Neuromodulation最新文献

Background: Exercise induces short-term pain relief (exercise-induced hypoalgesia, EIH), but this response is often blunted in people with knee osteoarthritis (OA). Transcranial direct current stimulation (tDCS) has been proposed as a potential enhancer of EIH.

Objective: This study aimed to determine whether a single session of 2-mA anodal tDCS applied for 20 minutes over the contralateral primary motor cortex augments the exercise-induced hypoalgesic response to isometric quadriceps exercise in individuals with knee OA.

Materials and methods: In this double-blind randomized cross-over trial, 27 participants with knee OA completed two experimental sessions (active anodal tDCS + exercise; sham tDCS + exercise) in counterbalanced order. Pressure pain thresholds (PPTs at the knee and forearm), resting knee pain, and evoked knee pain during stepping were assessed pre- and post intervention. Linear mixed models compared pre- and postexercise changes between active and sham conditions. Blinding success was evaluated using Bang's blinding index.

Results: Both sessions produced EIH (knee PPT increased pre-to-post; all p ≤ 0.001). Between active and sham conditions, there were no significant differences for knee PPT (mean difference 0 kPa [95% CI -50 to 40], p = 0.82), forearm PPT (-20 kPa [-60 to 30], p = 0.45), resting knee pain (1/100 [-13 to 15], p = 0.89), or evoked knee pain (1/100 [-7 to 8], p = 0.14). Blinding was successful, and no adverse events were reported.

Conclusions: These findings indicate that a single session of anodal tDCS does not augment the immediate EIH response to isometric quadriceps exercise in people with knee OA.

Perspective: This randomized cross-over trial found that anodal tDCS did not enhance EIH in people with knee OA. These findings suggest that a single session of anodal tDCS does not meaningfully augment the immediate exercise-induced hypoalgesic response in individuals with knee OA.

Clinical trial registration: The Australian New Zealand Clinical Trials Registry number for the study is ACTRN12621000787886, registered July 1, 2021, prospectively.

Objectives: Transcranial magnetic stimulation (TMS) and low-intensity focused ultrasound (LIFU) are neuromodulation techniques that use different types of energy and have disparate spatial profiles. The study aimed to quantify and compare both modalities' focality on a common cortical target.

Materials and methods: Magnetic resonance imaging-derived individualized head models were used to simulate TMS-induced electric fields and LIFU acoustic fields at 250 kHz and 500 kHz for a common standardized target located in the left dorsolateral prefrontal cortex in 20 subjects. Energy distribution was quantified using three relative thresholds (30%/50%/70%) and two metrics: % Engaged (percentage of a region's volume energized) and % Deposited (percentage of total energized tissue lying within a region). Regional analyses focused on the middle frontal gyrus (_MFGyr) and middle frontal sulcus (_MFSulc).

Results: TMS produced notably larger activation volumes than did both LIFU frequencies. TMS engaged 59% of _MFGyr and 29% of _MFSulc, whereas LIFU-250 kHz engaged 3% and 8%, and LIFU-500 kHz engaged <1% of each. TMS mainly engaged _MFGyr, whereas LIFU dispersed its energy more evenly between gyri and sulci. LIFU also indicated greater focality but exhibited significantly higher intersubject variability, particularly at 500 kHz. Reducing the fundamental frequency to 250 kHz increased coverage while maintaining focality.

Conclusions: Our modeling provides a quantification and contrast to the concept of focality between TMS and LIFU. It shows a trade-off between focality and sensitivity to anatomical variability: the greater the focality, the more sensitivity to anatomical variability, thus potentially requiring more sophisticated targeting methods and apparatus, and vice versa.

Clinical trial registration: The Clinicaltrials.gov registration number for the study is NCT02800226.

Introduction: Chronic constipation is a prevalent and heterogeneous disorder, affecting approximately 10% to 14% of adults and significantly influencing quality of life. Neuromodulation has been explored as a potential treatment; however, evidence remains limited. Therefore, this meta-analysis of randomized controlled trials (RCTs) aims to assess the efficacy and safety of vagus nerve-based neuromodulation techniques for chronic constipation, specifically transcutaneous auricular vagus nerve stimulation (taVNS) and transcutaneous electroacupuncture (TEA).

