Anti-Inflammatory Effects of Two-Week Sacral Nerve Stimulation Therapy in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Sacral nerve stimulation (SNS) showed anti-inflammatory properties in animal models of inflammatory bowel disease. We aimed to evaluate the effectiveness and safety of SNS in patients with ulcerative colitis (UC). MATERIALS AND METHODS: Twenty-six patients with mild and moderate disease were randomized into two groups: SNS (delivered at S3 and S4 sacral foramina) and sham-SNS (delivered 8-10 mm away from sacral foramina), with the therapy applied once daily for one hour, for two weeks. We evaluated the Mayo score and several exploratory biomarkers, including C-reactive protein in the plasma, pro-inflammatory cytokines and norepinephrine in the serum, assessment of autonomic activity, and diversity and abundance of fecal microbiota species. RESULTS: After two weeks, 73% of the subjects in the SNS group achieved clinical response, compared with 27% in the sham-SNS group. Levels of C-reactive protein, pro-inflammatory cytokines in the serum, and autonomic activity were significantly improved toward a healthy profile in the SNS group but not in the sham-SNS group. Absolute abundance of fecal microbiota species and one of the metabolic pathways were changed in the SNS group but not in the sham-SNS group. Significant correlations were observed between pro-inflammatory cytokines and norepinephrine in the serum on the one side and fecal microbiota phyla on the other side. CONCLUSIONS: Patients with mild and moderate UC were responsive to a two-week SNS therapy. After performing further studies to evaluate its efficacy and safety, temporary SNS delivered through acupuncture needles may become a useful screening tool for identifying SNS therapy responders before considering long-term implantation of the implantable pulse generator and SNS leads for performing long-term SNS therapy.

Neuromodulation for Gastroesophageal Reflux Disease: A Systematic Review.

Background and objectives: In this systematic review, we evaluated the efficacy, mechanisms and safety of three neuromodulation therapies in patients with gastroesophageal reflux disease (GERD), including the effect of neuromodulation therapies on symptoms and key GERD pathophysiologies, lower esophageal sphincter (LES) pressure, esophageal motility, gastric motility, and parasympathetic activity. The first therapy is LES electrical stimulation using an implantable electrical stimulator, the second is transcutaneous electrical acustimulation, and the third is manual acupuncture. Methods: A systematic review of literature according to the PRISMA guidelines was performed. Online databases searched include Medline (Ovid), Embase, and PubMed. Studies were assessed for inclusion and exclusion criteria with Covidence, a systematic review software. Results: The analysis included thirteen clinical studies. Four papers included were registered under two open-label trials on ClinicalTrials.gov for LES electrical stimulation; Five randomized trials with sham-treated controls were analyzed for transcutaneous electrical acustimulation; Four studies, including three involving standard therapy controls and one involving shamtreated controls were included for manual acupuncture. All evaluated studies demonstrated significant beneficial effects on GERD symptoms, using patient-completed questionnaires, objective 24-h measurement of esophageal pH, and patient-reported use of proton pump inhibitors. In evaluating the effect on key GERD pathophysiologies, electrical stimulation significantly increased LES pressure, and transcutaneous electrical acustimulation significantly improved esophageal motility, gastric motility, and parasympathetic activity. None of the evaluated neuromodulation methods produced severe adverse effects. Conclusions: Cumulative evidence from the evaluated studies indicates that neuromodulation therapies were effective in treating the GERD symptoms and key underlying GERD pathophysiologies. They are thus valuable options for individualized GERD treatment.

Bioelectronic medicine for restoring autonomic balance in autoimmune diseases.

The aim of this mini-review is to introduce most prevalent autoimmune diseases, emphasize the importance of sympatho-parasympathetic imbalance in these autoimmune diseases, demonstrate how such imbalance can be effectively treated using the bioelectronic medicine, and describe potential mechanisms of bioelectronic medicine effects on the autoimmune activity at the cellular and molecular levels.

Vagus Nerve Stimulation and Sacral Nerve Stimulation for Inflammatory Bowel Disease: A Systematic Review.

