Spinal cord stimulation (SCS) has become increasingly widespread in recent years for the management of refractory chronic pain, primarily owing to the development of novel waveform technology allowing variable spinal cord modulation, and indication expansion. The existing literature suggests that despite having favorable initial responses, the efficacy of SCS sometimes is reduced over time. To restore analgesic efficacy, a strategy of altering stimulation waveforms known as salvage therapy has been used. Here, we consolidate the existing evidence and describe the efficacy of salvage therapy. A literature search using relevant keywords was conducted on PubMed, Web of Sciences, and Cochrane Library data bases, yielding a total of 809 articles. After a full text review and screening for consistency with eligibility criteria were conducted, 22 studies with a collective sample size of 1591 patients were included in the final analysis. Data extraction was performed by six reviewers, with a secondary reviewer verifying each entry. Of the 1591 patients included in our review, the most frequent indication for salvage therapy was loss of waveform efficacy and paresthesia coverage. In most studies, patients received salvage therapy after experiencing loss of efficacy with a single waveform. Most studies also did not strictly control the phase in which salvage therapy was implemented, with only eight of 22 studies reporting exclusively trial phase interventions. The efficacy of salvage therapy was found to be favorable, with 685 of 879 salvage therapy trials (77.9%) being reported as successful. New waveform technologies in SCS have expanded therapeutic options for patients with refractory chronic pain. Available evidence suggests that waveform switching may restore analgesic benefit in a subset of patients who experience loss of efficacy after an initial favorable response. However, many salvage strategies involve device revision or generator replacement, and the long-term durability of these interventions remains uncertain. Further prospective studies are needed to better define patient selection, timing of intervention, and long-term outcomes after waveform-based salvage strategies.
The management of chronic constipation when it coexists with chronic pain syndrome is challenging because of complex pathophysiologic and constipating analgesic side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is an effective neuromodulation method to modulate gastrointestinal function and pain processing by targeting vagal pathways. Accordingly, this study evaluated the short-term effects of taVNS in patients with functional constipation (FC) comorbid with myofascial pain syndrome (MPS). A total of 38 female participants with FC and MPS (aged 20-50 years) were randomly allocated (1:1) using a computer-generated randomization to either taVNS or sham-taVNS groups. Participants received the intervention for 30 minutes, five days a week for two weeks. The complete spontaneous bowel movements per week (CSBMs/week) as the primary outcome was assessed at baseline and after the treatment. Secondary outcomes were Wexner constipation scores (WCS), patient assessment of constipation quality of life (PAC-QoL) score, visual analogue scale (VAS), pressure pain threshold (PPT), and heart rate variability (HRV). The result of analysis of covariance (ANCOVA) showed that taVNS significantly and clinically improved CSBMs/week compared with the sham-taVNS (p = 0.007; Cohen d = 0.97, 95% CI 0.26 - 1.66). The mean increase of CSBMs/week was 1.65 times compared with the baseline and 1.37 times compared with the sham-taVNS (MCID = 1.3 times). Moreover, the taVNS group had greater reduction in WCS and VAS compared with the sham group. In the HRV analysis, the taVNS enhanced high frequency (HF) and decreased low frequency (LF) and the LF/HF ratio compared with the sham-taVNS. However, there was no substantial difference in the PPT and PAC-QoL between groups. These promising findings provide preliminary evidence that taVNS may be an effective nonpharmacologic intervention in female patients with FC coexisting with chronic pain conditions, particularly MPS. Further large-scale studies with longer follow-up and mechanistic assessments are warranted.
