Computational modeling of dorsal root ganglion stimulation using an Injectrode.

Objective.Minimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated Platinum/Iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, it is important to note that the effectiveness of stimulation through TES relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures.Approach.We employed a hybrid computational modeling approach to analyze the impact of Injectrode system design parameters on charge delivery and neural response to stimulation. We constructed multiple finite element method models of DRG stimulation, followed by the implementation of multi-compartment models of DRG neurons. By calculating potential distribution during monopolar stimulation, we simulated neural responses using various parameters based on prior acute experiments. Additionally, we developed a canonical monopolar stimulation and full-scale model of bipolar bilateral L5 DRG stimulation, allowing us to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds.Main results.Our findings were in accordance with acute experimental measurements and indicate that the minimally invasive Injectrode system predominantly engages large-diameter afferents (Aß-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (Aδ-fibers) activity.Significance.The Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired Aßactivation from the undesired Aδ-fiber activation.

High-frequency amplitude-modulated sinusoidal stimulation induces desynchronized yet controllable neural firing.

Regaining sensory feedback is pivotal for people living with limb amputation. Electrical stimulation of sensory fibers in peripheral nerves has been shown to restore focal percepts in the missing limb. However, conventional rectangular current pulses induce sensations often described as unnatural. This is likely due to the synchronous and periodic nature of activity evoked by these pulses. Here we introduce a fast-oscillating amplitude-modulated sinusoidal (FAMS) stimulation waveform that desynchronizes evoked neural activity. We used a computational model to show that sinusoidal waveforms evoke asynchronous and irregular firing and that firing patterns are frequency dependent. We designed the FAMS waveform to leverage both low- and high-frequency effects and found that membrane non-linearities enhance neuron-specific differences when exposed to FAMS. We implemented this waveform in a feline model of peripheral nerve stimulation and demonstrated that FAMS-evoked activity is more asynchronous than activity evoked by rectangular pulses, while being easily controllable with simple stimulation parameters. These results represent an important step towards biomimetic stimulation strategies useful for clinical applications to restore sensory feedback.

Isoflurane anesthesia suppresses gastric myoelectric power in the ferret.

BACKGROUND: Gastric myoelectric signals have been the focus of extensive research; although it is unclear how general anesthesia affects these signals, and studies have often been conducted under general anesthesia. Here, we explore this issue directly by recording gastric myoelectric signals during awake and anesthetized states in the ferret and explore the contribution of behavioral movement to observed changes in signal power. METHODS: Ferrets were surgically implanted with electrodes to record gastric myoelectric activity from the serosal surface of the stomach, and, following recovery, were tested in awake and isoflurane-anesthetized conditions. Video recordings were also analyzed during awake experiments to compare myoelectric activity during behavioral movement and rest. KEY RESULTS: A significant decrease in gastric myoelectric signal power was detected under isoflurane anesthesia compared to the awake condition. Moreover, a detailed analysis of the awake recordings indicates that behavioral movement is associated with increased signal power compared to rest. CONCLUSIONS & INFERENCES: These results suggest that both general anesthesia and behavioral movement can affect the signal power of gastric myoelectric recordings. In summary, caution should be taken in studying myoelectric data collected under anesthesia. Further, behavioral movement could have an important modulatory role on these signals, affecting their interpretation in clinical settings.

SUPRASPINAL CONTROL OF MOTONEURONS AFTER PARALYSIS ENABLED BY SPINAL CORD STIMULATION.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.

Restoration of sensory feedback from the foot and reduction of phantom limb pain via closed-loop spinal cord stimulation.

Restoring somatosensory feedback in individuals with lower-limb amputations would reduce the risk of falls and alleviate phantom limb pain. Here we show, in three individuals with transtibial amputation (one traumatic and two owing to diabetic peripheral neuropathy), that sensations from the missing foot, with control over their location and intensity, can be evoked via lateral lumbosacral spinal cord stimulation with commercially available electrodes and by modulating the intensity of stimulation in real time on the basis of signals from a wireless pressure-sensitive shoe insole. The restored somatosensation via closed-loop stimulation improved balance control (with a 19-point improvement in the composite score of the Sensory Organization Test in one individual) and gait stability (with a 5-point improvement in the Functional Gait Assessment in one individual). And over the implantation period of the stimulation leads, the three individuals experienced a clinically meaningful decrease in phantom limb pain (with an average reduction of nearly 70% on a visual analogue scale). Our findings support the further clinical assessment of lower-limb neuroprostheses providing somatosensory feedback.

