Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

Does Sacral Nerve Stimulation Improve Continence Through Enhanced Sensitivity of the Anal Canal? A Pilot Study.

BACKGROUND: It has been suggested that the effects of sacral nerve stimulation against fecal incontinence involve neuromodulation at spinal or supraspinal levels. OBJECTIVE: This study aims to investigate the afferent sensory pathways from the anorectum before and during sacral nerve stimulation. DESIGN: This is an explorative study. PATIENTS: Fifteen women with idiopathic fecal incontinence (mean age, 58 ± 12.2 years) were selected. INTERVENTIONS: Cortical evoked potentials were recorded during repeated rapid balloon distension of the rectum and the anal canal both before and during temporary sacral nerve stimulation. Stimuli applied were individualized according to the subjective urge to defecate. MAIN OUTCOME MEASURES: The main outcomes measured were 1) stimulus intensity, 2) latencies and amplitudes of cortical evoked potentials, and 3) spectral content in predefined frequency bands of cortical evoked potentials. RESULTS: The median Wexner fecal incontinence score improved from 15.5 ± 3.6 before to 6.7 ± 5 during sacral nerve stimulation (p < 0.001). Sacral nerve stimulation did not affect the threshold for urge to defecate during rectal distension (p = 0.64) but reduced the threshold from stimulation of the anal canal by 50% (p = 0.03). No statistically significant differences were found in latencies, amplitudes, or spectral analysis. LIMITATIONS: This is a pilot study of limited size. CONCLUSIONS: In patients with idiopathic fecal incontinence, sacral nerve stimulation reduced the threshold for urge to defecate elicited from the anal canal, whereas supraspinal responses remained unaltered. This may suggest that sacral nerve stimulation, at least in part, acts via somatic afferent fibers enhancing anal sensation.

Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity.

BACKGROUND: The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy subjects. METHODS: Eighteen healthy subjects were randomized to a subject-blinded, sham-controlled, cross-over study with an active protocol including stimulation of auricular branch of the vagus nerve, and breathing at full inspiratory capacity and forced full expiration. Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle, and bone pressure algometry, conditioned pain modulation using a cold pressor test and a liquid meal ultrasonographic gastroduodenal motility test were performed. KEY RESULTS: Cardiac vagal tone increased during active treatment with t-VNS and DSB compared to sham (p = 0.009). In comparison to sham, thresholds to bone pain increased (p = 0.001), frequency of antral contractions increased (p = 0.004) and gastroduodenal motility index increased (p = 0.016) with active treatment. However, no effect on muscle pain thresholds and conditioned pain modulation was seen. CONCLUSIONS & INFERENCES: This experimental study suggests that this noninvasive approach with combined electrical and physiological modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. These findings warrant further investigation in patients with disorders characterized with chronic pain and gastrointestinal dysmotility such as functional dyspepsia and irritable bowel syndrome.

Sacral nerve stimulation changes rectal sensitivity and biomechanical properties in patients with irritable bowel syndrome.

BACKGROUND: Sacral nerve stimulation (SNS) has been demonstrated to alleviate symptoms and improve quality of life in selected patients with irritable bowel syndrome (IBS). The mechanisms of action, however, remain unknown. The aim of the study was to evaluate the effects of SNS on rectal sensitivity and biomechanical properties in patients with IBS. METHODS: Twenty patients with diarrhea-predominant (n = 11) or mixed (n = 9) IBS were treated with SNS in a controlled, randomized crossover trial. They were randomized to either 1 month of SNS (ON) or placebo (OFF) with the opposite setting for the next month. Sensory and biomechanical parameters were assessed by multimodal rectal stimulation at the end of each period. IBS-specific symptoms were evaluated at baseline and at the end of each treatment period. KEY RESULTS: Cold stimuli were better tolerated in the ON period (19.9 °C[± 0.6]) compared to the OFF period (21.8 °C[± 0.6]; p = 0.03). Significantly lower cross-sectional areas were needed to elicit sensory responses in the ON period (1545 mm(2) [± 95]) compared to the OFF period (1869 mm(2) [± 92]; p = 0.015). The association between reduced sensory threshold and improvement of constipation was of borderline significance (p = 0.05). Wall stiffness was significantly lower in the ON period (192 mmHg[± 10]) compared to the OFF period (234 mmHg[± 10]; p = 0.004). Reduced wall stiffness was significantly associated with improved overall GSRS-IBS symptom score (p = 0.01). Reduced sensory threshold to stretch (p = 0.02) and reduced wall stiffness (p < 0.001) were predictors of the GSRS-IBS symptom score. CONCLUSIONS & INFERENCES: SNS for diarrhea-predominant and mixed IBS relaxes the rectal wall, while making it more sensitive to stretch and less sensitive to cold. Reduced wall stiffness and increased sensitivity to stretch are associated with improved GSRS-IBS symptom score.

