Objective: Keloids represent a symptomatic, aberrant healing process that is difficult to treat with high recurrence rates spanning from 55% to 100% if treated via excision without adjuvant therapy. Electrical stimulation (ES) has demonstrated findings that suggest it could reduce the recurrence rate of keloids after resection. Therefore, the aim of this study is to conduct a scoping review to investigate ES as an adjuvant therapy for decreasing keloid recurrence after excision.Approach: A scoping review was performed using PubMed and Web of Science databases. The search strategy encompassed terms linking keloids and various aspects of electrical stimulation.Results: Our search yielded 2,229 articles, of which 115 articles were analyzed as full text and 1 article met inclusion criteria. Despite this, ES has demonstrated other evidence that suggests its utility. ES has been shown to counter keloidic features by reducing mast cell counts, shifting wound composition from M2 to M1 macrophages, promoting angiogenesis, and controlling fibroblast orientation and location. An alternating current will orient fibroblasts perpendicular to the current without unintended migration.Innovation: Our study indicates that, based on a compilation of clinical and preclinical in vitro data, the optimal scenario for ES in the role of keloid treatment is after excision with a biphasic pulsed application and square waveform.Conclusions: ES could serve as a multifaceted, adjuvant treatment after keloid excision, steering the healing process away from keloid-associated characteristics. Its cost-effectiveness means it could be adopted globally, providing a strategy to mitigate the burden of keloids irrespective of other available treatments or economic conditions.

Objective.Electrical stimulation of the baroreceptors pathways at the carotid sinus bulb-known as baroreflex activation therapy (BAT)-is intended to change autonomic tone and ultimately reduce blood pressure (BP) and heart rate. BAT is pre-market approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure and received an FDA humanitarian device exemption for drug resistant hypertension. However, responder rates are limited by side-effects including numbness in the head and neck, altered speech, respiratory constriction, dry cough, vomiting, and altered sensory and motor function of the tongue (TN). We hypothesized that these side-effects are driven by activation of other nearby nerve fibers of similar or lower threshold than the carotid sinus nerve. In this study, we sought to identify the neural sources responsible for off-target muscle activation contributing to these side-effects. These sources would inform strategies mitigating off-target activation in BAT therapy.Approach.Domestic swine were used in this work as the diameter and thickness of the swine carotid artery are closer to human than those of canine models. A monopolar disk electrode mimicking the clinical CVRx® Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in BP. Evoked responses were recorded during dose response testing from multiple neck muscles, and the corresponding off-target nerve pathways were identified by sequential transection of nearby nerves.Main results.The following activated off-target muscle groups and their corresponding nerve pathways were verified which included (1) the cricoarytenoid via recurrent laryngeal nerve, (2) cricothyroid via superior laryngeal nerve, (3) sternocleidomastoid via accessory nerve, and (4) the TN via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway.Significance.We identified multiple sources of therapy-limiting side-effects of BAT in the swine model. These results will help guide the design of improved stimulation electrodes, surgical placement, and parameter programming to reduce BAT-associated side-effects while increasing on-target activation in patients.

BACKGROUND:Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the upper extremities during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive treatment for medication-refractory ET. However, its mechanism remains unclear. OBJECTIVE:We hypothesize that TAPS reduces tremors through modulation of the VIM thalamus in the cerebello-thalamo-cortical network. METHODS:Employing refractory pure ET patients seeking VIM deep brain stimulation (DBS), we quantified clinical tremor improvement following TAPS treatment in a pre-operative setting, followed by intra-operative microelectrode recording of the contralateral thalamus with concurrent TAPS treatment on and off. RESULTS:After one preoperative session, TAPS significantly reduces upper limb tremor average (0.61, p = 0.002), with an asymmetric effect favoring the treated limb (p = 0.047) and the greatest improvement tending to kinetic tremor (R2 = 0.943, p = 0.002). The magnitude of TAPS-related tremor reduction demonstrates a positive correlation with the modulation of alpha (R2 = 0.213, p < 0.001) and beta band LFPs (R2 = 0.255, p < 0.001) in the VIM. TAPS also suppressed spiking activity in the VIM (R2 = 0.104, p = 0.029), though it was uncorrelated with the degree of tremor reduction. Of note, TAPS-related modulation of LFPs and spiking activity was greatest near the optimal placement location for the DBS lead in treating ET (R2 = 0.122, p = 0.006). CONCLUSION:In sum, TAPS likely reduces tremor in ET by modulating the VIM and connected nodes in the cerebello-thalamo-cortical pathway.