Background and objectives: In this systematic review, we assessed the efficacy, potential mechanisms, and safety of two neuromodulation therapies in patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. The first therapy is vagus nerve stimulation (VNS) utilizing implantable or transcutaneous electrodes, and the second is sacral nerve stimulation (SNS) using implantable or percutaneous electrodes. Methods: We conducted a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed database was comprehensively searched, and studies were rigorously assessed for inclusion and exclusion criteria. Results: Our analysis encompassed five clinical studies, three on VNS and two on SNS. Most investigated studies demonstrated significant beneficial effects on IBD symptoms, including disease activity, severity of intestinal lesions, and intestinal pain. When evaluating the impact on key IBD pathophysiologies, both VNS and SNS exhibited trends toward reducing biomarkers of intestinal mucosal inflammation and mitigating sympathetic dominance. Importantly, none of the evaluated neuromodulation methods resulted in long-term adverse effects. Conclusions: Cumulative evidence from the evaluated studies indicates that VNS and SNS therapies effectively alleviate IBD symptoms and may hold promise in addressing the underlying pathophysiologies of IBD, including intestinal mucosal inflammation and sympathetic dominance. Consequently, they represent valuable options for individualized IBD treatment.

Configuring intracortical microelectrode arrays and stimulus parameters to minimize neuron loss during prolonged intracortical electrical stimulation.

BACKGROUND: Previous studies have shown that neurons of the cerebral cortex can be injured by implantation of, and stimulation with, implanted microelectrodes. OBJECTIVES: Objective 1 was to determine parameters of microstimulation delivered through multisite intracortical microelectrode arrays that will activate neurons of the feline cerebral cortex without causing loss of neurons. OBJECTIVE: 2 was to determine if the stimulus parameters that induced loss of cortical neurons differed for all cortical neurons vs. the subset of inhibitory neurons expressing parvalbumin. METHODS: The intracortical microstimulation was applied for 7 h/day for 20 days (140 h). Microelectrode site areas were 2000 and 4000 µm2, Q was 2-8 nanocoulombs (nC) at 50 Hz, and QD was 50-400 µcoulombs/cm2. RESULTS: Neuron loss due to stimulation was minimal at Q = 2 Ncp, but at 8 Ncp, 20%-50% of neurons within 250 µm of the stimulated microelectrodes were lost, compared to unstimulated microelectrodes. Loss was greatest in tissue facing electrode sites. Stimulation-induced loss was similar for neurons labeled for NeuN and for inhibitory neurons expressing parvalbumin. Correlation between neuron loss and QD was not significant. Electrodes in the medullary pyramidal tract recorded neuronal activity evoked by stimulation in the cerebral cortex. The pyramidal neurons were activated by intracortical stimulation of 2 nC/phase. 140 h of microstimulation at 2 nC/phase and 50 Hz induced minimal neuron loss.

Blocking Ocular Sympathetic Activity Inhibits Choroidal Neovascularization.

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD). Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the ß-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the ß-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA. Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury. Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD.

Intraspinal stimulation with a silicon-based 3D chronic microelectrode array for bladder voiding in cats.

Objective.Bladder dysfunction is a significant and largely unaddressed problem for people living with spinal cord injury (SCI). Intermittent catheterization does not provide volitional control of micturition and has numerous side effects. Targeted electrical microstimulation of the spinal cord has been previously explored for restoring such volitional control in the animal model of experimental SCI. Here, we continue the development of the intraspinal microstimulation array technology to evaluate its ability to provide more focused and reliable bladder control in the feline animal model.Approach.For the first time, a mechanically robust intraspinal multisite silicon array was built using novel microfabrication processes to provide custom-designed tip geometry and 3D electrode distribution. Long-term implantation was performed in eight spinally intact animals for a period up to 6 months, targeting the dorsal gray commissure area in the S2 sacral cord that is known to be involved in the coordination between the bladder detrusor and the external urethral sphincter.Main results.About one third of the electrode sites in the that area produced micturition-related responses. The effectiveness of stimulation was further evaluated in one of eight animals after spinal cord transection (SCT). We observed increased bladder responsiveness to stimulation starting at 1 month post-transection, possibly due to supraspinal disinhibition of the spinal circuitry and/or hypertrophy and hyperexcitability of the spinal bladder afferents.Significance. 3D intraspinal microstimulation arrays can be chronically implanted and provide a beneficial effect on the bladder voiding in the intact spinal cord and after SCT. However, further studies are required to assess longer-term reliability and safety of the developed intraspinal microstimulation array prior to eventual human translation.

Sympathetic Effects of Internal Carotid Nerve Manipulation on Choroidal Vascularity and Related Measures.