This study aimed to provide real-world data on the utilization of ziconotide-containing intrathecal (IT) treatment. This ongoing European multicenter, prospective observational study included patients experiencing severe refractory chronic pain, eligible for IT analgesia using ziconotide. Patients are treated and observed according to the site's usual practice. The study includes an interim analysis of the French cohort of patients with cancer pain. The study analyzed 211 patients, with a median age of 61.7 years and a median baseline numerical rating scale (NRS) pain score of 5 (0‒10), with a neuropathic component in 39%. At IT treatment initiation, approximately 50% of participants received antidepressants and 45% antiepileptics; the median dose of oral opioids was 300 oral morphine equivalents (OME) (4.5‒2400). Mean and median initial doses of ziconotide were 0.4 and 0.5 μg/d, respectively, administered in combination with morphine and local anesthetics. Dose increased over time but remained low (median: 1.6 μg/d at three months). A reduction in pain was observed in most patients, particularly in those with pain scores ≥5 (n = 90, 18% with NRS score of 0 and 14.4% with score of 1 or 2 at one month). After three months, pain scores remained globally stable; the median OME reduction was 89.7%. Most adverse events (AEs) (62%) were reported within the first month, primarily graded 1 or 2. The most frequently reported AEs were drowsiness (51% of patients), confusion (46%), hallucinations (40%), nausea (37%), memory disorders (29%), asthenia (22%), dizziness (21%), constipation (17%), diarrhea (17%), and vomiting (12%). AEs resolved completely in 70.1% of patients, partially in 10%, remained stable in 12.3%, and worsened in 1.9% (issue not known in 16.6%). IT therapy combining ziconotide with morphine and a local anesthetic is an effective option for managing cancer-related pain in patients who have inadequate response to, or poor tolerance of, conventional systemic analgesics. The Clinicaltrials.gov registration number for the study is NCT04321408.
Noninvasive transcranial alternating current stimulation (tACS) of the cochlea might be a promising new therapeutic option for patients with chronic tinnitus. However, electric stimulation of small, sensitive target regions, such as the inner ear, can cause adverse side effects (SEs). The objective of this study was to identify stimulation parameters with low SE profiles while reliably stimulating the cochlea, thereby improving patient comfort and safety. This pilot study also aims to identify stimulation settings suited for developing a medical device intended to treat patients with chronic tinnitus. Participants with healthy hearing were stimulated with electrodes in the ear canal. Stimulation of the cochlea elicits a soft hearing impression (HI) in participants, indicating successful stimulation of the auditory pathway. We systematically compare HIs and SEs across distinct electrode configurations and stimulation parameters, including stimulation frequency and the presence of a direct current (DC)-offset. We record SE severity ratings through visual analog scales after stimulation. We find that tACS between 250 Hz and 2000 Hz reliably elicits HIs in participants. SE severity depends on the stimulation parameters. No magnitude of SEs caused participant withdrawal or severe adverse events, with only phosphenes, skin tingling, and a sense of vibration being reported as impactful. The addition of a slight DC-offset increases the magnitude of phosphenes but does not alter HI occurrence. Our results show the feasibility of tACS to stimulate the auditory pathway noninvasively with minimal adverse SEs. Stimulation parameters with a low SE profile can be applied in further studies with patients with tinnitus. This study was preregistered at the German Register of Clinical Studies (DRKS, https://drks.de/search/de/trial/DRKS00033120).
Deep brain stimulation (DBS) of the globus pallidus internus (GPi) can reduce levodopa-induced dyskinesias, yet GPi targeting sometimes fails or worsens them, suggesting distinct prokinetic/antikinetic circuit mechanisms. Using the broad globus pallidus (GP) sampling from the Veteran Affairs Cooperative Study Program 468 (CSP-468) trial, we sought to identify stimulation zones and connectivity maps that predict dyskinesia outcomes in patients treated with GPi-DBS. Data were drawn from the multicenter, randomized CSP-468 study which compared subthalamic nucleus with GPi-DBS in Parkinson disease. Postoperative imaging from patients treated with bilateral GPi-DBS with substantial presurgical dyskinesia (n = 69) was analyzed to relate lead location to change in hours of dyskinesia at six months postop. Cranial Suite and LeadDBSv3.0 enabled nonlinear registration to Montreal Neurologic Institute space and generation of volumes-of-tissue-activated (VTAs). Patients were pseudorandomly divided into model or hold-out cohorts. Outcome-weighted VTAs in the model cohort were used to derive above-average (sweet spot) and below-average (suboptimal) stimulation zones through t-tests. Outcome-weighted structural fibers were identified using the Parkinson Progressive Marker Initiative connectome. Normative resting state functional magnetic resonance imaging (rsfMRI) connectivity maps were generated using patient VTAs and the Brain Genomics Superstruct Project-1000 connectome, visualizing regions with significant synchrony differences between patients with improved vs worsened dyskinesias. All models were tested on the hold-out cohort. The sweet spot/suboptimal zone predicted outcomes in the hold-out cohort (RSpearman = 0.55, p = 0.004, q = 0.018). The sweet spot localized to the ventral posterior GPi, extending below the GPi, whereas the suboptimal zone capped the GPi UPDRS sweet spot, spanning mid-medial GP externa to dorsal GPi to mid-medial GPi. Neither overlapped the Unified Parkinson's Disease Rating Scale sweet spot. Fibers linked to antidyskinetic effects coursed beneath the GPi, similar to the path of the Ansa Lenticularis (RSpearman = 0.46, p = 0.02, q = 0.028). Normative rsfMRI maps showed greater supplementary motor area or premotor synchrony correlated with worse outcomes (RSpearman = 0.5, p = 0.008, q = 0.018). This analysis identified stimulation zones and connectivity that predict dyskinesia outcomes in an independent cohort, underscoring the relevance of the (sub)ventral GPi, Ansa Lenticularis, and supplementary motor area or premotor networks.
