Magnetically coupled percutaneous connector for chronic electrical peripheral nerve stimulation and recording in awake rats.

Unlabelled: A fast-growing field of neuroscience and medicine is the treatment of disease via electrical stimulation of the peripheral nervous system. Peripheral nerve stimulation delivers stimulation to nerves of the periphery where the target nerve can and is often located deep within the abdomen. Long-term preclinical animal models that demonstrate the safety and/or efficacy of electrical stimulation have predominantly used a skull mount to connect to neural interfaces.

Implantation Surgery for Abdominal Vagus Nerve Stimulation and Recording Studies in Awake Rats.

Abdominal 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.

Selective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array.

Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class.

Stimulation parameters for directional vagus nerve stimulation.

Background: Autonomic 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.

Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers.

Introduction: Electrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges.

Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach.

Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model.

Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high-fat diet and low doses of streptozotocin.

Computational modelling of nerve stimulation and recording with peripheral visceral neural interfaces.

Neuromodulation of visceral nerves is being intensively studied for treating a wide range of conditions, but effective translation requires increasing the efficacy and predictability of neural interface performance. Here we use computational models of rat visceral nerve to predict how neuroanatomical variability could affect both electrical stimulation and recording with an experimental planar neural interface.We developed a hybrid computational pipeline,sceralervensembleecording andtimulation (ViNERS), to couple finite-element modelling of extracellular electrical fields with biophysical simulations of individual axons.

Recording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array.

Bioelectronic 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).

Differential effects of vagus nerve stimulation strategies on glycemia and pancreatic secretions.

Despite 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.

Transmural impedance detects graded changes of inflammation in experimental colitis.

Ulcerative 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.

Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation.

Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation.

Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms.

The 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.

Modeling experimental recordings of vagal afferent signaling of intestinal inflammation for neuromodulation.

Objective: 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.

An objective diagnostic method for inflammatory bowel disease.

Inflammatory 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.

Peripheral injury of pelvic visceral sensory nerves alters GFRα (GDNF family receptor alpha) localization in sensory and autonomic pathways of the sacral spinal cord.

GDNF (glial cell line-derived neurotrophic factor), neurturin and artemin use their co-receptors (GFRα1, GFRα2 and GFRα3, respectively) and the tyrosine kinase Ret for downstream signaling. In rodent dorsal root ganglia (DRG) most of the unmyelinated and some myelinated sensory afferents express at least one GFRα. The adult function of these receptors is not completely elucidated but their activity after peripheral nerve injury can facilitate peripheral and central axonal regeneration, recovery of sensation, and sensory hypersensitivity that contributes to pain.

Neurite outgrowth in normal and injured primary sensory neurons reveals different regulation by nerve growth factor (NGF) and artemin.

Neurotrophic factors have been intensively studied as potential therapeutic agents for promoting neural regeneration and functional recovery after nerve injury. Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) that forms a signalling complex with GFRα3 and the tyrosine kinase Ret. Systemic administration of artemin in rodents is reported to facilitate regeneration of primary sensory neurons following axotomy, improve recovery of sensory function, and reduce sensory hypersensitivity that is a cause of pain.

Regeneration of sensory but not motor axons following visceral nerve injury.

Following peripheral nerve injury, restoration of function may occur via the regeneration of injured axons or compensatory sprouting of spared axons. Injury to visceral nerves that control urogenital organs is a common consequence of pelvic surgery, however their capacity to reinnervate organs is poorly understood. To determine if and how sensory and motor connections to the bladder are re-established, a novel surgical model of visceral nerve injury was performed unilaterally in adult male Wistar rats.

Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment.

Secondary degeneration of nerve tissue adjacent to a traumatic injury results in further loss of neurons, glia and function, via mechanisms that may involve oxidative stress. However, changes in indicators of oxidative stress have not yet been demonstrated in oligodendrocytes vulnerable to secondary degeneration in vivo. We show increases in the oxidative stress indicator carboxymethyl lysine at days 1 and 3 after injury in oligodendrocytes vulnerable to secondary degeneration.

Early proliferation does not prevent the loss of oligodendrocyte progenitor cells during the chronic phase of secondary degeneration in a CNS white matter tract.

Partial injury to the central nervous system (CNS) is exacerbated by additional loss of neurons and glia via toxic events known as secondary degeneration. Using partial transection of the rat optic nerve (ON) as a model, we have previously shown that myelin decompaction persists during secondary degeneration. Failure to repair myelin abnormalities during secondary degeneration may be attributed to insufficient OPC proliferation and/or differentiation to compensate for loss of oligodendrocyte lineage cells (oligodendroglia).

Myelin sheath decompaction, axon swelling, and functional loss during chronic secondary degeneration in rat optic nerve.

Purpose: To examine chronic changes occurring at 6 months following partial optic nerve (ON) transection, assessing optic axons, myelin, and visual function.

Methods: Dorsal ON axons were transected, leaving ventral optic axons vulnerable to secondary degeneration. At 3 and 6 months following partial transection, toluidine-blue stained sections were used to assess dimensions of the ON injury site.

Chronic swelling and abnormal myelination during secondary degeneration after partial injury to a central nervous system tract.

Secondary degeneration is a serious consequence of traumatic injury to the central nervous system (CNS) and involves the progressive loss of neurons and function. However, while disruption to myelin has been observed in spared axons, the ultrastructural abnormalities that occur in myelin and axons spatially separated from the primary injury and susceptible exclusively to secondary degeneration are unknown. We used a model of secondary degeneration in which the dorsal aspect of rat optic nerve (ON) was transected leaving the central/ventral ON undamaged, but vulnerable to secondary degeneration.

Near infrared light reduces oxidative stress and preserves function in CNS tissue vulnerable to secondary degeneration following partial transection of the optic nerve.

Traumatic injury to the central nervous system (CNS) is accompanied by the spreading damage of secondary degeneration, resulting in further loss of neurons and function. Partial transection of the optic nerve (ON) has been used as a model of secondary degeneration, in which axons of retinal ganglion cells in the ventral ON are spared from initial dorsal injury, but are vulnerable to secondary degeneration. We have recently demonstrated that early after partial ON injury, oxidative stress spreads through the ventral ON vulnerable to secondary degeneration via astrocytes, and persists in the nerve in aggregates of cellular debris.

Secondary retinal ganglion cell death and the neuroprotective effects of the calcium channel blocker lomerizine.

Purpose: After partial optic nerve (ON) injury, intact retinal ganglion cells (RGCs) undergo secondary death, but the topographic distribution of this death is unknown, and it is unclear which cell death pathways are involved. Although the calcium channel blocker lomerizine reduces RGC death after partial ON injury, it is unknown whether this drug alleviates necrotic or apoptotic death.

Methods: The dorsal ON was transected in adult Piebald-Virol-Glaxo (PVG) rats, and the site of secondary RGC death was determined using anterograde and retrograde DiI tracing.