Objective. Evoked compound action potentials (ECAPs) measured during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain and inform closed-loop control of SCS. Previous studies have used ECAPs to characterize neural responses to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model.Approach. We characterized sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode™ lead.Main results. Spinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby muscles of the back, and motion artifact. The capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. EMG bleed-through can have phase shifts across the electrode array, similar to the phase shift anticipated by propagation of an evoked A-beta fiber response. The short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in CSF between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of recorded ECAPs.Significance. Controls must be implemented to separate neural signal from sources of artifact in SCS ECAPs. We suggest experimental procedures and reporting requirements necessary to disambiguate underlying neural response from these confounds. These data are important to better understand the framework for epidural spinal recordings (ESRs), with components such as ECAPs, EMG, and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

Objective.The development of electrodes for chronic peripheral nerve stimulation faces several challenges, including complex compositions, intricate manufacturing processes, and high costs associated with the availability and fabrication of suitable materials. These limitations hinder the accessibility and feasibility of producing effective devices for chronic preclinical studies. This study evaluated the feasibility of a simple-to-manufacture gold helical microwire structure electrode (Au-HMSE) for peripheral nerve stimulation, electromyography (EMG) recording, and preliminary tissue response on the rat sciatic nerve.Approach.Manufactured electrodes were used for up to 8 weeks in rats for nerve stimulation and EMG recordings, with electrode-tissue impedances and motor thresholds measured to assessin vivostability and feasibility. Evoked motor responses were measured via gastrocnemius muscle activity and ankle torque. Terminal histology was performed at 12 weeks to assess chronic tissue response to the implanted electrodes.Main results.Implanted electrodes with impedances <10 kΩ effectively evoked motor responses in monopolar and bipolar configurations and successfully recorded EMG activity. Gastrocnemius activation overlapped with off-target motor responses, likely due to the electrode's size relative to rat nerve anatomy and the absence of anchoring, which may have allowed migration. High impedance failure appeared related to interconnects between electrodes and tunneled leads and at solder joints in the stimulating and recording setup. Histology showed typical fibrotic encapsulation, with the helical design promoting tissue in-growth around the microwires, creating a high surface area electrode-tissue interface.Significance.This study evaluated the early feasibility of Au-HMSE for chronically implanted rodent nerve stimulation and EMG recordings. While gold electrodes are non-standard for chronic stimulation, the construction of these devices may be appropriate for the evaluation of chronic peripheral nerve stimulation in the preclinical setting due to their simple composition, manufacturing, and availability of gold microwire as a raw material. The findings provide valuable insights for developing future implantable leads used for peripheral nerve stimulation.

Objective Cranial nerve stimulation (CNS) uses electric current to modulate higher-order brain activity and organ function via nerves, including the vagus and trigeminal, with applications in migraine, epilepsy, and pediatric ADHD. The trigeminal nerve is an emerging target for non-invasive neuromodulation due to the superficial trajectory of its branches, the supraorbital (SON), infraorbital (ION), and mental nerves (MN), and the predominantly sensory composition of the SON and ION. However, the parameters and outcomes of trigeminal nerve stimulation (TNS) remain varied. Approach This study characterizes the anatomical course, tissue composition, and activation profiles of the SON, ION, and MN using five human donors. CT imaging was utilized to localize each nerve’s exit foramen and distance to midline. Microdissections quantified nerve circumference and depth relative to the skin surface. Histological analysis described the number of fascicles and fascicular tissue area. Nerve depths were incorporated into computational models to illustrate the activation function across tissue layers, comparing expected nociceptor and nerve trunk activation functions as a measure of neural engagement. Main Results The SON was found to be significantly more superficial than the ION and MN and had a higher nerve-to-connective tissue ratio relative to the MN. Computational modeling demonstrated that the activation function at the depths of nociceptors was orders of magnitude greater than within the main nerve trunks, suggesting preferential recruitment of cutaneous nociceptors, dependent on nociceptor density. Significance The SON presents the most accessible and anatomically favorable target for transcutaneous trigeminal nerve stimulation among the branches examined due to its superficial location. However, preferential activation of low-threshold nociceptors compared to nerve trunks may lead to treatment-limiting off-target side effects, favoring strategies that target fibers of interest within the skin. These findings offer an anatomically informed framework to guide further computational modeling and electrode design for targeted trigeminal neuromodulation. ### Competing Interest Statement KAL and JCW are co-founders and equity holders of NeuraWorx, a privately held neuromodulation company investigating cranial nerve stimulation for glymphatic clearance. KAL is also a co-founder and equity holder for Neuronoff, Inc. KAL is a scientific board member and has stock interests in NeuroOne Medical Inc. KAL is also a paid member of the scientific advisory board of Abbott and Presidio Medical, and a paid consultant for the Alfred Mann Foundation, ONWARD and Restora Medical. the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO) Targeted Neuroplasticity Training Program, N66001-17-2-4010