Electrical low-frequency stimulation induces central neuroplastic changes of pain processing in man.

Electrical low-frequency stimulation (LFS) inhibits pain perception and nociceptive processing as shown by psychophysical and electrophysiological means (long-term depression, LTD). Information regarding central mechanisms involved in LTD induction and maintenance are still missing. This study hypothesizes that electrical LFS induces changes in activation pattern of pain-related brain areas. Thirty-two electrophysiological and psychophysical experiments were performed in 16 healthy volunteers. Painful electrical test stimulation (0.125 Hz, 60 pulses) and conditioning LFS (1 Hz, 1200 pulses) were applied by a concentric electrode to the right hand. Test stimulation series were performed before (Pre) and after LFS (Post) or no stimulation period (Control). Volunteers rated pain perception according to a verbal rating scale (0-100). Somatosensory evoked cortical potentials were recorded with 64-channel electroencephalography. Individual dipole source modeling using CURRY software (Compumedics, Hamburg, Germany) yielded information about dipole location and strength. The strongest decrease in LFS-induced pain perception was shown after LFS (p < 0.01). Topographic distribution of cortical potentials revealed reproducible negative (N1, N2) and positive (P2) components. Dipole magnitude analysis showed a significant difference between Post LFS and Post Control for P2 (p < 0.01). P2 dipole location analysis yielded a significant posterior (p < 0.05) shift following LTD induction. Thus, data reveal central changes of pain processing after LTD induction. These experiments may help judging the potency of LTD as model for electrostimulation in future analgesic therapy.

Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method.

Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto-sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross-sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 degrees C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P-values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between-days reproducibility was good for all modalities [intra-class correlation (ICC) > or = 0.6]. At sensory threshold, CSA showed best reproducibility (ICC > or = 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.

Cerebral processing of painful oesophageal stimulation: a study based on independent component analysis of the EEG.

BACKGROUND AND AIMS: Independent component analysis (ICA) of the electroencephalogram (EEG) overcomes many of the classical problems in EEG analysis. We used ICA to determine the brain responses to painful stimulation of the oesophagus. METHODS: Twelve subjects with a median age of 41 years were included. With a nasal endoscope, two series of 35 electrical stimuli at the pain threshold were given to the distal oesophagus and the EEG was subjected to ICA. The sessions were separated by 30 minutes. For each component head models, event related images, spectral perturbation, coherence analysis, and dipoles were extracted. The most valid components were found according to time/frequency information and reliability in both experiments. RESULTS: Reliable components with the most valid dipoles were found in the thalamus, insula, cingulate gyrus, and sensory cortex. Time locked activities were consistent with upstream activation of these areas, and cross coherence analysis of the sources demonstrated dynamic links in the beta(14-25 Hz) and gamma(25-50 Hz) bands between the suggested networks of neurones. The thalamic components were time and phase locked intermittently, starting around 50 ms. In the cingulate gyrus, the posterior areas were always firstly activated, followed by the middle and anterior regions. Components with dipoles in the sensory cortex were localised in several regions of the somatosensory area. CONCLUSIONS: The method gives new information relating to the localisation and dynamics between neuronal networks in the brain to pain evoked from the human oesophagus, and should be used to increase our understanding of clinical pain.