients who underwent PNS therapy, a total of 173 patients were included in the final analysis and were stratified into either the temporary PNS cohort (n = 112) or the permanent PNS cohort (n = 61). Overall, 77.5% of all patients (134/173) underwent a preimplant diagnostic peripheral nerve block and reported a mean percentage relief of 70.1 ± 27.0 from the diagnostic block. Of patients in the temporary PNS cohort, there was no difference in postimplant percentage pain relief between patients who received a diagnostic block (n = 93) and control patients (n = 19) at three months (35.4 ± 36.0 vs 49.8 ± 36.1, respectively; β -14.45, 95% CI -32.98 to 4.07, p = 0.125) or at six months (23.3 ± 30.8 vs 45.7 ± 40.0, respectively; β -22.39, 95% CI -46.86 to 2.08, p = 0.072). Of patients in the permanent PNS cohort, there was no difference in postimplant percentage pain relief between patients who received a diagnostic block (n = 41) and control patients (n = 20) at three months (42.4 ± 34.3 vs 43.2 ± 42.4, respectively; β -0.79, 95% CI -23.56 to 21.99, p = 0.945) or at six months (44.3 ± 35.0 vs 38.8 ± 40.9, respectively; β 5.42, 95% CI -20.04 to 30.88, p = 0.669). Pain relief from preimplant diagnostic blocks was associated with postimplant pain relief from temporary PNS at three months (β 0.33, 95% CI 0.04-0.61, p = 0.025). However, pain relief from preimplant diagnostic blocks did not predict postimplant pain relief from temporary PNS at six months, or permanent PNS at three months and six months., Conclusions: Administration of a diagnostic block is not associated with superior pain relief at three or six months after PNS implantation to that of an approach without diagnostic block. Pain relief from a diagnostic block may potentially predict short-term pain relief after temporary PNS therapy, although future prospective studies are warranted to evaluate the prognostic utility of diagnostic blocks., Competing Interests: Conflict of Interest Chelsey M. Hoffmann provides general consulting for Nalu Medical and SPR Therapeutics. Ryan S. D’Souza receives investigator-initiated research funding from Nevro Corp and Saol Therapeutics that is paid to his institution. The remaining authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to determine how severe acute hypoxia alters neural mechanisms during, and following, a sustained fatiguing contraction. Fifteen participants (25 ± 3.2 years, six female) were exposed to a sham condition and a hypoxia condition where they performed a 10 min elbow flexor contraction at 20% of maximal torque. For hypoxia, peripheral blood oxygen saturation (SpO2) was titrated to 80% over a 15 min period and maintained for 2 h. Maximal voluntary contraction torque, EMG root mean square, voluntary activation, rating of perceived muscle fatigue, and corticospinal excitability (motor‐evoked potential) and inhibition (silent period duration) were then assessed before, during and for 6 min after the fatiguing contraction. No hypoxia‐related effects were identified for neuromuscular variables during the fatigue task. However, for recovery, voluntary activation assessed by motor point stimulation of biceps brachii was lower for hypoxia than sham at 4 min (sham: 89% ± 7%; hypoxia: 80% ± 12%; P = 0.023) and 6 min (sham: 90% ± 7%; hypoxia: 78% ± 11%; P = 0.040). Similarly, voluntary activation (P = 0.01) and motor‐evoked potential area (P = 0.002) in response to transcranial magnetic stimulation of the motor cortex were 10% and 11% lower during recovery for hypoxia compared to sham, respectively. Although an SpO2 of 80% did not affect neural activity during the fatiguing task, motor cortical output and corticospinal excitability were reduced during recovery in the hypoxic environment. This was probably due to hypoxia‐related mechanisms involving supraspinal motor circuits. Key points: Acute hypoxia has been shown to impair voluntary activation of muscle and alter the excitability of the corticospinal motor pathway during exercise.However, little is known about how hypoxia alters the recovery of the motor system after performing fatiguing exercise.Here we assessed hypoxia‐related responses of motor pathways both during active contractions and during recovery from active contractions, with transcranial magnetic stimulation and motor point stimulation of the biceps brachii.Fatiguing exercise caused reductions in voluntary activation, which was exacerbated during recovery from a 10 min sustained elbow flexion in a hypoxic environment.These results suggest that reductions in blood oxygen concentration impair the ability of motor pathways in the CNS to recover from fatiguing exercise, which is probably due to hypoxia‐induced mechanisms that reduce output from the motor cortex. [ABSTRACT FROM AUTHOR]