Digital implementations of discrete Fourier transforms (DFT) are a mainstay in feature assessment of recorded biopotentials, particularly in the quantification of biomarkers of neurological disease state for adaptive deep brain stimulation. Fast Fourier transform (FFT) algorithms and architectures present a substantial power demand from onboard batteries in implantable medical devices, necessitating the development of ultra-low power Fourier transform methods in resource-constrained environments. Numerous FFT architectures aim to optimize power and resource demand through computational efficiency; however, prioritizing the reduction of logic complexity at the cost of additional computations can be equally or more effective. This paper introduces a minimal-architecture single-delay feedback discrete Fourier transform (mSDF-DFT) for use in ultra-low-power field programmable gate array applications and shows energy and power improvements over state-of-the-art low-power DFT and FFT methods. In a neural sensing application, we observe a 33% reduction in dynamic power and 4% reduction in resource utilization when compared to state-of-the-art FFT algorithms; 38% reduction in dynamic power and 4% reduction in resource utilization when compared to Goertzel Algorithm. While designed for use in closed-loop deep brain stimulation and medical device implementations, the mSDF-DFT is also easily extendable to any ultra-low-power embedded application.

Objective.Improving the efficacy of vagus nerve (VN) stimulation therapy requires a detailed understanding of the anatomical and functional organization of nerve fiber bundles and their fascicles. Variousex-vivoimaging platforms have been optimized for this purpose. However, all existing tools with micrometer resolution require labeling to enhance the fascicle contrast, and this labeling is resource-intensive and time-consuming. Polarization-sensitive optical coherence tomography (PS-OCT) was previously used to perform high-speed, label-free small animal (rat) sciatic nerve imaging but has not been applied for imaging the full-thickness large animal VNs (>1 mm diameter thick) due to tissue-limited imaging depth. We developed a PS-OCT platform that circumvents this problem and demonstrate high-speed label-free imaging of full-depth, multiple centimeters-long mammalian VNs for the first time.Approach.We employed a custom-built PS-OCT system with a dual-surface scanning microscope to capture opposite sides of the sample in a single frame. A tailored post-processing algorithm maximized fascicle contrast and merged the two surfaces together. Multi-centimeter-long porcine VNs were imaged.Main Results.Our approach reconstructed fascicle information throughout the full-thickness of the VN when compressed to a 650μm thickness. Moreover, we cross-validated PS-OCT measurements of fascicular organization and retardance to assess myelination against pair histology from the same specimens, showing Spearman's rank correlation coefficient value of 0.69 (p-value < 0.001).Significance.We demonstrated a label-free optical imaging method for large-volume VN imaging. The time to image a 6.8 cm nerve was 680 s with 0.1 mm s-1longitudinal sample translation speed, which is more than two orders of magnitude faster than existing modalities that require labeling. With this gain in speed and the possibility of label-free quantification of a fascicle's myelination level, important studies on inter-sample variability in fascicle organization become feasible.