Concurrent transcranial magnetic stimulation and functional magnetic resonance imaging (TMS-fMRI) provides a mechanism for assessing the acute effects of transcranial magnetic stimulation (TMS) on functional connectivity (FC), allowing a unique perspective of how TMS induces antidepressant effects over the course of treatment. The aim of this secondary analysis of clinical trial data was to interrogate the relevance of the triple network theory in low-frequency TMS to the right dorsolateral prefrontal cortex (DLPFC) (low-frequency repetitive TMS [LFR]) by assessing perturbations in salience (SN), control (CN), and default mode (DMN) networks during TMS-fMRI. A total of 38 subjects with treatment-resistant depression underwent one session of concurrent TMS-fMRI at 1 Hz to the right DLPFC (LFR), with resting-state scans acquired immediately before and after. Patients subsequently underwent a four-week treatment course using the same protocol. Whole-brain FC was computed, as well as within- and between- network FC for the SN, CN, and DMN for each scan. FC modulation scores were computed to capture changes between resting-state and TMS-fMRI and were used to test for relationships between acute changes in FC during a single repetitive TMS treatment and clinical outcomes after a course of treatment. Whole-brain FC decreased during the TMS-fMRI scan, as did within- and between-network FC for the SN, CN, and DMN. Resting-state scans acquired immediately before and after TMS-fMRI showed no differences in FC. After the four-week treatment course, eight subjects were classified as remitters (21%), eight subjects were responders but fell short of remission (21%), with the remaining 22 subjects (58%) showing nonresponse. FC modulation scores for the whole-brain were significantly associated with decreased depression scores at the end of treatment. Between-network FC modulation was initially correlated with clinical improvement, but these correlations did not persist when controlling for whole-brain FC modulation. When tested using predictive modeling, both whole-brain and network-level data significantly predicted treatment outcomes, with modulation involving SN predicting outcomes as effectively as whole-brain models. LFR acutely disrupts FC at a global, whole-brain level that encompasses the triple networks. Modulation of the SN-CN and SN-DMN connectivity hold predictive value for clinical improvement comparable with that of global, whole-brain connectivity. This widespread global disruption may be an important mechanism through which TMS exerts antidepressant effects. Limitations include the use of atlas-based network definitions, small sample, and generalizability limited to LFR protocols only.
To evaluate the efficacy and safety of minimally invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). This prospective exploratory trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM through an implanted device or ENM through surface electrodes. Stimulation was delivered at 14 Hz, 210 μs pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; p = 0.0018). Treatment success was observed in 80% (24/30) of the ENM cohort and 83% (15/18) of SNM cohort. No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27%; SNM 17%). Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach. This trial is registered at clinicaltrials.gov (ID NCT04713085, title "Sacral Neuromodulation in Children and Adolescents"). Web link: https://clinicaltrials.gov/study/NCT04713085.
