There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do ...not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Deep brain stimulation (DBS), a surgical technique to treat certain neurologic and psychiatric conditions, relies on pre-determined stimulation parameters in an open-loop configuration. The major ...advancement in DBS devices is a closed-loop system that uses neurophysiologic feedback to dynamically adjust stimulation frequency and amplitude. Stimulation-driven neurochemical release can be measured by fast-scan cyclic voltammetry (FSCV), but existing FSCV electrodes rely on carbon fiber, which degrades quickly during use and is therefore unsuitable for chronic neurochemical recording. To address this issue, we developed durable, synthetic boron-doped diamond-based electrodes capable of measuring neurochemical release in humans. Compared to carbon fiber electrodes, they were more than two orders-of-magnitude more physically-robust and demonstrated longevity in vitro without deterioration. Applied for the first time in humans, diamond electrode recordings from thalamic targets in patients (n = 4) undergoing DBS for tremor produced signals consistent with adenosine release at a sensitivity comparable to carbon fiber electrodes. (Clinical trials # NCT01705301).
Objective. Given current clinical interest in vagus nerve stimulation (VNS), there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to ...on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the pig, whose vagus nerve organization and size approximates the human vagus nerve. Approach. Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans. Main results. In a swine model we quantified the nerve diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for VNS with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the vagus nerve. This often leads to a distinct bimodal organization, or 'vagotopy'. This vagotopy was supported by immunohistochemistry where approximately half of the fascicles were immunoreactive for choline acetyltransferase, and reactive fascicles were generally grouped in one half of the nerve. Significance. The vagotopy observed via histology may be advantageous to exploit in design of electrodes/stimulation paradigms. We also placed our data in context of historic and recent histology spanning multiple models, thus providing a comprehensive resource to understand similarities and differences across species.
Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a ...growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins.
As VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain.
We injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle).
We found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups.
(s): This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.
•The waste clearance systems of the brain are important for healthy brain homeostasis.•Clinically patterned vagus nerve stimulation enhanced cerebrospinal fluid penetrance.•These findings represent a new potential therapeutic mechanism of vagus stimulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
. Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to ...facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized.
. We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials (CAPs) and neck muscle motor evoked potentials (MEPs) in an acute intraoperative swine experiment.
. We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS.
. This work lays the foundation to develop endovascular VNS strategies to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist.
ObjectiveClinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic ...outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig-an animal model with vagus anatomy similar to human-using the bipolar helical lead deployed clinically. ApproachIntrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Main resultsContraction of the cricoarytenoid muscle occurred at low amplitudes (∼0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (∼1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. SignificanceOur data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 μA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.
Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal ...anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal.
Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein. However, it lacks sufficient resolution to provide details about the vagus fascicular organization, or detail about smaller neural structures such as the recurrent and superior laryngeal branch responsible for therapy limiting side effects. Here, we characterize the use of ultrasound with the transducer placed in the surgical pocket to improve resolution without adding significant additional risk to the surgical procedure in the pig model.
Ultrasound images were obtained from a point of known functional organization at the nodose ganglia to the point of placement of stimulating electrodes within the surgical window. Naïve volunteers with minimal training were then asked to use these ultrasound videos to trace afferent groupings of fascicles from the nodose to their location within the surgical window where a stimulating cuff would normally be placed. Volunteers were asked to select a location for epineural electrode placement away from the fascicles containing efferent motor nerves responsible for therapy limiting side effects. 2-D and 3-D reconstructions of the ultrasound were directly compared to
histology in the same animals.
High-resolution ultrasound from the surgical pocket enabled 2-D and 3-D reconstruction of the cervical vagus and surrounding structures that accurately depicted the functional vagotopy of the pig vagus nerve as confirmed via histology. Although resolution was not sufficient to match specific fascicles between ultrasound and histology 1 to 1, it was sufficient to trace fascicle groupings from a point of known functional organization at the nodose ganglia to their locations within the surgical window at stimulating electrode placement. Naïve volunteers were able place an electrode proximal to the sensory afferent grouping of fascicles and away from the motor nerve efferent grouping of fascicles in each subject (
= 3).
The surgical pocket itself provides a unique opportunity to obtain higher resolution ultrasound images of neural targets responsible for intended therapeutic effect and limiting off-target effects. We demonstrate the increase in resolution is sufficient to aid patient-specific electrode placement to optimize outcomes. This simple technique could be easily adopted for multiple neuromodulation targets to better understand how patient specific anatomy impacts functional outcomes.
Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, ...chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles-a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.
The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver ...electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the
and
safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 μs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies.
. To modify off-the-shelf components to build a device for collecting electroencephalography (EEG) from macroelectrodes surrounded by large fluid access ports sampled by an integrated microperfusion ...system in order to establish a method for sampling brain interstitial fluid (ISF) at the site of stimulation or seizure activity with no bias for molecular size.
. Twenty-four 560
m diameter holes were ablated through the sheath surrounding one platinum-iridium macroelectrode of a standard Spencer depth electrode using a femtosecond UV laser. A syringe pump was converted to push-pull configuration and connected to the fluidics catheter of a commercially available microdialysis system. The fluidics were inserted into the lumen of the modified Spencer electrode with the microdialysis membrane removed, converting the system to open flow microperfusion. Electrical performance and analyte recovery were measured and parameters were systematically altered to improve performance. An optimized device was tested in the pig brain and unbiased quantitative mass spectrometry was used to characterize the perfusate collected from the peri-electrode brain in response to stimulation.
. Optimized parameters resulted in >70% recovery of 70 kDa dextran from a tissue analog. The optimized device was implanted in the cortex of a pig and perfusate was collected during four 60 min epochs. Following a baseline epoch, the macroelectrode surrounded by microperfusion ports was stimulated at 2 Hz (0.7 mA, 200
s pulse width). Following a post-stimulation epoch, the cortex near the electrode was stimulated with benzylpenicillin to induce epileptiform activity. Proteomic analysis of the perfusates revealed a unique inflammatory signature induced by electrical stimulation. This signature was not detected in bulk tissue ISF.
. A modified dual-sensing electrode that permits coincident detection of EEG and ISF at the site of epileptiform neural activity may reveal novel pathogenic mechanisms and therapeutic targets that are otherwise undetectable at the bulk tissue level.
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