Browsing by Author "Payne, Sophie"
Now showing 1 - 8 of 8
Results Per Page
Sort Options
- ItemAnti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation(Frontiers, 2019-05) Payne, Sophie; Furness, John; Burns, Owen; Sedo, Alicia; Hyakumura, Tomoko; Shepherd, Robert; Fallon, JamesElectrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, cervical vagal nerve stimulation (VNS) can produce unwanted side effects. Here, we investigated whether stimulating the vagus nerve closer to the end organ has fewer off-target effects, while reducing intestinal inflammation. An electrode array was developed to stimulate and record vagal neural responses in rats. Acute VNS off-target experiment: The cervical and abdominal vagus nerves of anaesthetised rats (n=5) were acutely implanted with an electrode array, stimulation delivered (10 Hz; symmetric biphasic current pulse; 320 nC per phase) and changes to heart rate, respiration and blood pressure assessed. Chronic VNS efficacy experiment: The abdominal vagus nerve was chronically implanted with an electrode array. After 2 weeks, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid), an established method for rodent models of IBD. Rats were randomly selected to receive therapeutic VNS (n=7; 10 Hz; symmetric biphasic current pulse; 320 nC per phase; 3 hours/day) or no stimulation (n=8) for 5 days. Stool quality, C-reactive protein in blood and histology of the inflamed intestine were assessed. VNS off-target experiment: Abdominal VNS had no effect (two-way RM-ANOVA: P>0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P>0.05), respiration was inhibited and blood pressure decreased. VNS efficacy experiment: During the implantation period, electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P>0.05), and were below stimulation levels. VNS rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: P<0.0001), no blood in faeces (P<0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: P<0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal-Wallis: P<0.05). Abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans.
- ItemBioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms(Nature Reviews, 2018-05) Payne, Sophie; Furness, John; Stebbing, MartinThe gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system. This provides the opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders. Bioelectric neuromodulation technology has considerably advanced in the past decade, but sacral nerve stimulation for faecal incontinence currently remains the only neuromodulation protocol in general use for a gastrointestinal disorder. Treatment of other conditions, such as IBD, obesity, nausea and gastroparesis, has had variable success. That nerves modulate inflammation in the intestine is well established, but the anti-inflammatory effects of vagal nerve stimulation have only recently been discovered, and positive effects of this approach were seen in only some patients with Crohn's disease in a single trial. Pulses of high-frequency current applied to the vagus nerve have been used to block signalling from the stomach to the brain to reduce appetite with variable outcomes. Bioelectric neuromodulation has also been investigated for postoperative ileus, gastroparesis symptoms and constipation in animal models and some clinical trials. The clinical success of this bioelectric neuromodulation therapy might be enhanced through better knowledge of the targeted nerve pathways and their physiological and pathophysiological roles, optimizing stimulation protocols and determining which patients benefit most from this therapy.
- ItemDifferential effects of vagus nerve stimulation strategies on glycemia and pancreatic secretions(Wiley Periodicals LLC, 2020-06) Payne, Sophie; Ward, Glenn; MacIsaac, Richard; Hyakumura, Tomoko; Fallon, James; Villalobos, JoelDespite advancements in pharmacotherapies, glycemia is poorly controlled in type 2 diabetic patients. As the vagus nerve regulates energy metabolism, here we evaluated the effect various electrical vagus nerve stimulation strategies have on glycemia and glucose-regulating hormones, as a first step to developing a novel therapy of type 2 diabetes. Sprague-Dawley rats were anesthetized, the abdominal (anterior) vagus nerve implanted, and various stimulation strategies applied to the nerve: (a) 15 Hz; (b) 4 kHz, or 40 kHz and; (c) a combination of 15 Hz and 40 kHz to directionally activate afferent or efferent vagal fibers. Following a glucose bolus (500 mg/kg, I.V.), stimulation strategies were applied (60 min) and serial blood samples taken. No stimulation was used as a crossover control sequence. Applying 15 Hz stimulation significantly increased glucose (+2.9 ± 0.2 mM·hr, p = .015) and glucagon (+17.1 ± 8.0 pg·hr/ml, p = .022), compared to no stimulation. Application of 4 kHz stimulation also significantly increased glucose levels (+1.5 ± 0.5 mM·hr, p = .049), while 40 kHz frequency stimulation resulted in no changes to glucose levels but did significantly lower glucagon (-12.3 ± 1.1 pg·hr/ml, p = .0009). Directional afferent stimulation increased glucose (+2.4 ± 1.5 mM·hr) and glucagon levels (+39.5 ± 15.0 pg·hr/ml). Despite hyperglycemia resulting when VNS, aVNS, and 4 kHz stimulation strategies were applied, the changes in insulin levels were not significant (p ≥ .05). In summary, vagus nerve stimulation modulates glycemia by effecting glucagon and insulin secretions, and high-frequency 40 kHz stimulation may have potential application for the treatment of type 2 diabetes.