This study aimed to evaluate the clinical outcomes of sacral neuromodulation (SNM) for fecal incontinence (FI) caused by diverse etiologies. This retrospective study, conducted between April 2021 and December 2024, analyzed 34 consecutive patients with FI who underwent SNM. Preoperative examinations included high-resolution anorectal manometry, magnetic resonance imaging, and endoscopy. Symptom severity was assessed using the Wexner or low anterior resection syndrome (LARS) score, and quality of life was evaluated using the Fecal Incontinence Quality of Life scores (FIQL) pre- and postoperatively. The cohort included 14 women and 20 men with a median age of 52 years and a median FI duration of five years. Etiologies included LARS (n = 11), neurogenic bowel (n = 9), congenital malformations (n = 5), idiopathic FI (n = 3), and trauma- or radiation-related FI (n = 6). After successful lead implantation, >50% symptom relief was achieved in 29 patients (85.3%) during the testing phase, and 27 patients (79.4%) subsequently underwent permanent implantable pulse generator implantation. During a median follow-up of 32 months, Wexner scores decreased significantly from baseline (18.1 ± 2.3) to 6.6 ± 5.4 (testing phase), 5.3 ± 2.7 (six months), 8.8 ± 2.6 (12 months), and 8.2 ± 1.5 (24 months) (all p < 0.001). Significant improvements also were observed in the FIQL domains for lifestyle, coping/behavior, and depression (p < 0.05), whereas the embarrassment domain remained unchanged. Reported complications included surgical site infections (n = 2), delayed wound healing (n = 1), and one case of late efficacy that was successfully managed with device revision. SNM provides safe, effective, and sustained relief in symptoms and improvements in quality of life for patients with FI across a spectrum of complex etiologies. The Chinese Clinical Trial Registry registration number for the study is ChiCTR2100054268.
Deep-brain stimulation (DBS) systems are implanted for movement disorders, epilepsy, and psychiatric conditions. Neurologic surgery remains the only discipline credentialed to implant DBS devices, although significant practice variation exists, partly due to heterogeneous training. The North American Neuromodulation Society (NANS) education committee offers a granular recommendation for the progression of an early learner through the practitioner level. It is contextualized within the six-core competency rubric for the surgical implantation of DBS devices. Guided by the Accreditation Council for Graduate Medical Education (ACGME) core competencies, a subcommittee of the NANS education committee met virtually and in-person over two years to develop a curriculum. The subcommittee used a consensus approach and an evidence-based development strategy; once completed, the NANS board approved the DBS curriculum. The DBS curriculum was developed for implanting surgeons and neurosurgical trainees. The table was vertically oriented into the six ACGME educational core competencies. A horizontal progression across 57 competencies defines expected skills for early learners, advanced learners, and independent practitioners. DBS devices are implanted by neurologic surgeons; education variability in acquired surgical skills and judgment may influence practice variation. This DBS curriculum presents consensus recommendations for competency progression within the six core competencies of the ACGME.
High-frequency deep brain stimulation (DBS) of the ventromedial prefrontal cortex (vmPFC-DBS) has shown promising long-term antidepressant effects in patients with depression, although the underlying mechanisms remain unclear. This study aims to investigate the sustained improvement of bilateral vmPFC-DBS on depression-like behaviors induced by chronic unpredictable mild stress (CUMS) in mice and the role of brain immune dysregulation in this process. Male mice subjected to CUMS received high-frequency DBS over a six-week period. The therapeutic efficacy of DBS was evaluated through sucrose preference tests, open field tests, and forced swim tests. Subsequently, changes in glial cell activity in the hippocampal region were analyzed by immunofluorescence. The levels of neuroinflammation and oxidative stress were assessed through Western blotting. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) was knocked down by short hairpin RNA, and microglia were depleted at specific timepoints during the first two weeks and the last two weeks of stimulation to assess the changes in antidepressant effect. Sustained stimulation completely reversed the depression-like and anxiety-like behaviors induced by CUMS in mice after four weeks and maintained these effects during subsequent continuous stimulation. The long-term antidepressant effect may be related to functional alterations in microglia. Furthermore, DBS reduced proinflammatory cytokine levels, including interleukin (IL) 1-β, IL-6, and tumor necrosis factor-α, and normalized redox signaling and its downstream components, including Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and superoxide dismutase. After Nrf2 silencing, the antidepressant and anxiolytic-like effects produced by vmPFC-DBS were reduced. The antidepressant effect of sustained vmPFC-DBS may rely on its antiinflammatory and antioxidative stress effects.