Introduction: Peripheral nerve reinnervation following nerve injury is often a slow and incomplete process, resulting in significant morbidity and permanent loss of function of the injured extremity in many patients. Prior studies have shown the efficacy of electrical stimulation to synchronize the axonal regeneration of both motor and sensory neurons in peripheral nerve injury models. Moreover, separate investigations have also shown the use of cranial nerve stimulation, principally the vagus nerve, to improve functional outcomes. However, no study has investigated the synergistic effects of both intraoperative electrical stimulation and cranial nerve stimulation for functional improvement within a peripheral nerve injury model. This investigation quantifies the efficacy of combined intraoperative electrical stimulation and trigeminal nerve stimulation on motor and sensory functional recovery in a rat peripheral nerve injury model. Methods: Twelve adult male Lewis rats were trained in a reach and pull task for a food reward using their right forelimb with baseline force thresholds and percent success of the pull task recorded. Baseline sensory data was retrieved using an automated von Frey monofilament test. All rats underwent surgical transection and 2mm gap repair of their median and ulnar nerve of their right forelimb followed by 1 hour of intraoperative electrical stimulation. Trigeminal nerve stimulation throughout the rehabilitation period was completed via supraorbital nerve headcap electrodes. Motor and sensory data were compared to historic cohorts comprised of sham surgery (no nerve injury), brief intraoperative electrical stimulation, trigeminal nerve stimulation, and a sham peripheral and trigeminal nerve stimulation group. Results: The combined cohort of rodents were able to recover to their pre-injury motor function by the third week of rehabilitation, faster than either of the singular electrical stimulation cohorts assessed previously. Moreover, functional sensory data of the combined stim cohort demonstrated no change when compared to their pre-injury baseline. Conclusions: Peripheral nerve electrical stimulation and trigeminal nerve stimulation are two separately acting mechanisms of therapy that employ electric waveforms to improve the functional recovery of injured peripheral nerves. The former acts within the periphery to synchronize axonal growth and regeneration of the injured neurons, while the latter acts centrally to augment neuroplasticity. When used simultaneously in a rodent peripheral nerve injury model, these modalities have shown to build upon each other to deliver a faster functional motor recovery, while sensory recovery outcomes remain to be demonstrated. ### Competing Interest Statement KAL is a co-founder and equity holder for Neuronoff, Inc. KAL is also a co-founder and equity holder of NeuraWorx. KAL is a scientific board member and has stock interests in NeuroOne Medical Inc. KAL is also a paid member of the scientific advisory board of Abbott and Presidio Medical, and a paid consultant for the Alfred Mann Foundation, ONWARD and Restora Medical. All other authors have no conflicts to declare.

OBJECTIVES:A spinal cord stimulation (SCS) approach has been developed that uses inactive electrode contacts to record epidural spinal recordings (ESRs) generated during SCS. ESRs contain evoked compound action potentials (ECAPs) which represent a quantitative measure of synchronous neural recruitment in the spinal cord. ECAPs may be utilized as a control signal for closed-loop stimulation and aid in optimal electrode placement and parameter selection. However, the various physiological and technical factors underlying the composition of these signals are difficult to obtain experimentally due to subject variability and sources of noise, which may limit the use of ECAPs in elucidating mechanisms of SCS-induced analgesia. Therefore, the goal of this study was to use computational modeling based on detailed anatomical imaging paired with preclinical physiological data to investigate the neuromodulatory effects of SCS. MATERIALS AND METHODS:We developed a computational model from an experimental data set containing imaging and ESRs from six swine. We coupled our finite element method model with multicompartment cable models to simulate the neural response to SCS. We then used a reciprocity-based approach to calculate model ECAP recordings. RESULTS:Model ECAPs were dependent on stimulation parameters (ie, tonic stimulation waveform and configuration) and anatomical variations (ie, dorsal cerebrospinal fluid thickness and mediolateral lead location). Our modeling results indicate that the combined choice of stimulation waveform and stimulation configuration may result in action potential initiation at different locations, which, when recorded, gives rise to ECAPs with different morphologies and amplitudes, even for approximately the same level of underlying neural activation. CONCLUSIONS:Our findings suggest that ECAP characteristics may not directly represent the level of neural recruitment to a stimulus and are highly dependent on stimulation parameters. Overall, the results of this study provide a mechanistic understanding of how various factors affect the composition of ECAP recordings and will help optimize the utility of ESRs in SCS.