Peripheral nerve stimulation (PNS) was the first application of neuromodulation. Widespread application of PNS was limited by technical concerns. Recent advances now allow the percutaneous placement of leads with ultrasound or fluoroscopic guidance, while the transcutaneous powering of these leads removes the need for leads to cross major joints. This systematic review was written to assess the current status of high-quality evidence supporting the use of PNS for pain conditions treated by interventional pain physicians. The available literature on PNS, limited to conditions treated by interventional pain physicians, was reviewed and the quality assessed. Literature from 1966 to June 2021 was reviewed. The outcome measures were pain relief and functional improvement. One hundred and two studies were identified. Five randomized controlled trials (RCT) and four observational studies, all case series, met the inclusion criteria. One RCT was of high quality and four were of moderate quality; all four case series were of moderate quality. Three of the RCTs and all four case series evaluated peripheral nerve neuropathic pain. Based upon these studies, there is level II evidence supporting the use of PNS to treat refractory peripheral nerve injury. One moderate-quality RCT evaluated tibial nerve stimulation for pelvic pain, providing level III evidence for this indication. One moderate-quality RCT evaluated surgically placed cylindrical leads for cluster headaches, providing level III evidence for this indication. The evidence suggests that approximately two-thirds of patients with peripheral neuropathic pain will have at least 50% sustained pain relief. Adverse events from PNS are generally minor. A major advantage of PNS over spinal cord stimulation is the absence of any risk of central cord injury. The study was limited by the paucity of literature for some indications. No studies dealt with joint-related osteoarthritic pain. [ABSTRACT FROM AUTHOR]

Background: Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain.Methods: (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0-10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS.Results: (1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI - 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen's D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia.Conclusions: Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663. [ABSTRACT FROM AUTHOR]

Objective: Intuitive control of conventional prostheses is hampered by their inability to provide the real-time tactile and proprioceptive feedback of natural sensory pathways. The macro-sieve electrode (MSE) is a candidate interface to amputees' truncated peripheral nerves for introducing sensory feedback from external sensors to facilitate prosthetic control. Its unique geometry enables selective control of the complete nerve cross-section by current steering. Unlike previously studied interfaces that target intact nerve, the MSE's implantation requires transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE's suitability for this task is whether it can elicit sensory percepts at low current levels in the face of altered morphology and caliber distribution inherent to axon regeneration. The present in vivo study describes a combined rat sciatic nerve and behavioral model developed to answer this question. Approach: Rats learned a go/no-go detection task using auditory stimuli and then underwent surgery to implant the MSE in the sciatic nerve. After healing, they were trained with monopolar electrical stimuli with one multi-channel and eight single-channel stimulus configurations. Psychometric curves derived by the method of constant stimuli (MCS) were used to calculate 50% detection thresholds and associated psychometric slopes. Thresholds and slopes were calculated at two time points 3 weeks apart. Main Results: For the multi-channel stimulus configuration, the average current required for stimulus detection was 19.37 μA (3.87 nC) per channel. Single-channel thresholds for leads located near the nerve's center were, on average, half those of leads located near the periphery (54.92 μA vs. 110.71 μA, or 10.98 nC vs. 22.14 nC). Longitudinally, 3 of 5 leads' thresholds decreased or remained stable over the 3-week span. The remaining two leads' thresholds increased by 70–74%, possibly due to scarring or device failure. Significance: This work represents an important first step in establishing the MSE's viability as a sensory feedback interface. It further lays the groundwork for future experiments that will extend this model to the study of other devices, stimulus parameters, and task paradigms. [ABSTRACT FROM AUTHOR]