This study aimed to systematically synthesize the evidence on high cervical intrathecal drug delivery (IDD) for the management of craniofacial pain, focusing on indications, catheter location, drug regimens, pain outcomes, and safety. A systematic review was conducted according to Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed was searched from inception to July 25, 2025. Eligible studies included adults with craniofacial pain treated with IDD using high cervical catheters. Outcomes of interest included pain scores, catheter location, medications and dosing, and complications. Two reviewers independently screened studies and extracted data. Methodological quality was assessed using Joanna Briggs Institute tools. A total of 14 studies comprising 143 patients were included. Craniofacial pain etiologies were predominantly cancer related, with smaller cohorts of neuropathic and mixed pain syndromes. Catheter tips were most commonly positioned at C1-C2, the prepontine cistern, or cisterna magna, with imaging confirmation in all cases. Intrathecal regimens were carried out, most frequently using an opioid alone or in combination with a local anesthetic. Baseline pain was uniformly severe and improved substantially following intervention. Follow-up ranged from one to 27 months. Marked reductions or complete discontinuation of systemic opioids were commonly reported. Device-related complications were infrequent and primarily included catheter migration and infection. High cervical IDD is associated with reductions in pain and systemic opioid use in carefully selected patients with refractory craniofacial pain. Although current evidence is limited to small observational studies, outcomes were consistently favorable across all selected studies. Common complications were similar to those observed following IDD at lower neuraxial levels, including catheter migration and infections. Prospective studies using standardized outcome measures are needed to define optimal patient selection, catheter positioning, and drug regimens.
Transcranial focused ultrasound stimulation (tFUS), also known as low-intensity focused ultrasound pulsation, may noninvasively modulate key brain networks subserving consciousness and carries promise as a novel interventional tool to stimulate recovery of consciousness in individuals with disorders of consciousness (DoC) after severe brain injury. However, the novelty of this approach and its attendant effects raise underexplored ethical considerations warranting explicit attention to ensure responsible development and deployment in clinical research and practice. Our objectives here are to develop an ethical framework for responsible translation of this emerging neurotechnology. To identify and critically evaluate the responsible use of tFUS to promote recovery of consciousness in individuals with DoC, we evaluate ethical considerations through the lens of the principles of biomedical ethics, coupled with thematic, normative, and philosophical analysis. We describe safeguards for innovation and clinical translation in this domain. Specific ethical domains evaluated include respect for autonomy, beneficence, nonmaleficence, justice, enrollment considerations, and fair study access, which synergistically inform an ethical framework for stakeholders involved in pioneering and early use of tFUS. To provide support for clinicians and investigators navigating complex decision-making at the nexus of neurotechnology and neuroethics, we propose a practical checklist for ethical implementation and evaluation of tFUS studies for patients with DoC.
The study aimed to investigate the effects and mechanisms of high-frequency short-pulse gastric electrical stimulation (GES) on gastric emptying and specific myenteric neurons of the gastric antrum in healthy beagle dogs. Four healthy adult dogs were implanted with gastric electrical devices, randomly divided into two groups, and given high-frequency short-pulse GES and sham GES (SGES) separately for four weeks in a crossover design, with a three-week washout period. The GES parameters were set 5 mA, 15 Hz, 0.33 ms, cycle on 0.2 s and off 3 s, and the SGES group received no stimulation. Food and water intake, body weight, and gastric emptying scintigraphy were evaluated before and after stimulation. The total neurons, choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin (CALR)-immunoreactivity (IR) positive neurons were measured by indirect immunofluorescence double staining in the gastric antral specimens. After four weeks of GES, dogs were shown significantly higher relative food intake and water intake, along with greater median weight gain compared with the SGES group. GES produced no significant effect on gastric emptying. The total number of antral myenteric neurons in full-thickness biopsies remained comparable between two groups; the proportion of nNOS-IR neurons was significantly higher in GES group than in SGES group (34.9% ± 1.7% vs 27.8% ± 1.9%, p = 0.004). Conversely, the proportion of VIP-IR neurons was lower in GES group than in SGES group (62.5% ± 1.5% vs 65.0% ± 1.8%, p = 0.019). No significant differences were observed in the proportions of ChAT-IR or CALR-IR neurons. High-frequency short-pulse GES selectively increased the proportion of gastric nitrergic (nNOS-IR) neurons and improved feeding tolerance without altering gastric emptying in healthy dogs. This finding indicates that inhibitory nitrergic neuronal remodeling constitutes a key mechanism underlying GES, probably enhancing gastric accommodation.