- ItemModeling experimental recordings of vagal afferent signaling of intestinal inflammation for neuromodulation(IOP Publishing, 2018-08) O'Sullivan-Greene, Elma; Kameneva, Tatiana; Trevaks, David; Shafton, Anthony; Payne, Sophie; McAllen, Robin; Furness, John; Grayden, DavidObjective Artificial modulation of peripheral nerve signals (neuromodulation) by electrical stimulation is an innovation with potential to develop treatments that replace or supplement drugs. One function of the nervous system that can be exploited by neuromodulation is regulation of disease intensity. Optimal interfacing of devices with the nervous system requires suitable models of peripheral nerve systems so that closed-loop control can be utilized for therapeutic benefit. Approach We use physiological data to model afferent signaling in the vagus nerve that carries information about inflammation in the small intestine to the brain. Main results The vagal nerve signaling system is distributed and complex; however, we propose a class of reductive models using a state-space formalism that can be tuned in a patient-specific manner. Significance These models provide excellent fits to a large range of nerve recording data but are computationally simple enough for feedback control in implantable neuromodulation devices.
- ItemAn objective in vivo diagnostic method for inflammatory bowel disease(Royal Society Open Science, 2018-03) Payne, Sophie; Shepherd, Robert; Sedo, Alicia; Fallon, James; Furness, JohnInflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (p < 0.05). Changes in intestinal transmural impedance were correlated (p < 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.
- ItemRecording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array(Frontiers, 2020-12) Payne, Sophie; Wiedmann, Nicole; Eiber, Calvin; Wong, Agnes; Senn, Philipp; Osborne, Peregrine; Keast, Janet; Fallon, JamesBioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in naïve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.
- ItemTransmural impedance detects graded changes of inflammation in experimental colitis(The Royal Society Publishing, 2020-02) Payne, Sophie; Alexandrovics, Jack; Thomas, Ross; Shepherd, Robert; Furness, John; Fallon, JamesUlcerative colitis is a chronic disease in which the mucosa of the colon or rectum becomes inflamed. An objective biomarker of inflammation will provide quantitative measures to support qualitative assessment during an endoscopic examination. Previous studies show that transmural electrical impedance is a quantifiable biomarker of inflammation. Here, we hypothesize that impedance detects spatially restricted areas of inflammation, thereby allowing the distinction between regions that differ in their severity of inflammation. A platinum ball electrode was placed into minimally inflamed (i.e. normal) or 2,4,6-trinitrobenzene sulphonic acid (TNBS)-inflamed colonic regions of rats and impedance measurements obtained by passing current between the intraluminal and subcutaneous return electrode. Histology of the colon was correlated with impedance measurements. The impedance of minimally inflamed (normal) tissue was 1.5–1.9 kΩ. Following TNBS injection, impedance significantly decreased within the inflammatory penumbra ( p < 0.05), and decreased more in the inflammatory epicentre ( p = 0.02). Histological damage correlated with impedance values ( p < 0.05). Thus, impedance values of 1.5–1.9, 1.3–1.4 and 0.9–1.1 kΩ corresponded to minimally inflamed, mildly inflamed and moderately inflamed tissue, respectively. In conclusion, transmural impedance is an objective, spatially localized biomarker of mucosal integrity, and distinguishes between severities of intestinal inflammation.
- ItemVagus nerve stimulation to treat inflammatory bowel disease: a chronic, preclinical safety study in sheep(Future Medicine, 2019-02) Payne, Sophie; Burns, Owen; Stebbing, Martin; Thomas, Ross; de Silva, Angel; Sedo, Alicia; Weissenborn, Frank; Hyakumura, Tomoko; Huynh, Mario; May, Clive; Williams, Richard; Furness, John; Fallon, James; Shepherd, RobertAim: Electrical stimulation of the left cervical vagus nerve is a feasible therapy for inflammatory bowel disease (IBD). However, due to the location of the electrode placement, stimulation is often associated with side effects. Methods: We developed a cuff electrode array, designed to be implanted onto the vagus nerve of the lower thorax or abdomen, below branches to vital organs, to minimize off-target effects to stimulation. Results: Following chronic implantation and electrical stimulation, electrodes remained functional and neural thresholds stable, while there were minimal off-target affects to stimulation. No nerve damage or corrosion of stimulated electrodes was observed. Conclusion: This novel electrode array, located on the vagus nerve below branches to vital organs, is a safe approach for the treatment of inflammatory bowel disease.