Browsing by Author "Hyakumura, Tomoko"
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- 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.
- 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.
- ItemImplantation Surgery for Abdominal Vagus Nerve Stimulation and Recording Studies in Awake Rats.(Journal of Visualized Experiments, 2024-01-19) Hyakumura, Tomoko; Fallon, James B; Payne, Sophie CAbdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does not have any respiratory and cardiac off-target effects commonly associated with cervical VNS. The lack of respiratory and cardiac off-target effects means that the intensity of stimulation does not need to be lowered to reduce side effects commonly experienced during cervical VNS. Few recent studies demonstrate the anti-inflammatory effects of abdominal VNS in rat models of inflammatory bowel disease, rheumatoid arthritis, and glycemia reduction in a rat model of type 2 diabetes. Rat is a great model to explore the potential of this technology because of the well-established anatomy of the vagus nerve, the large size of the nerve that allows easy handling, and the availability of many disease models. Here, we describe the methods for cleaning and sterilizing the abdominal VNS electrode array and surgical protocol in rats. We also describe the technology required for confirmation of suprathreshold stimulation by recording evoked compound action potentials. Abdominal VNS has the potential to offer selective, effective treatment for a variety of conditions, including inflammatory diseases, and the application is expected to expand similarly to cervical VNS.
- ItemAn In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants(Mary Ann Liebert Inc Publishers, 2013-03) Nayagam, Bryony; Edge, Albert; Needham, Karina; Hyakumura, Tomoko; Leung, Jessie; Nayagam, David; Dottori, MirellaIn mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. To successfully replace auditory neurons, stem cell-derived neurons must be electrically active, capable of organized outgrowth of processes, and of making functional connections with appropriate tissues. We have developed an in vitro assay to test these parameters using cocultures of developing cochlear explants together with neural progenitors derived from human embryonic stem cells (hESCs). We found that these neural progenitors are electrically active and extend their neurites toward the sensory hair cells in cochlear explants. Importantly, this neurite extension was found to be signifi- cantly greater when neural progenitors were predifferentiated toward a neural crest-like lineage. When grown in coculture with hair cells only (denervated cochlear explants), stem cell-derived processes were capable of lo- cating and growing along the hair cell rows in an en passant-like manner. Many presynaptic terminals (synapsin 1-positive) were observed between hair cells and stem cell-derived processes in vitro. These results suggest that differentiated hESC-derived neural progenitors may be useful for developing therapies directed at auditory nerve replacement, including complementing emerging hair cell regeneration therapies.This is a copy of an article published in the Stem Cells and Development Journal © 2013 [copyright Mary Ann Liebert, Inc.]; Stem Cells and Development is available online at: http://online.liebertpub.com.
- ItemOrganotypic Cocultures of Human Pluripotent Stem Cell Derived- Neurons with Mammalian Inner Ear Hair Cells and Cochlear Nucleus Slices(Hindawi, 2019-12) Hyakumura, Tomoko; McDougall, Stuart; Finch, Sue; Needham, Karina; Dottori, Mirella; Nayagam, BryonyStem cells have been touted as a source of potential replacement neurons for inner ear degeneration for almost two decades now; yet to date, there are few studies describing the use of human pluripotent stem cells (hPSCs) for this purpose. If stem cell therapies are to be used clinically, it is critical to validate the usefulness of hPSC lines in vitro and in vivo. Here, we present the first quantitative evidence that differentiated hPSC-derived neurons that innervate both the inner ear hair cells and cochlear nucleus neurons in coculture, with significantly more new synaptic contacts formed on target cell types. Nascent contacts between stem cells and hair cells were immunopositive for both synapsin I and VGLUT1, closely resembling expression of these puncta in endogenous postnatal auditory neurons and control cocultures. When hPSCs were cocultured with cochlear nucleus brainstem slice, significantly greater numbers of VGLUT1 puncta were observed in comparison to slice alone. New VGLUT1 puncta in cocultures with cochlear nucleus slice were not significantly different in size, only in quantity. This experimentation describes new coculture models for assessing auditory regeneration using well-characterised hPSC-derived neurons and highlights useful methods to quantify the extent of innervation on different cell types in the inner ear and brainstem.
- ItemStimulation parameters for directional vagus nerve stimulation.(Bioelectronic Medicine, 2023-07-18) Villalobos, Joel; Payne, Sophie C; Ward, Glenn M; Andrikopoulos, Sofianos; Hyakumura, Tomoko; MacIsaac, Richard J; Fallon, James BAutonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.
- 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.