Despite three decades of experience with Deep Brain Stimulation (DBS) in the management of motor disorders in children and young people (CYP), it remains unclear what proportion experience meaningful improvement. We aimed to establish i) the most common outcomes measures used for DBS in CYP, ii) evidence for minimally clinically important difference (MCID) for measures identified, and iii) the proportion of CYP achieving such MCID. A scoping review was performed and reported following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, identifying CYP (≤18 years) undergoing DBS for the management of their motor disorder. Evidence for MCID was explored for the five most common outcome measures. Individual patient data were identified for 641 CYP across 157 studies. The most common outcome measures were the Burke-Fahn-Marsden Dystonia rating scale (BFMDRS) (539/641, 84.1%), the Barry-Albright Dystonia Scale (BADS) (71/641, 11.1%), the Gross Motor Function Measure-88 (GMFM-88) (63/641, 9.8%), the Canadian Occupational Performance Measure (COPM) (60/641, 9.4%), and the Unified Myoclonus Rating Scale (UMRS) (32/641, 5.0%). Whilst a 25% improvement in BFMDRS was often cited as the threshold for clinical response (achieved by 327/539, 60.7%), no evidence was identified to support this value as MCID. Considering a mild-to-moderate improvement in GMFM of 1.3%-24.5%, a significant change was seen in 25 of 62 CYP, a two-point change in COPM score was identified as MCID (achieved by 39/55, 70.9%). For the GMFM MCID appears to differ by both age and functional level and has not been determined for non-CP dystonia etiologies. No MCID could be identified for either the BADS or UMRS. Whilst improvements are reported for most CYP undergoing DBS it remains uncertain for what proportion this translates into a clinically significant change. A consensus is required on what defines "response" to DBS to support counselling for CYP and families who may be considered for this intervention.
This retrospective study aimed to evaluate the long-term efficacy of sacral neuromodulation (SNM) in managing vesicoureteral reflux (VUR) secondary to neurogenic lower urinary tract dysfunction (NLUTD) and identified predictors of success. A total of 26 patients with NLUTD and urodynamically confirmed VUR(21 unilateral, 5 bilateral) underwent SNM test stimulation. Video-urodynamic studies assessed VUR grade, safe bladder capacity, and detrusor pressure pre- and posttest. Success criteria were as follows: VUR reduced to grade I or lower or VUR still grade II or higher but with delayed onset of reflux and safe bladder capacity clinically judged to be suitable for clean intermittent catheterization (CIC). Patients with success proceeded to permanent implantable pulse generator placement, with annual follow-up. During the test phase (mean 27.9 days), VUR resolved in 13 of 31 refluxing ureters. Safe bladder capacity significantly increased (119.7 ± 18.0 mL to 240.9 ±2 1.3 mL, p < 0.05) and maximum detrusor pressure during the storage phase decreased (45.0 ± 6.9 to 31.0 ± 5.9 cmH2O, p < 0.05). A total of 21 patients received permanent implants. In 13 patients with long-term follow-up (1-4 years), VUR resolved in five patients who had persistent reflux post-test, whereas recurrence occurred in two patients. Multivariate analysis identified pretreatment VUR grade as the only significant predictor of success (odds ratio = 0.30; p < 0.05), with higher grades associated with lower odds of resolution. SNM can improve or resolve VUR in select patients with NLUTD by enhancing bladder compliance and reducing storage pressure. Higher baseline VUR grade predicts a lower likelihood of success. Long-term success requires adherence to CIC.