Sensory Restoration for Improved Motor Control of Prostheses.

Somatosensory neuroprostheses are devices with the potential to restore the senses of touch and movement from prosthetic limbs for people with limb amputation or paralysis. By electrically stimulating the peripheral or central nervous system, these devices evoke sensations that appear to emanate from the missing or insensate limb, and when paired with sensors on the prosthesis, they can improve the functionality and embodiment of the prosthesis. There have been major advances in the design of these systems over the past decade, although several important steps remain before they can achieve widespread clinical adoption outside the lab setting. Here, we provide a brief overview of somatosensory neuroprostheses and explores these hurdles and potential next steps towards clinical translation.

Computational modeling of dorsal root ganglion stimulation using an Injectrode.

Objective: Minimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated platinum/iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, effectiveness of stimulation relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures. Approach: We employed a hybrid computational modeling approach to analyze the impact of the Injectrode system design parameters on charge delivery and the neural response to stimulation. We constructed multiple finite element method models of DRG stimulation and multi-compartment models of DRG neurons. We simulated the neural responses using parameters based on prior acute preclinical experiments. Additionally, we developed multiple human-scale computational models of DRG stimulation to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds. Main results: Our findings were in accordance with acute experimental measurements and indicated that the Injectrode system predominantly engages large-diameter afferents (Aß-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (Aδ-fibers) activity. Significance: The Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired Aß activation from the undesired Aδ-fiber activation.

Prediction of gastrointestinal functional state based on myoelectric recordings utilizing a deep neural network architecture.

Functional and motility-related gastrointestinal (GI) disorders affect nearly 40% percent of the population. Disturbances of GI myoelectric activity have been proposed to play a significant role in these disorders. A significant barrier to usage of these signals in diagnosis and treatment is the lack of consistent relationships between GI myoelectric features and function. A potential cause of this issue is the use of arbitrary classification criteria, such as percentage of power in tachygastric and bradygastric frequency bands. Here we applied automatic feature extraction using a deep neural network architecture on GI myoelectric signals from free-moving ferrets. For each animal, we recorded during baseline control and feeding conditions lasting for 1 h. Data were trained on a 1-dimensional residual convolutional network, followed by a fully connected layer, with a decision based on a sigmoidal output. For this 2-class problem, accuracy was 90%, sensitivity (feeding detection) was 90%, and specificity (baseline detection) was 89%. By comparison, approaches using hand-crafted features (e.g., SVM, random forest, and logistic regression) produced an accuracy from 54% to 82%, sensitivity from 46% to 84% and specificity from 66% to 80%. These results suggest that automatic feature extraction and deep neural networks could be useful to assess GI function for comparing baseline to an active functional GI state, such as feeding. In future testing, the current approach could be applied to determine normal and disease-related GI myoelectric patterns to diagnosis and assess patients with GI disease.

Neurotechnology for Pain.

Neurotechnologies for treating pain rely on electrical stimulation of the central or peripheral nervous system to disrupt or block pain signaling and have been commercialized to treat a variety of pain conditions. While their adoption is accelerating, neurotechnologies are still frequently viewed as a last resort, after many other treatment options have been explored. We review the pain conditions commonly treated with electrical stimulation, as well as the specific neurotechnologies used for treating those conditions. We identify barriers to adoption, including a limited understanding of mechanisms of action, inconsistent efficacy across patients, and challenges related to selectivity of stimulation and off-target side effects. We describe design improvements that have recently been implemented, as well as some cutting-edge technologies that may address the limitations of existing neurotechnologies. Addressing these challenges will accelerate adoption and change neurotechnologies from last-line to first-line treatments for people living with chronic pain.

Anesthesia suppresses gastric myoelectric power in the ferret.

BACKGROUND: Gastrointestinal myoelectric signals have been the focus of extensive research; although it is unclear how general anesthesia affects these signals, studies have often been conducted under general anesthesia. Here, we explore this issue directly by recording gastric myoelectric signals during awake and anesthetized states in the ferret and also explore the contribution of behavioral movement to observed changes in signal power. METHODS: Ferrets were surgically implanted with electrodes to record gastric myoelectric activity from the serosal surface of the stomach, and, following recovery, were tested in awake and isoflurane-anesthetized conditions. Video recordings were also analyzed during awake experiments to compare myoelectric activity during behavioral movement and rest. KEY RESULTS: A significant decrease in gastric myoelectric signal power was detected under isoflurane anesthesia compared to the awake condition. Moreover, a detailed analysis of the awake recordings indicates that behavioral movement is associated with increased signal power compared to rest. CONCLUSIONS & INFERENCES: These results suggest that both general anesthesia and behavioral movement can affect the amplitude of gastric myoelectric. In summary, caution should be taken in studying myoelectric data collected under anesthesia. Further, behavioral movement could have an important modulatory role on these signals, affecting their interpretation in clinical settings.