Purpose: To investigate specific effects of denervation and stimulation of the internal carotid nerve (ICN) on the choroid and retina. Methods: Female Sprague Dawley rats underwent unilateral ICN transection (n = 20) or acute ICN electrical stimulation (n = 7). Rats in the denervation group were euthanized 6 weeks after nerve transection, and eyes were analyzed for changes in choroidal vascularity (via histomorphometry) or angiogenic growth factors and inflammatory markers (via ELISA). Rats in the stimulation group received acute ICN electrical stimulation with a bipolar cuff electrode over a range of stimulus amplitudes, frequencies, and pulse widths. Choroidal blood flow and pupil diameter were monitored before, during, and after stimulation. Results: Six weeks after unilateral ICN transection, sympathectomized choroids exhibited increased vascularity, defined as the percentage of choroidal surface area occupied by blood vessel lumina. Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein levels in denervated choroids were 61% and 124% higher than in contralateral choroids, respectively. TNF-α levels in denervated retinas increased by 3.3-fold relative to levels in contralateral retinas. In animals undergoing acute ICN electrical stimulation, mydriasis and reduced choroidal blood flow were observed in the ipsilateral eye. The magnitude of the reduction in blood flow correlated positively with stimulus frequency. Conclusions: Modulation of ICN activity reveals a potential role of the ocular sympathetic system in regulating endpoints related to neovascular diseases of the eye.

EMG characteristics of the external anal sphincter guarding reflex and effects of a unilateral ventral root avulsion injury in rhesus macaques ( Macaca mulatta).

The external anal sphincter (EAS) is important for the maintenance of bowel continence and may be compromised by a variety of neuropathic conditions. However, large animal models for the study of EAS functions have been sparse. The EAS guarding reflex was examined by electromyography (EMG) in neurologically intact rhesus macaques ( n = 6) and at 4-6 wk after a unilateral EAS denervation from an L6-S3 ventral root avulsion (VRA) injury ( n = 6). Baseline EAS EMG recordings were quiescent in all subjects, and evoked responses showed an initial large-amplitude EMG activity, which gradually returned to baseline within 1-2 min. At 4-6 wk postoperatively, the EAS guarding reflex showed a significantly reduced EMG response duration of 47 ± 15 s and area under the curve (AUC) of 0.198 ± 0.097 mV·s compared with the corresponding evoked EAS EMG duration of 102 ± 19 s and AUC of 0.803 ± 0.225 mV·s ( P < 0.05) in the control group. Detailed time- and frequency-domain analysis of the evoked EAS EMG responses for the first 40 s showed no difference between groups for the maximum amplitude but a significant decrease for the mean amplitude across the study period and an early AUC reduction for the first 10 s in the VRA injury group. Time-frequency analysis and power spectrum plots indicated decreased intensity and a narrower midrange of frequencies in the VRA injury group. We conclude that the EAS guarding reflex in rhesus macaques shows characteristic EMG features in control subjects and signs of partial target denervation after a unilateral L6-S3 VRA injury. NEW & NOTEWORTHY The external anal sphincter guarding reflex showed initial large-amplitude peaks and a gradual return to a quiescent baseline after a rectal probe stimulus in rhesus macaques. At 4-6 wk after a unilateral ventral root avulsion (VRA) injury, the electromyography duration, mean amplitude, and area under the curve measurements were decreased. Time-frequency analysis and power spectrum plots indicated decreased intensity and a narrowed midrange of frequencies in the VRA injury cohort.

High-Frequency Electrical Modulation of the Superior Ovarian Nerve as a Treatment of Polycystic Ovary Syndrome in the Rat.

The polycystic ovary syndrome (PCOS) is the most prevalent ovarian pathology in women, with excessive sympathetic activity in the superior ovarian nerve (SON) playing an important role in inducing the PCOS symptoms in the rats and humans. Our previous studies have shown that surgical transection of the SON can reverse the disease progression, prompting us to explore the effect of the kilohertz frequency alternating current (KHFAC) modulation as a method of reversible non-surgical suppression of the nerve activity in the rodent model of PCOS. 56 animals were randomly allocated to three groups: the Control group (n = 18), the PCOS group (n = 15), and the PCOS + KHFAC group (n = 23). The physiological, anatomical, and biochemical parameters of ovarian function were evaluated during the progression of the experimentally-induced PCOS and during long-term KHFAC modulation applied for 2-3 weeks. The KHFAC modulation has been able to reverse the pathological changes in assessed PCOS parameters, namely the irregular or absent estrous cycling, formation of ovarian cysts, reduction in the number of corpora lutea, and ovarian norepinephrine concentration. The fertility capacity was similar in the PCOS and the PCOS + KHFAC groups, indicating the safety of KHFAC modulation approach. In summary, these results suggest that the KHFAC modulation approach of suppressing the SON activity could become a useful treatment modality for PCOS and potentially other pathological ovarian conditions.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes.

AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents. METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT. RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks. CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Long-term stability of intracortical recordings using perforated and arrayed Parylene sheath electrodes.

OBJECTIVE: Acquisition of reliable and robust neural recordings with intracortical neural probes is a persistent challenge in the field of neuroprosthetics. We developed a multielectrode array technology to address chronic intracortical recording reliability and present in vivo recording results. APPROACH: The 2 × 2 Parylene sheath electrode array (PSEA) was microfabricated and constructed from only Parylene C and platinum. The probe includes a novel three-dimensional sheath structure, perforations, and bioactive coatings that improve tissue integration and manage immune response. Coatings were applied using a sequential dip-coating method that provided coverage over the entire probe surface and interior of the sheath structure. A sharp probe tip taper facilitated insertion with minimal trauma. Fabricated probes were subject to examination by optical and electron microscopy and electrochemical testing prior to implantation. MAIN RESULTS: 1 × 2 arrays were successfully fabricated on wafer and then packaged together to produce 2 × 2 arrays. Then, probes having electrode sites with adequate electrochemical properties were selected. A subset of arrays was treated with bioactive coatings to encourage neuronal growth and suppress inflammation and another subset of arrays was implanted in conjunction with a virally mediated expression of Caveolin-1. Arrays were attached to a custom-made insertion shuttle to facilitate precise insertion into the rat motor cortex. Stable electrophysiological recordings were obtained during the period of implantation up to 12 months. Immunohistochemical evaluation of cortical tissue around individual probes indicated a strong correlation between the electrophysiological performance of the probes and histologically observable proximity of neurons and dendritic sprouting. SIGNIFICANCE: The PSEA demonstrates the scalability of sheath electrode technology and provides higher electrode count and density to access a greater volume for recording. This study provided support for the importance of creating a supportive biological environment around the probes to promote the long-term electrophysiological performance of flexible probes in the cerebral cortex. In particular, we demonstrated beneficial effects of the Matrigel coating and the long-term expression of Caveolin-1. Furthermore, we provided support to an idea of using an artificial acellular tissue compartment as a way to counteract the walling-off effect of the astrocytic scar formation around the probes as a means of establishing a more intimate and stable neural interface.

Correlations between histology and neuronal activity recorded by microelectrodes implanted chronically in the cerebral cortex.

OBJECTIVE: To quantify relations between the neuronal activity recorded with chronically-implanted intracortical microelectrodes and the histology of the surrounding tissue, using radial distance from the tip sites and time after array implantation as parameters. APPROACH: 'Utah'-type intracortical microelectrode arrays were implanted into cats' sensorimotor cortex for 275-364 days. The brain tissue around the implants was immuno-stained for the neuronal marker NeuN and for the astrocyte marker GFAP. Pearson's product-moment correlations were used to quantify the relations between these markers and the amplitudes of the recorded neuronal action potentials (APs) and their signal-to-noise ratios (S/N). MAIN RESULTS: S/N was more stable over post-implant time than was AP amplitude, but its increased correlation with neuronal density after many months indicates ongoing loss of neurons around the microelectrodes. S/N was correlated with neuron density out to at least 140 µm from the microelectrodes, while AP amplitude was correlated with neuron density and GFAP density within ∼80 µm. Correlations between AP amplitude and histology markers (GFAP and NeuN density) were strongest immediately after implantation, while correlation between the neuron density and S/N was strongest near the time the animals were sacrificed. Unlike AP amplitude, there was no significant correlation between S/N and density of GFAP around the tip sites. SIGNIFICANCE: Our findings indicate an evolving interaction between changes in the tissue surrounding the microelectrodes and the microelectrode's electrical properties. Ongoing loss of neurons around recording microelectrodes, and the interactions between their delayed electrical deterioration and early tissue scarring around the tips appear to pose the greatest threats to the microelectrodes' long-term functionality.

Matrigel coatings for Parylene sheath neural probes.