Materials and methods: A comprehensive search of PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials was performed from inception to June 2025. Data were pooled using risk ratios for dichotomous outcomes and mean differences (MD) or standardized mean differences (SMD) for continuous outcomes, with 95% CIs, applying a random-effects model. Statistical analyses were conducted using R (version 4.4.2) in R-Studio, International Prospective Register of Systematic Reviews identification: (CRD420251132888).

Results: Six RCTs involving 356 participants were included. Vagal nerve stimulation (VNS) significantly improved the visual analog pain scale (MD: -1.76 [95% CI: -2.92 to -0.60], p = 0.003), Bristol stool form scale (BSFS) (MD: 0.99 [95% CI: 0.30-1.68], p = 0.005), weekly spontaneous bowel movements (SBM) frequencies (MD: 1.75 [95% CI: 0.93-2.58], p < 0.0001), weekly complete spontaneous bowel movements (CSBM) frequencies (MD of 1.10 [95% CI: 0.40-1.80]), p = 0.002), and irritable bowel syndrome symptom severity (IBS-SSS) score (SMD of -1.68 [95% CI: -3.13; -0.24], p = 0.023). Still, there was no significant difference between the groups regarding Self-Rating Anxiety Scale (MD: -1.84 [95% CI: -6.19 to 2.52], p = 0.41), Self-Rating Depression Scale (SDS) scores (MD: -2.06 [95% CI: -6.14 to 2.02], p = 0.32), and anorectal function (p > 0.05).

Conclusion: VNS substantially improves VAS, BSFS, weekly SBM, weekly CSBM, and IBS-SSS scores.

Objective: Our aim was to assess the effectiveness and complication rate of occipital nerve stimulation (ONS) using a recently developed anchoring lead dedicated to ONS in patients treated for refractory chronic cluster headache (rCCH).

Materials and methods: Patients with rCCH were included in a prospective multicenter ONS registry from 2019 to 2024 and treated by ONS using anchored ONS-dedicated leads. The effectiveness of ONS was evaluated by the frequency of chronic cluster headache (CCH) attacks, abortive and preventive medication use, quality of life (EuroQol-5 Dimensions scale), and the functional (Headache Impact Test-6) and emotional (Hospital Anxiety and Depression Scale) impacts. Complications were monitored, focusing on electrode migration, device malfunction, infections, and local pain.

Results: Overall, 40 (16 women, mean age 46 years) and 24 patients were followed for one and two years after ONS, respectively. The mean weekly attack frequency significantly decreased, from 24.3 before ONS to 12.7 (p = 0.006) at one year and to 11.7 (p = 0.002) at two years. Functional and emotional impacts and quality of life significantly improved. During the follow-up period, 16 patients experienced device-related complications, including infection (7.5%), lead migration (5%), hardware dysfunction (15%), and pain at the lead insertion site (12.5%).

Conclusion: ONS using ONS-dedicated leads showed similar effectiveness, while also presenting a low risk of migration, to ONS using other leads reported in previous studies.

Clinical trial registration: The Clinicaltrials.gov registration number for the study is NCT01842763.

Objectives: Experimental studies in nonobese diabetic mice show that electrical stimulation of sympathetic nerves innervating pancreatic lymph nodes (LNs) reduces T cell activation through β-2 adrenergic signaling and limits further β-cell destruction. Neuromodulation of pancreatic LNs may therefore represent a novel therapeutic approach for early-stage type 1 diabetes (T1D) in humans. This study aims to explore the presence of a sympathetic neuro-immune link in human pancreatic LNs and to identify surgically accessible neuromodulation sites.

Materials and methods: Upstream pancreatic LNs 8a and 8p were selected as primary targets because they drain lymph from multiple downstream pancreatic LNs. The suitability of two potential stimulation sites to target the sympathetic innervation of these LNs, being the LN capsule and the nerve plexus surrounding the proximal common hepatic artery (CHA), was evaluated. Ten formaldehyde-fixed human cadavers were studied, and various techniques were used to collect macro- and microscopic data on pancreatic LNs and the proximal CHA with its surrounding nerve plexus.

Results: Human pancreatic LNs contain sympathetic nerves in both their capsule and parenchyma, the latter occasionally as discrete nerves located close to T cells. Of the two upstream LNs studied, LN 8a was consistently present, easily accessible, and showed clear sympathetic connections to the celiac and CHA nerve plexuses. However, its position varied, and it was located near the pancreas. The nerve plexus around the CHA was consistently observed and contained predominantly sympathetic nerves, with nerves to LN 8a originating from its anterior-caudal region.