In this retrospective study, we evaluated high-frequency spinal cord stimulation (SCS) as an alternative neuromodulation strategy for patients with medically intractable chronic cluster headache (MICCH) in whom occipital nerve stimulation (ONS) had failed. MICCH represents a severe and treatment-resistant form of cluster headache, for which preventive pharmacologic treatment options are limited. ONS is increasingly used as a peripheral neuromodulation strategy for MICCH, but a subset of patients remains refractory despite treatment. Cervical SCS could be a central neuromodulation strategy for these patients. This retrospective study included 14 patients with MICCH (nine female, five male; mean age 47 years) who were treated with high cervical 10 kHz SCS after ONS failure. Clinical data were collected on attack frequency, attack duration, intensity of attacks, and quality of life throughout the duration of neuromodulation treatment. Mean SCS follow up duration is 33 ± 21 months. At the last SCS follow-up, ten of 14 patients had a lower mean attack frequency compared with their last ONS assessment (64 ± 33 vs 36 ± 34 weekly attacks, p = 0.02). At the last SCS follow-up six patients obtained a reduction in attack frequency relative to baseline. Mean attack duration decreased from 110 ± 86 to 88 ± 56 minutes, whereas attack intensity remained unchanged. Quality-of-life outcomes were inconsistent and did not uniformly correspond with clinical improvement. High cervical 10 kHz SCS may represent a feasible rescue neuromodulation strategy for patients with MICCH unresponsive to ONS, with a subset achieving sustained reductions in attack frequency. Interpretation of the effects of SCS on attack duration and pain intensity is limited due to missing data. Nevertheless, these findings support its potential as a treatment option in this highly resistant population. Well-controlled prospective studies are needed to confirm efficacy and further define the role of SCS in treatment algorithms. This study was not registered as a clinical trial it is a retrospective observational cohort study. The intervention was offered as a last-resort treatment within regular clinical care to patients with medically intractable chronic cluster headache and was therefore not prospectively designed or conducted as a trial.
Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulation technique that modulates central vagal and attentional circuits through stimulation of the auricular branch of the vagus nerve (ABVN). Although the cymba conchae is the most common target due to its dense ABVN innervation, its variable surface region and irregular shape complicate electrode placement and consistent current delivery. The mastoid process, located posterior to the auricle, offers easier accessibility and a larger stimulation surface, but the neural effects of its stimulation remain unclear. To determine whether mastoid stimulation elicits brain activation patterns comparable with traditional cymba stimulation. In this single-blinded, sham-controlled study, 24 healthy participants received stimulation at three sites (i.e., cymba conchae, mastoid process, and earlobe) in a block-design paradigm (30-second "ON"/"OFF" cycles), whereas functional MRI data were collected concurrently to assess whole-brain activation patterns and network-specific responses. Both mastoid and cymba stimulation produced highly similar spatial patterns of brain activation, with activation in the anterior insula and temporoparietal junction, and deactivation in the sensorimotor cortex. Earlobe stimulation (sham condition) also elicited a similar spatial pattern of brain activation, but substantially weaker compared with mastoid and cymba stimulation. No adverse events were reported. Our findings show that mastoid stimulation elicits neural activation patterns comparable to cymba stimulation, engaging core vagal and attentional networks. These results suggest that the mastoid process may serve as a feasible and accessible alternative stimulation site for taVNS, potentially improving wearability, reproducibility, and patient treatment adherence in future clinical applications.