The biologically derived hydrogel Matrigel (MG) was used to coat a Parylene-based sheath intracortical electrode to act as a mechanical and biological buffer as well as a matrix for delivering bioactive molecules to modulate the cellular response and improve recording quality. MG was loaded with dexamethasone to reduce the immune response together with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to maintain neuronal density and encourage neuronal ingrowth toward electrodes within the sheath. Coating the Parylene sheath electrode with the loaded MG significantly improved the signal-to-noise ratio for neural events recorded from the motor cortex in rat for more than 3 months. Electron microscopy showed even coverage of both the Parylene substrate and the platinum recording electrodes. Electrochemical impedance spectroscopy (EIS) of coated electrodes in 1× phosphate-buffered saline demonstrated low impedance required for recording neural signals. This result was confirmed by in vivo EIS data, showing significantly decreased impedance during the first week of recording. Dexamethasone, NGF, and BDNF loaded into MG were released within 1 day in 1× phosphate-buffered saline. Although previous studies showed that MG loaded with either the immunosuppressant or the neurotrophic factor cocktail provided modest improvement in recording quality in a 1-month in vivo study, the combination of these bioactive molecules did not improve the signal quality over coating probes with only MG in a 3-month in vivo study. The MG coating may further improve recording quality by optimizing the in vivo release profile for the bioactive molecules.

Effects of millimeter wave irradiation and equivalent thermal heating on the activity of individual neurons in the leech ganglion.

Many of today's radiofrequency-emitting devices in telecommunication, telemedicine, transportation safety, and security/military applications use the millimeter wave (MMW) band (30-300 GHz). To evaluate the biological safety and possible applications of this radiofrequency band for neuroscience and neurology, we have investigated the physiological effects of low-intensity 60-GHz electromagnetic irradiation on individual neurons in the leech midbody ganglia. We applied incident power densities of 1, 2, and 4 mW/cm(2) to the whole ganglion for a period of 1 min while recording the action potential with a standard sharp electrode electrophysiology setup. For comparison, the recognized U.S. safe exposure limit is 1 mW/cm(2) for 6 min. During the exposure to MMWs and gradual bath heating at a rate of 0.04°C/s (2.4°C/min), the ganglionic neurons exhibited similar dose-dependent hyperpolarization of the plasma membrane and decrease in the action potential amplitude. However, narrowing of the action potential half-width during MMW irradiation at 4 mW/cm(2) was 5 times more pronounced compared with that during equivalent bath heating of 0.6°C. Even more dramatic difference in the effects of MMW irradiation and bath heating was noted in the firing rate, which was suppressed at all applied MMW power densities and increased in a dose-dependent manner during gradual bath heating. The mechanism of enhanced narrowing of action potentials and suppressed firing by MMW irradiation, compared with that by gradual bath heating, is hypothesized to involve specific coupling of MMW energy with the neuronal plasma membrane.

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine.

Migraine symptoms often include auditory discomfort. Nitroglycerin (NTG)-triggered central sensitization (CS) provides a rodent model of migraine, but auditory brainstem pathways have not yet been studied in this example. Our objective was to examine brainstem auditory evoked potentials (BAEPs) in rat CS as a measure of possible auditory abnormalities. We used four subdermal electrodes to record horizontal (h) and vertical (v) dipole channel BAEPs before and after injection of NTG or saline. We measured the peak latencies (PLs), interpeak latencies (IPLs), and amplitudes for detectable waveforms evoked by 8, 16, or 32 kHz auditory stimulation. At 8 kHz stimulation, vertical channel positive PLs of waves 4, 5, and 6 (vP4, vP5, and vP6), and related IPLs from earlier negative or positive peaks (vN1-vP4, vN1-vP5, vN1-vP6; vP3-vP4, vP3-vP6) increased significantly 2h after NTG injection compared to the saline group. However, BAEP peak amplitudes at all frequencies, PLs and IPLs from the horizontal channel at all frequencies, and the vertical channel stimulated at 16 and 32 kHz showed no significant/consistent change. For the first time in the rat CS model, we show that BAEP PLs and IPLs ranging from putative bilateral medial superior olivary nuclei (P4) to the more rostral structures such as the medial geniculate body (P6) were prolonged 2h after NTG administration. These BAEP alterations could reflect changes in neurotransmitters and/or hypoperfusion in the midbrain. The similarity of our results with previous human studies further validates the rodent CS model for future migraine research.

Cuff electrodes for very small diameter nerves -- prototyping and first recordings in vivo.