Conclusion: Human pancreatic LNs contain a sympathetic neuro-immune link that could be targeted for T1D treatment. The proximal CHA's nerve plexus appears the most promising neuromodulation site owing to its surgical accessibility, sympathetic predominance, and suitability for safe device implantation.

Objectives: Cannabis use disorder (CUD) is a significant public health problem and no medical treatments have received regulatory approval to date. Deep repetitive transcranial magnetic stimulation (dTMS) provides brief powerful bursts of electromagnetic stimulation to brain networks implicated in psychiatric disorders and the Hesed (H)-4 coil, which targets the lateral prefrontal cortex and anterior insula, is approved for tobacco use disorder. This phase 1 open-label pilot study evaluated the feasibility and tolerability of H4 dTMS in conjunction with standard care for adults with moderate-to-severe CUD who were seeking treatment.

Materials and methods: Participants received 18 sessions of H4 dTMS (three weeks of five sessions per week, one week of three sessions) in conjunction with standard care. Feasibility was operationalized as treatment completion and attainment of therapeutic dose (≥ 90% resting motor threshold). Tolerability was operationalized as adverse events. Exploratory clinical and mechanistic outcomes were 5-mg standard units of Δ⁹-tetrahydrocannabinol (THC), CUD symptoms, cravings, cannabis reinforcing value, self-efficacy, internalizing and somatic symptoms, and neuropsychological performance.

Results: Of 11 participants (64% female, CUD symptoms mean ± SD = 9.27 ± 1.10), 92% completed all dTMS treatments, of whom 91% reached therapeutic dose. Tolerability was high, with the most common adverse events being low rates (2.4%-9.2%) of headache, drowsiness, and scalp pain, primarily during the first week. No participants experienced serious adverse events. Regarding exploratory clinical outcomes, significant reductions were observed in THC consumption, CUD symptoms, cravings, cannabis reinforcing value, and depressive, anxiety, and somatic symptoms (ps < 0.01-0.001), and significant increases were observed in self-efficacy (p < 0.001). No significant effects on neuropsychological performance were detected.

Conclusions: These findings suggest this H4 dTMS protocol was feasible, tolerable, and associated with clinically meaningful reductions in clinical outcomes and related mechanisms, albeit in an uncontrolled design. The results support the prospect of a randomized controlled trial to test the efficacy of this novel intervention for CUD.

Clinical trial registration: The Clinicaltrials.gov registration number for the study is NCT06114212.

Objectives: Deep brain stimulation (DBS) of the ventralis intermedius nucleus of the thalamus (VIM DBS) effectively suppresses upper limb tremor in the setting of essential tremor (ET); however, its effect on motor learning remains unclear. This study aimed to evaluate the influence of DBS on movement consolidation, an important feature of motor learning.

Materials and methods: A total of 16 individuals with ET undergoing VIM DBS treatment and 16 healthy controls (HC) matched for age and sex participated in this study. Participants with ET performed a goal-directed ankle dorsiflexion task over two consecutive days. On day 1, a group of participants with ET (n = 8) practiced the task with DBS off (DBS OFF), whereas the comparison group (n = 8) practiced with DBS on (DBS ON). Task retention was assessed on day 2 with the alternate condition for each group. Spatial accuracy, movement smoothness (Jerk), and tibialis anterior (TA) muscle activity were recorded during practice (day 1) and retention (day 2) for both groups.

Results: During the practice session, spatial error and movement smoothness were not significantly different among the three groups. However, on retention, spatial error and Jerk magnitude were greater in the DBS OFF group than in the DBS ON group and HC group. A significant positive association was found between practice and retention Jerk magnitude (R² = 0.48). All participants manifested 4-to-8-Hz oscillations in the TA muscle, which predicted Jerk magnitude during both practice (R² = 0.37) and retention (R² = 0.27).

Conclusions: These findings suggest that thalamic neurostimulation improves consolidation and may influence other motor learning processes. The presence of 4-to-8-Hz TA oscillations in all individuals with ET and their association with movement smoothness highlight a potential area of interest for further research.