As a promising noninvasive brain stimulation technique, transcutaneous vagus nerve stimulation (tVNS) is considered to positively modulate the inhibitory control (IC) process by activating the locus coeruleus-norepinephrine pathway and increasing neurotransmitter release. However, the neuroplasticity regulation mechanisms underlying tVNS-induced IC improvement remain unclear. We explored the neuroplastic mechanisms of tVNS effects on IC by a multidimensional electroencephalogram (EEG) analysis framework, focusing on brain activity during both resting-state and IC task-state. A total of 21 young male college students were recruited to undergo EEG recording using a counterbalanced and randomized within-subjects crossover design. EEG data were collected before and after stimulation, and the participants were required to perform a two-stage stop-signal task during stimulation. No significant difference was observed between tVNS and sham-tVNS (sham) in the behavioral performance of stop-signal task or the N2 component. However, compared with the resting-state EEG following sham, tVNS induced a decrease in delta and theta oscillations, and an increase in beta oscillations in fronto-central region. In addition, tVNS strengthened the small-world coefficient (Sigma). Meanwhile, compared with the task-state EEG following sham, tVNS increased alpha oscillations and attenuated task-state FC. These results suggested that tVNS positively modulates resting-state brain activity. The data further indicated that tVNS can increase neural efficiency during IC-state brain activity, as well as improve the information transmission efficiency of the IC-state brain network, which provided empirical evidence supporting tVNS as an effective strategy for enhancing IC capabilities through neuroplasticity modulation.
Olfactory dysfunction is highly prevalent worldwide and linked to major neurologic and psychiatric disorders. Electrical stimulation of the olfactory bulb (OB) and olfactory tract (OT) has emerged as a potential therapeutic approach to restore olfactory percepts and possibly improve associated conditions. This study aimed to systematically review preclinical and clinical electrical stimulation studies of the OB and OT, evaluate their relevance for olfactory prosthesis development, and identify key technical and translational requirements for clinical implementation. Following Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines, PubMed, EMBASE, and Web of Science were searched until December 31, 2025. Eligible studies reported in vivo electrical stimulation of the OB or OT in mammals. A narrative synthesis of the data was undertaken. Overall, 42 studies were included (38 animal, four human). Critically for prosthesis development, all four human studies successfully elicited olfactory perceptions through OB/OT stimulation. In rodent anosmia models, electrical stimulation evoked spatially selective neural responses, with animals indicating discrimination between stimulation sites spaced as close as 250 μm-establishing proof of principle for encoding distinct odor percepts. Stimulation parameters significantly influenced outcomes: Spatially targeted, patterned stimulation produced odor-like responses and supported associative learning, whereas diffuse, high-frequency stimulation modulated mood and memory circuits. The OB/OT's extensive connectivity to limbic structures offers potential therapeutic benefits beyond smell restoration, although this requires careful parameter optimization. OB and OT stimulation are accessible neuromodulation targets with promising but context-dependent effects. Translation requires standardized protocols, large-mammal validation, and early-phase adult human studies.
Transcranial alternating current stimulation (tACS) with a combined theta-gamma (TG) waveform can boost human motor performance, but its effects on primary motor cortex (M1) plasticity remain unclear. This study investigated the effects of concurrent TG tACS and repetitive paired-pulse transcranial magnetic stimulation (rppTMS) on M1 excitability and plasticity. A total of 22 healthy young adults completed four experimental sessions involving concurrent application of tACS and rppTMS over M1. Fifteen minutes of rppTMS (1.5 ms interstimulus interval, [ISI]) was applied during tACS with either a 75-Hz gamma burst nested in the peak (TGP) or trough (TGT) of a 6-Hz theta carrier wave, theta in isolation (TP), or sham (ten second ramp at start/end). Single- and paired-pulse TMS was performed before and after the rppTMS intervention to assess motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (2 ms ISI), and short-interval intracortical facilitation (1.5 ms ISI). Paired-pulse MEP amplitude during rppTMS (online effects) increased with active (TGP, TGT, TP; all p < 0.045) but not sham (all p > 0.222) tACS. In contrast, examination of offline responses showed that single-pulse MEP amplitude and short-interval intracortical facilitation increased, whereas short-interval intracortical inhibition decreased, after the intervention (all p < 0.008), but this change was not different across tACS conditions (all p > 0.050). Our study shows that tACS resulted in an increase in M1 excitability during rppTMS, but this was not different between peak- and trough-coupled TG tACS, or theta tACS. Furthermore, TG tACS did not influence offline neuroplastic effects with rppTMS. As these studies were performed at rest, it is possible that tACS may be more effective during a motor task that activates a broader motor network.