Sacral neuromodulation is increasingly utilized clinically to treat conditions such as overactive bladder, urinary incontinence, and various pelvic pain disorders. Given their anatomical similarities to humans, porcine models have become prevalent in neuromodulation device research. This study introduces a validated fluoroscopy-guided implantation protocol for precise needle-based electrode placement onto porcine sacral nerves. "Blind" targeting through the posterior foramen results in an unreliable nerve-electrode interface. To address this challenge, we performed a detailed dissection and microCT characterization of pig sacral anatomy to accurately visualize the sacral nerves exiting the anterior foramen. We critically assessed the needle angles projecting through the S1, S2, and S3 foramina, with lateral fluoroscopic views confirming these angles. Delivery through the S2 and S3 foramen was deemed feasible, while S1 was deemed infeasible due to the relative positions of the posterior and anterior foramen. A step-by-step protocol for consistently achieving activation of the S2 and S3 sacral nerves was written and carried out in Yucatan minipigs (n=6). Specific fluoroscopic features corresponding to both posterior and anterior foramina were annotated in the images accompanying the procedure. We confirmed this percutaneous technique in vivo via recruitment of the bladder and external anal sphincter in response to electrical stimulation. Our results suggest that this method can significantly improve both the accuracy and precision of electrode placement onto porcine sacral nerves using minimally invasive techniques.Clinical Relevance—A standardized electrode insertion protocol was established to efficiently place electrodes onto the S2-S3 porcine sacral nerves to generate reliable bladder activation.

Objective.Parkinson's disease (PD) is a multifactorial, progressive neurodegenerative disease that has a profound impact on those it afflicts. Its hallmark pathophysiology is characterized by degeneration of dopaminergic (DA) neurons in the midbrain which trigger a host of motor and non-motor symptoms. Many preclinical research efforts utilize unilateral lesion models to assess the neural mechanisms of PD and explore new therapeutic approaches because these models produce similar motor symptoms to those of PD patients. The goal of this work is to examine changes in brain structure resulting from a unilateral lesion both within the nigrostriatal system, where DA neurons are lost, and throughout the brain.Methods.Using multi-shell diffusion magnetic resonance imaging and correlational tractography, we assessed microstructural changes throughout the brain resulting from unilateral injection of 6-hydroxydopamine in the median forebrain bundle.Resutls.Following lesioning, the PD phenotype was confirmed using behavioral and histological assessment. Correlational tractography found networks of fiber tracts that were either positively or negatively correlated with lesion status throughout the brain. Analyzing patterns of intra- and inter-hemispheric connectivity between the positively and negatively correlated fiber tracts revealed two separate neural networks. The first contained only negatively correlated fibers in the lesioned hemisphere consistent with the local effects of the lesion (i.e. DA depletion in the nigrostriatal system). The second contained systematically overlapping fiber tracts in the lesioned and non-lesioned hemispheres including the olfactory system and cerebellum, which we suggest are indicative of adaptive mechanisms to compensate for the lesion.Conclusion.Taken together, these results suggest that correlational tractography is a reasonable tool to examine whole brain structural changes in rodent models of neurodegenerative disease, and may have future translational value as a diagnostic tool for patients with PD.

Minimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode® is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. The Injectrode serves as a low-impedance conduit to guide current to the deep on-target nerve, reducing activation thresholds by an order of magnitude compared to using only surface stimulation electrodes. To minimize off-target recruitment of cutaneous fibers, the energy transfer efficiency from the surface electrodes to the Injectrode must be optimized. TES energy is transferred to the Injectrode through both capacitive and resistive mechanisms. Electrostatic finite element models generally used in TES research consider only the resistive means of energy transfer by defining tissue conductivities. Here, we present an electroquasistatic model, taking into consideration both the conductivity and permittivity of tissue, to understand transcutaneous power delivery to the Injectrode. The model was validated with measurements taken from (n = 4) swine cadavers. We used the validated model to investigate system and anatomic parameters that influence the coupling efficiency of the Injectrode energy delivery system. Our work suggests the relevance of electroquasistatic models to account for capacitive charge transfer mechanisms when studying TES, particularly when high-frequency voltage components are present, such as those used for voltage-controlled pulses and sinusoidal nerve blocks.

Currently there are numerous methods to evaluate peripheral nerve stimulation interfaces in rats, with stimulation-evoked ankle torque being one of the most prominent. Commercial rat ankle torque measurement systems and custom one-off solutions have been published in the literature. However, commercial systems are proprietary and costly and do not allow for customization. One-off lab-built systems have required specialized machining expertise, and building plans have previously not been made easily accessible. Here, detailed building plans are provided for a low-cost, open-source, and basic ankle torque measurement system from which additional customization can be made. A hindlimb stabilization apparatus was developed to secure and stabilize a rat's hindlimb, while allowing for simultaneous ankle-isometric torque and lower limb muscle electromyography (EMG). The design was composed mainly of adjustable 3D-printed components to accommodate anatomical differences between rat hindlimbs. Additionally, construction and calibration procedures of the rat hindlimb stabilization apparatus were demonstrated in this study. In vivo torque measurements were reliably acquired and corresponded to increasing stimulation amplitudes. Furthermore, implanted leads used for intramuscular EMG recordings complemented torque measurements and were used as an additional functional measurement in evaluating the performance of a peripheral nerve stimulation interface. In conclusion, an open-source and noninvasive platform, made primarily with 3D-printed components, was constructed for reliable data acquisition of evoked motor activity in rat models. The purpose of this apparatus is to provide researchers a versatile system with adjustable components that can be tailored to meet user-defined experimental requirements when evaluating motor function of the rat hindlimbs.

