Impact of adaptive gastric electrical stimulation on weight, food intake, and food intake rate in dogs.

BACKGROUND: Gastric electrical stimulation (GES) has been studied for decades as a promising treatment for obesity. Stimulation pulses with fixed amplitude and pulse width are usually applied, but these have limitations with regard to overcoming habituation to GES and inter-subject variation. This study aims to analyze the efficacy of an adaptive GES protocol for reducing food intake and maintaining lean weight in dogs. METHODS: Six beagle dogs were implanted with a remotely programmable gastric stimulator. An adaptive protocol was designed to increase the stimulation energy proportionally to the excess of food consumption, with respect to the dogs' maintenance energy requirements. After surgery and habituation to experimental conditions, the dogs went through both a control and a stimulation period of 4 weeks each, in a randomized order. The stimulation parameters were adapted daily. Body weight, food intake, food intake rate, and postprandial cutaneous electrogastrograms (EGG) were recorded to assess the effect of adaptive GES. RESULTS: Adaptive GES decreased food intake and food intake rate (p < 0.05) resulting in weight maintenance. In the absence of GES, the dogs gained weight (p < 0.05). Postprandial EGG dominant frequency was accelerated by GES (p < 0.05). The strategy of adapting the stimulation energy was effective in causing significant mid-term changes. CONCLUSION: Adaptive GES is effective for reducing food intake and maintaining lean weight. The proposed adaptive strategy may offer benefits to counter habituation and adapt to inter-subject variation in clinical use of GES for obesity.

Chronic recording of the vagus nerve to analyze modulations by the light-dark cycle.

Objective.The vagus nerve is considered to play a key role in the circadian rhythm. Chronic continuous analysis of the vagus nerve activity could contribute to a better understanding of the role of the vagus nerve in light-dark modulations. This paper presents a continuous analysis of spontaneous vagus nerve activity performed in four rats.Approach.We analyzed the vagus electroneurogram (VENG) and electroencephalogram (EEG) over a recording period of 28 d. Spike activity and heart rate estimation were derived from the VENG, and slow-wave activity was derived from the EEG. The presence of repetitive patterns was investigated with periodograms, cosinor fitting, autocorrelation, and statistical tests. The light-dark variations derived from the VENG spikes were compared with EEG slow waves, an established metric in circadian studies.Results.Our results demonstrate that light-dark variations can be detected in long-term vagus nerve activity monitoring. A recording period of about 7 d is required to characterize accurately the VENG light-dark variations.Significance.As a major outcome of this study, vagus nerve recordings hold the promise to help understand circadian regulation.

Optical birefringence changes in myelinated and unmyelinated nerves: A comparative study.

The measurement of birefringence variations related to nerve activity is a promising label-free technique for sensing compound neural action potentials (CNAPs). While widely applied in crustaceans, little is known about its efficiency on mammal peripheral nerves. In this work, birefringence recordings to detect CNAPs, and Stokes parameters measurements were performed in rat and lobster nerves. While single-trial detection of nerve activity in crustaceans was achieved successfully, no optical signal was detected in rats, even after extensive signal filtering and averaging. The Stokes parameters showed that a high degree of polarization of light is maintained in lobster sample, whereas an almost complete light depolarization occurs in rat nerve. Our results indicate that depolarization itself is not sufficient to explain the absence of birefringence signals in rats. We hypothesize that this absence comes from the myelin sheets, which constraint the birefringence changes to only take place at the nodes of Ranvier.

Vagus Nerve Electroneurogram-Based Detection of Acute Pentylenetetrazol Induced Seizures in Rats.

On-demand stimulation improves the efficacy of vagus nerve stimulation (VNS) in refractory epilepsy. The vagus nerve is the main peripheral parasympathetic connection and seizures are known to exhibit autonomic symptoms. Therefore, we hypothesized that seizure detection is possible through vagus nerve electroneurogram (VENG) recording. We developed a metric able to measure abrupt changes in amplitude and frequency of spontaneous vagus nerve action potentials. A classifier was trained using a "leave-one-out" method on a set of 6 seizures and 3 control recordings to utilize the VENG spike feature-based metric for seizure detection. We were able to detect pentylenetetrazol (PTZ) induced acute seizures in 6/6 animals during different stages of the seizure with no false detection. The classifier detected the seizure during an early stage in 3/6 animals and at the onset of tonic clonic stage of the seizure in 3/6 animals. EMG and motion artefacts often accompany epileptic activity. We showed the "epileptic" neural signal to be independent from EMG and motion artefacts. We confirmed the existence of seizure related signals in the VENG recording and proved their applicability for seizure detection. This detection might be a promising tool to improve efficacy of VNS treatment by developing new responsive stimulation systems.