A fabrication method for cuff electrodes to interface small nerves was developed. Medical grade silicone rubber conforms the body of the cuff and insulation of the wires, platinum was used as metal for the embedded wiring and contacts. Planar electrode arrays where fabricated using a picosecond laser and then positioned into a carrying tube to provide the third dimension with the desired inner diameter (Ø 0.3-0.5 mm). The post preparation of the cuffs after structuring allows the fabrication of a stable self-closing flap that insulates the opening slit of the cuff without the need of extra sutures. Basic for the success of the cuff is the laser-based local thinning of both the silicone rubber and the metal at defined sections. This is critical to permit the PDMS' body to dominate the mechanical properties. Finite element modeling was applied to optimize the displacement ability of the cuff, leading to design capable of withstanding multiple implantation procedures without wire damage. Furthermore, the contact's surface was roughened by laser patterning to increase the charge injection capacity of Pt to 285 µC/cm(2) measured by voltage transient detection during pulse testing. The cuff electrodes were placed on a small sympathetic nerve of an adult female Sprague-Dawley rat for recording of spontaneous and evoked neural activity in vivo.

Encoding of the amplitude modulation of pulsatile electrical stimulation in the feline cochlear nucleus by neurons in the inferior colliculus; effects of stimulus pulse rate.

OBJECTIVES: Persons without a functional auditory nerve cannot benefit from cochlear implants, but some hearing can be restored by an auditory brainstem implant (ABI) with stimulating electrodes implanted on the surface of the cochlear nucleus (CN). Most users benefit from their ABI, but speech recognition tends to be poorer than for users of cochlear implants. Psychophysical studies suggest that poor modulation detection may contribute to the limited performance of ABI users. In a cat model, we determined how the pulse rate of the electrical stimulus applied within or on the CN affects temporal and rate encoding of amplitude modulation (AM) by neurons in the central nucleus of the inferior colliculus (ICC). APPROACH: Stimulating microelectrodes were implanted chronically in and on the cats' CN, and multi-site recording microelectrodes were implanted chronically into the ICC. Encoding of AM pulse trains by neurons in the ICC was characterized as vector strength (VS), the synchrony of neural activity with the AM, and as the mean rate of neuronal action potentials (neuronal spike rate (NSR)). MAIN RESULTS: For intranuclear microstimulation, encoding of AM as VS was up to 3 dB greater when stimulus pulse rate was increased from 250 to 500 pps, but only for neuronal units with low best acoustic frequencies, and when the electrical stimulation was modulated at low frequencies (10-20 Hz). For stimulation on the surface of the CN, VS was similar at 250 and 500 pps, and the dynamic range of the VS was reduced for pulse rates greater than 250 pps. Modulation depth was encoded strongly as VS when the maximum stimulus amplitude was held constant across a range of modulation depth. This 'constant maximum' protocol allows enhancement of modulation depth while preserving overall dynamic range. However, modulation depth was not encoded as strongly as NSR. SIGNIFICANCE: The findings have implications for improved sound processors for present and future ABIs. The performance of ABIs may benefit from using pulse rates greater than those presently used in most ABIs, and by sound processing strategies that enhance the modulation depth of the electrical stimulus while preserving dynamic range.

Light-triggered modulation of cellular electrical activity by ruthenium diimine nanoswitches.

Ruthenium diimine complexes have previously been used to facilitate light-activated electron transfer in the study of redox metalloproteins. Excitation at 488 nm leads to a photoexcited state, in which the complex can either accept or donate an electron, respectively, in the presence of a soluble sacrificial reductant or oxidant. Here, we describe a novel application of these complexes in mediating light-induced changes in cellular electrical activity. We demonstrate that RubpyC17 ([Ru(bpy)(2)(bpy-C17)](2+), where bpy is 2,2'-bipyridine and bpy-C17 is 2,2'-4-heptadecyl-4'-methyl-bipyridine), readily incorporates into the plasma membrane of cells, as evidenced by membrane-confined luminescence. Excitable cells incubated in RubpyC17 and then illuminated at 488 nm in the presence of the reductant ascorbate undergo membrane depolarization leading to firing of action potentials. In contrast, the same experiment performed with the oxidant ferricyanide, instead of ascorbate, leads to hyperpolarization. These experiments suggest that illumination of membrane-associated RubpyC17 in the presence of ascorbate alters the cell membrane potential by increasing the negative charge on the outer face of the cell membrane capacitor, effectively depolarizing the cell membrane. We rule out two alternative explanations for light-induced membrane potential changes, using patch clamp experiments: (1) light-induced direct interaction of RubpyC17 with ion channels and (2) light-induced membrane perforation. We show that incorporation of RubpyC17 into the plasma membrane of neuroendocrine cells enables light-induced secretion as monitored by amperometry. While the present work is focused on ruthenium diimine complexes, the findings point more generally to broader application of other transition metal complexes to mediate light-induced biological changes.