BACKGROUND:Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief. METHODS:Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C-reactive protein, [18F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control. KEY RESULTS:Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C-reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T-cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C-reactive protein. CONCLUSIONS AND INFERENCES:These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects.

Background and PurposeSpinal cord stimulation (SCS) is approved by the Food and Drug Administration for treating chronic intractable pain in the back, trunk, or limbs through stimulation of the dorsal column. Numerous studies have used swine as an analog of the human spinal cord to better understand SCS and further improve its efficacy. We performed high-resolution imaging of the porcine spinal cord with intact dura mater using micro-computed tomography (mu CT) to construct detailed 3-dimensional (3D) visualizations of the spinal cord and characterize the morphology of the dorsal and ventral rootlets.MethodsWe obtained spinal cords from Yorkshire/Landrace crossbred swine (N = 7), stained samples with osmium tetroxide, and performed mu CT imaging of the T12-T15 levels at isotropic voxel resolutions ranging from 3.3 to 50 mu m. We measured the anatomical morphology using the 3D volumes and compared our results to measurements previously collected from swine and human spinal cords via microdissection techniques in prior literature.ResultsWhile the porcine thoracic-lumbar spinal cord is a popular model for SCS, we highlight multiple notable differences compared to previously published T8-T12 human measurements including rootlet counts (porcine dorsal/ventral: 12.2 +/- 2.6, 26.6 +/- 3.4; human dorsal/ventral: 5.3 +/- 1.3, 4.4 +/- 2.4), rootlet angles (porcine ventral-rostral: 161 +/- 1 degrees, ventral-caudal: 155 +/- 6 degrees, dorsal-rostral: 148 +/- 9 degrees, dorsal-caudal: 142 +/- 6 degrees; human ventral-rostral: 170 +/- 3 degrees, ventral-caudal: 22 +/- 10 degrees, dorsal-rostral: 171 +/- 3 degrees, dorsal-caudal: 15 +/- 7 degrees), and the presence and count of dorsal rootlet bundles.ConclusionsDetailed measurements and highlighted differences between human and porcine spinal cords can inform variations in modeling and electrophysiological experiments between the two species. In contrast to other approaches for measuring the spinal cord and rootlet morphology, our method keeps the dura intact, reducing potential artifacts from dissection.

Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the arms during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical (CTC) network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive therapy for medication refractory ET. However, its mechanism remains unclear. We hypothesize that TAPS reduces tremor through modulation of the VIM thalamus in the CTC network. Employing refractory ET patients seeking VIM deep brain stimulation (DBS), we quantified clinical tremor improvement following TAPS treatment in a pre-operative setting, followed by intra-operative, microelectrode recording of the contralateral thalamus with concurrent TAPS treatment on and off. After one preoperative session, TAPS significantly reduces upper limb tremor, with asymmetric effect favoring the treated limb and greatest improvement tending to kinetic tremor. The magnitude of TAPS-related tremor reduction demonstrates a positive correlation with the modulation of alpha and beta band LFPs in the VIM. TAPS also modulated spiking activity in the VIM, though it was uncorrelated with the degree of tremor reduction. Of note, TAPS related modulation of LFPs and spiking activity was greatest near the optimal placement location for DBS lead in treating ET. In sum, TAPS likely reduces tremor in ET by modulating the VIM and connected nodes in the cerebello-thalamo-cortical pathway. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Study focused on testing for mechanism, not appropriate for clinical trial registration. ### Funding Statement AJS and WBL received partial funding for this study from Cala Health, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Institutional Review Board (IRB) at the University of Wisconsin, Madison (IRB ID: 2018-1052). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Raw neural data structures are not openly available due to the inclusion of private health information and are available from the corresponding author upon reasonable request. The de-identified data supporting the findings of this study will be shared on DRYAD once accepted for publication.