Infrared neurostimulation inex-vivorat sciatic nerve using 1470 nm wavelength.

Objective.To design and implement a setup forex-vivooptical stimulation for exploring the effect of several key parameters (optical power and pulse duration), activation features (threshold, spatial selectivity) and recovery characteristics (repeated stimuli) in peripheral nerves.Approach.A nerve chamber allowing ex-vivo electrical and optical stimulation was designed and built. A 1470 nm light source was chosen to stimulate the nerve. A photodiode module was implemented for synchronization of the electrical and optical channels.Main results. Compound neural action potentials (CNAPs) were successfully generated with infrared light pulses of 200-2000µs duration and power in the range of 3-10 W. These parameters determine a radiant exposure for stimulation in the range 1.59-4.78 J cm-2. Recruitment curves were obtained by increasing durations at a constant power level. Neural activation threshold is reached at a mean radiant exposure of 3.16 ± 0.68 J cm-2and mean pulse energy of 3.79 ± 0.72 mJ. Repetition rates of 2-10 Hz have been explored. In eight out of ten sciatic nerves (SNs), repeated light stimuli induced a sensitization effect in that the CNAP amplitude progressively grows, representing an increasing number of recruited fibres. In two out of ten SNs, CNAPs were composed of a succession of peaks corresponding to different conduction velocities.Significance.The reported sensitization effect could shed light on the mechanism underlying infrared neurostimulation. Our results suggest that, in sharp contrast with electrical stimuli, optical pulses could recruit slow fibres early on. This more physiological order of recruitment opens the perspective for specific neuromodulation of fibre population who remained poorly accessible until now. Short high-power light pulses at wavelengths below 1.5µm offer interesting perspectives for neurostimulation.

Analysing vagus nerve spontaneous activity using finite element modelling.

Objective.Finite element modelling has been widely used to understand the effect of stimulation on the nerve fibres. Yet the literature on analysis of spontaneous nerve activity is much scarcer. In this study, we introduce a method based on a finite element model, to analyse spontaneous nerve activity with a typical bipolar electrode recording setup, enabling the identification of spontaneously active fibres. We applied our method to the vagus nerve, which plays a key role in refractory epilepsy.Approach.We developed a 3D model including dynamic action potential (AP) propagation, based on the vagus nerve geometry. The impact of key recording parameters-inter-electrode distance and temperature-and uncontrolled parameters-fibre size and position in the nerve-on the ability to discriminate active fibres were quantified. A specific algorithm was implemented to detect and classify APs from recordings, and tested on six ratin-vivovagus nerve recordings.Main results.Fibre diameters can be discriminated if they are below 3µm and 7µm, respectively for inter-electrode distances of 2 mm and 4 mm. The impact of the position of the fibre inside the nerve on fibre diameter discrimination is limited. The range of active fibres identified by modelling in the vagus nerve of rats is in agreement with ranges found at histology.Significance.The nerve fibre diameter, directly proportional to the AP propagation velocity, is related to a specific physiological function. Estimating the source fibre diameter is thus essential to interpret neural recordings. Among many possible applications, the present method was developed in the context of a project to improve vagus nerve stimulation therapy for epilepsy.

Optimization and assessment of a novel gastric electrode anchoring system designed to be implanted by minimally invasive surgery.

