Neuromodulation: Overview

Abstract
Objective: Despite neuropathic pain affecting a significant portion of the population, many people still experience refractory conditions. Here, we evaluated the efficacy and safety of posterior-superior insula deep brain stimulation for pharmaco-resistant neuropathic pain.

Materials and methods: This was a phase 2 randomized, double-blind, sham-controlled, cross-over trial. Subjects with chronic pharmaco-resistant neuropathic pain, whose pain had previously responded to deep repetitive transcranial magnetic stimulation of the posterior-superior insula, underwent stereotactically guided implantation of electrodes targeting this same region. The study comprised three phases: double-blind (2 × three months), single-blind (three months), and open-label (six months). The primary outcome was the proportion of participants achieving ≥30% reduction in average pain intensity compared with baseline. Secondary outcomes included pain interference, quality of life, and neuropsychiatric assessments.

Results: Ten participants (80% men; age range: 31-67 years) were enrolled. There was an 82.3% posterior probability that active posterior-superior insula-deep brain stimulation yields a higher responder rate than does sham stimulation after three months, with a 95% credible interval for the difference ranging from 10% to 130%. Probabilities of pain interference score reduction exceeded 95% during follow-up, particularly concerning sleep and mood. Quality-of-life scores also showed significant improvements under active, compared with sham, stimulation treatments. No major adverse events were reported, and the stimulation was well tolerated.

Interpretation: This study showed that posterior-superior insula deep brain stimulation is a feasible and potentially useful treatment for people with refractory neuropathic pain, with reasonable safety profiles. Phase 3 trials are warranted to confirm these findings and to explore the applicability of this intervention.

Clinical trial registration: The Clinicaltrials.gov registration number for the study is NCT04279548.

Abstract
Objectives: Neuropathic pain and spasticity after spinal cord injury (SCI) are intractable conditions that represent distinct outcomes of sensory and motor dysfunction. Spinal cord stimulation (SCS) has been proposed as a potential therapy for these conditions. However, the therapeutic effects of different SCS parameters and their underlying mechanisms remain unclear. The present study aimed to investigate the therapeutic effects of a developed epidural SCS system on SCI-induced pain and spasticity, and to explore its underlying mechanisms in modulating microglia activation.

Materials and methods: Male Sprague-Dawley rats underwent contusive SCI at T10 segment using an Infinite Horizons impactor, and an epidural SCS system was implanted two weeks after SCI. Mechanical sensitivity and spasticity were assessed using paw withdrawal threshold and modified Ashworth scale. Epidural SCS was applied at low frequency (LF; 50 Hz) or high frequency (HF; 1 kHz) with intensities of 40% or 80% of the motor threshold (MT). Sham control rats underwent SCS implantation without electrical stimulation. Immunohistochemistry was performed to evaluate microglia activation in the lumbar spinal segments.

Results: HF with 80% MT intensity showed a higher effect on neuropathic pain and spasticity, whereas LF with 40% MT intensity showed a lower effect. Although SCS did not alter the number of microglia in the lumbar spinal segments, both LF and HF with 80% MT intensity significantly decreased the proportion of activated microglia in both dorsal and ventral horns compared with the sham group.

Conclusion: These findings show that the epidural SCS with 80% MT effectively alleviates neuropathic pain and spasticity by reducing spinal microglial activation. These results highlight the importance of optimizing stimulation parameters to achieve therapeutic benefits in clinical settings.

Abstract
Objectives: Neuropathic craniofacial pain syndromes are heterogeneous with regards to clinical presentation and etiology. As such, they pose a diagnostic and management challenge, and are often refractory to medical and interventional management. High cervical intrathecal drug delivery has been reported in the management of refractory cancer-related craniofacial pain, although the literature regarding its use in neuropathic craniofacial pain remains limited. This study aims to describe the successful management of a series of patients with refractory neuropathic craniofacial pain who underwent implantation of a high cervical intrathecal drug delivery system (IDDS).

Materials and methods: A single-center retrospective chart review was conducted in patients with refractory non-cancer neuropathic craniofacial pain who underwent implantation of an IDDS with the intrathecal catheter tip placed at a high cervical level. A variety of medical, interventional, and neuromodulation modalities had failed in these patients. Data collection spanned 2016 through March 2025. Medical charts were reviewed for demographic data, operative details, pain severity outcomes, intrathecal medication dosing, and the incidence of complications.

Results: Overall, 12 patients (ten women, two men) underwent a high cervical intrathecal catheter trial. Nine patients had successful trials with reported improvement in pain >50%, with no significant reported side effects to a combination of fentanyl/bupivacaine. All patients suffered from neuropathic pain in the trigeminal distribution, with three patients experiencing corneal neuropathy. Patients were observed for a mean of 64.8 ± 48.1 months. Pain severity was significantly lower at last follow-up than at baseline (numeric rating scale of 9.5 ± 0.9 vs 4.3 ± 2.3) (p < 0.01). Three patients required catheter revision owing to migration. No patients were explanted for loss of efficacy.

Conclusions: High cervical intrathecal drug delivery can be an effective treatment option for patients with refractory neuropathic craniofacial pain, even in patients presenting with heterogeneous pain of differing etiologies and failure with other treatments.