Introduction: During the last century, many ethics codes have emerged, sometimes embedding legally binding instruments, sometimes encoding good clinical practice for the first time. Apart from the general ethical considerations in use of neuromodulation devices, regulators have tried to shield the patient, implanters, and society from possible risks related to such devices, namely, the protection of the patient's privacy and ensuring enduring manufacturer responsibility for the lifecycle of the device. This review aims to reveal the limits of ethics guidelines, the personal responsibility of the researcher, and the usefulness of the European legal, in addition to the international, ethics and deontology frameworks for clinical investigations in neuromodulation. It also introduces a practical tool, the Chimaera Contemplation Checklist, to support researchers throughout the clinical research cycle.

Materials and methods: In this narrative review, the full research cycle for clinical investigations with neuromodulation devices is discussed. Practical advice building on multidisciplinary experience in clinical neuromodulation practice, involving social researchers and legal and ethics advisors, is provided. The review integrates the Chimaera Contemplation Checklist as a structured aid for ethical and legal reflection.

Results: The article focuses on common hurdles, namely, patient-centered study designs, obtaining true informed consent, clear contracts between sponsors and research partners, posttrial accessibility and support of the device, usefulness of standards, and expectations with respect to institutional review boards. The Chimaera Contemplation Checklist summarizes these challenges and offers practical prompts for researchers at each stage.

Discussion: This review highlights that general ethical guidelines and legislation do not easily translate to the practical needs of neuromodulation research. Addressing this gap is essential to support robust, ethical, and legally compliant research that prioritizes patient well-being. With the growing number of regulations concerning medical devices, raising awareness and fostering a deeper understanding of these guidelines is crucial. Collaboration among experts from diverse fields, including law, information technology, research, medical ethics committees, and policy, will play a key role in shaping the future of clinical trials in neuromodulation. The Chimaera Contemplation Checklist serves as a concrete, multidisciplinary tool to guide this process.

Objectives: Neuropathic pain is associated with hyperexcitability of spinal cord dorsal horn neurons. Spinal cord stimulation (SCS) can reduce this hyperexcitability and provide analgesia. We evaluated the effects of two novel SCS waveforms, designed with long pulse widths and short interpulse intervals with slowly varying amplitudes, on neuropathic pain behaviors and dorsal horn neuronal activity in a rat model of tibial nerve injury (TNI).

Materials and methods: Rats underwent TNI followed by implantation of epidural stimulation leads. Novel waveforms, specifically stochastic amplitude modulated pulse train and delayed discharge pulse train, were delivered at 60% and 80% of motor threshold and compared with DeRidder Burst stimulation. Behavioral assays included von Frey and pin-prick testing for mechanical hypersensitivity, dynamic weight bearing for ongoing pain, and acute place preference for motivational aspects of pain. In vivo extracellular recordings from dorsal horn wide-dynamic-range (WDR) neurons at lamina V depth (500-600 μm) were performed before and after stimulation.

Results: Both novel waveforms significantly increased withdrawal thresholds to mechanical stimulation (p < 0.01), reduced pin-evoked hypersensitivity (p < 0.05), restored weight-bearing asymmetry (p <0.05), and increased time spent in stimulation-paired compartments (p < 0.01). Electrophysiology confirmed increased thresholds and reduced evoked firing rates of WDR neurons.

Conclusions: Novel SCS waveforms using varying amplitudes reduce behavioral and electrophysiologic correlates of neuropathic pain in rats. Sub-motor-threshold stimulation with varying amplitude trains can attenuate dorsal horn hyperexcitability. These results support further investigation of waveform design as a strategy for improving neuromodulation therapies.

Objectives: Clinical studies of implantable neural devices raise unique ethical and legal challenges owing to the distinctive nature of these technologies and their research contexts. Persistent issues such as inadequate posttrial arrangements, psychologic risks, and study team roles have been highlighted in the literature. This study aims to address ongoing ethical challenges in clinical studies of implantable neural devices by providing practical recommendations for researchers and research ethics committees (RECs).

Materials and methods: Based on the synthesis of a comprehensive review of academic literature, existing ethical and legal guidelines, empirical studies, and input from various stakeholders, recommendations and their practical translation for RECs and researchers have been formulated.

Results: The study presents recommendations organized into five central themes: 1) the study team, 2) participant selection and recruitment, 3) informed consent processes, 4) risk-benefit assessment, and 5) posttrial responsibilities. Moreover, two procedural recommendations aim to enhance REC review processes specific to investigational implantable neural devices studies.

Conclusions: These recommendations offer actionable guidance to help researchers align protocols with ethical and legal standards, and to assist RECs in anticipating and mitigating ethical risks in clinical studies involving implantable neural devices.