A novel electrode anchoring design and its implantation procedure, aiming for a minimally invasive solution for gastric electrical stimulation, are presented. The system comprises an anchor made of a flexible body embedding two needle-shaped electrodes. The electrodes can easily switch from a parallel position - to pierce the stomach - to a diverging position - enabling them to remain firmly anchored into the muscular layer of the stomach. Key device parameters governing anchoring stability were assessed on a traction test bench, and optimal values were derived. The device was then implanted in six dogs by open surgery to assess its anchoring durability in vivo. Computed tomography images showed that the electrodes remained well placed within the dogs' gastric wall over the entire assessment period (more than one year). Finally, a prototype of a surgical tool for the minimally invasive device placement was manufactured, and the anchoring procedure was tested on a dog cadaver, providing the proof of concept of the minimally invasive implantation procedure. The use of our electrode anchoring system in long-term gastric electrical stimulation is promising in terms of implantation stability (the anchor withstands a force up to 0.81 N), durability (the anchor remains onto the stomach over one year) and minimal invasiveness of the procedure (the diameter of the percutaneous access is smaller than 12 mm). Moreover, the proposed design could have clinical applications in other hollow organs, such as the urinary bladder.

Recording of spontaneous vagus nerve activity during Pentylenetetrazol-induced seizures in rats.

BACKGROUND: Vagus nerve stimulation is a treatment for refractory epilepsy. The vagus nerve carries parasympathetic information and innervates multiple organs. As seizures are commonly associated with autonomic manifestations, we believe that biomarkers for diseases affecting autonomic functions such as epilepsy can be found in vagus nerve signals. NEW METHOD: We present a method to record vagus nerve electroneurogram (VENG) and detect in the VENG single unit activity in anesthetized rats during Pentylenetetrazol induced seizures using a true tripolar cuff electrode. RESULTS: The VENG consisted of high amplitude bursts and lower amplitude bursts synchronous to respiration and heartbeat respectively. The average spikes exhibited a triphasic shape with duration below 1.5ms and root mean square amplitude varied between 5.5 +/- 0.2 µV and 11.4 +/- 3.1 µV depending on the type of recording. An increase of the contact distance resulted in a signal amplitude increase. Application of Lidocaine led to a total disappearance of the recorded spontaneous spiking of the nerve. COMPARISON WITH EXISTING METHODS: True tripolar cuff electrodes exhibited a better performance in terms of artefact rejection, stability and reproducibility of the signal compared to commonly used hook electrodes which is of special interest in seizures where important motion and EMG artifacts are expected. CONCLUSION: We present a new method to record single unit activity of the vagus nerve during acute chemically induced seizures in rats and verified the neural origin of the recorded signals. This recording method might be a powerful tool to develop seizure biomarkers based on VENG.

Vagus Nerve Stimulation-Induced Laryngeal Motor Evoked Potentials: A Possible Biomarker of Effective Nerve Activation.

Vagus nerve stimulation (VNS) therapy is associated with laryngeal muscle activation and induces voice modifications, well-known side effects of the therapy resulting from co-activation of the recurrent laryngeal nerve. In this study, we describe the non-invasive transcutaneous recording of laryngeal motor evoked potentials (LMEPs), which could serve as a biomarker of effective nerve activation and individual titration in patients with drug-resistant epilepsy. We recruited drug-resistant epileptic patients treated for at least 6 months with a VNS. Trains of 600-1200 VNS pulses were delivered with increasing current outputs. We placed six skin electrodes on the ventral surface of the neck, in order to record LMEPs whenever the laryngeal muscular threshold was reached. We studied the internal consistency and the variability of LMEP recordings, and compared different methods for amplitude calculation. Recruitment curves were built based on the stimulus-response relationship. We also determined the electrical axis of the LMEPs dipole in order to define the optimal electrode placement for LMEPs recording in a clinical setting. LMEPs were successfully recorded in 11/11 patients. The LMEPs threshold ranged from 0.25 to 1 mA (median 0.50 mA), and onset latency was between 5.37 and 8.77 ms. The signal-to-noise ratio was outstanding in 10/11 patients. In these cases, excellent reliability (Intraclass correlation coefficient, ICC > 0.90 across three different amplitude measurements) was achieved with 10 sample averages. Moreover, our recordings showed very good internal consistency (Cronbach's alpha > 0.95 for 10 epochs). Area-under-the-curve and peak-to-peak measurement proved to be complementary methods for amplitude calculation. Finally, we determined that an optimal derivation requires only two recording electrodes, aligned on a horizontal axis around the laryngeal prominence. In conclusion, we describe here an optimal methodology for the recording of VNS-induced motor evoked responses from the larynx. Although further clinical validation is still necessary, LMEPs might be useful as a non-invasive marker of effective nerve activation, and as an aid for the clinician to perform a more rational titration of VNS parameters.