Epidural stimulation of the cervical spinal cord for post-stroke upper-limb paresis.

Cerebral strokes can disrupt descending commands from motor cortical areas to the spinal cord, which can result in permanent motor deficits of the arm and hand. However, below the lesion, the spinal circuits that control movement remain intact and could be targeted by neurotechnologies to restore movement. Here we report results from two participants in a first-in-human study using electrical stimulation of cervical spinal circuits to facilitate arm and hand motor control in chronic post-stroke hemiparesis ( NCT04512690 ). Participants were implanted for 29 d with two linear leads in the dorsolateral epidural space targeting spinal roots C3 to T1 to increase excitation of arm and hand motoneurons. We found that continuous stimulation through selected contacts improved strength (for example, grip force +40% SCS01; +108% SCS02), kinematics (for example, +30% to +40% speed) and functional movements, thereby enabling participants to perform movements that they could not perform without spinal cord stimulation. Both participants retained some of these improvements even without stimulation and no serious adverse events were reported. While we cannot conclusively evaluate safety and efficacy from two participants, our data provide promising, albeit preliminary, evidence that spinal cord stimulation could be an assistive as well as a restorative approach for upper-limb recovery after stroke.

Amputee, clinician, and regulator perspectives on current and prospective upper extremity prosthetic technologies.

Existing prosthetic technologies for people with upper limb amputation are being adopted at moderate rates. Once fitted for these devices, many upper limb amputees report not using them regularly or at all. The primary aim of this study was to solicit feedback about prosthetic technology and important device design criteria from amputees, clinicians, and device regulators. We compare these perspectives to identify common or divergent priorities. Twenty-one adults with upper limb loss, 35 clinicians, and 3 regulators completed a survey on existing prosthetic technologies and a conceptual sensorimotor prosthesis driven by implanted myoelectric electrodes with sensory feedback via spinal root stimulation. The survey included questions from the Trinity Amputation and Prosthesis Experience Scale, the Disabilities of the Arm, Shoulder, and Hand, and novel questions about technology acceptance and neuroprosthetic design. User and clinician ratings of satisfaction with existing devices were similar. Amputees were most accepting of the proposed sensorimotor prosthesis (75.5% vs clinicians (68.8%), regulators (67.8%)). Stakeholders valued user-centered outcomes like individualized task goals, improved quality of life, device reliability, and user safety; regulators emphasized these last two. The results of this study provide insight into amputee, clinician, and regulator priorities to inform future upper-limb prosthetic design and clinical trial protocol development.

A systematic review of computational models for the design of spinal cord stimulation therapies: from neural circuits to patient-specific simulations.

Seventy years ago, Hodgkin and Huxley published the first mathematical model to describe action potential generation, laying the foundation for modern computational neuroscience. Since then, the field has evolved enormously, with studies spanning from basic neuroscience to clinical applications for neuromodulation. Computer models of neuromodulation have evolved in complexity and personalization, advancing clinical practice and novel neurostimulation therapies, such as spinal cord stimulation. Spinal cord stimulation is a therapy widely used to treat chronic pain, with rapidly expanding indications, such as restoring motor function. In general, simulations contributed dramatically to improve lead designs, stimulation configurations, waveform parameters and programming procedures and provided insight into potential mechanisms of action of electrical stimulation. Although the implementation of neural models are relentlessly increasing in number and complexity, it is reasonable to ask whether this observed increase in complexity is necessary for improved accuracy and, ultimately, for clinical efficacy. With this aim, we performed a systematic literature review and a qualitative meta-synthesis of the evolution of computational models, with a focus on complexity, personalization and the use of medical imaging to capture realistic anatomy. Our review showed that increased model complexity and personalization improved both mechanistic and translational studies. More specifically, the use of medical imaging enabled the development of patient-specific models that can help to transform clinical practice in spinal cord stimulation. Finally, we combined our results to provide clear guidelines for standardization and expansion of computational models for spinal cord stimulation.

High-density spinal cord stimulation selectively activates lower urinary tract nerves.

Objective.Epidural spinal cord stimulation (SCS) is a potential intervention to improve limb and autonomic functions, with lumbar stimulation improving locomotion and thoracic stimulation regulating blood pressure. Here, we asked whether sacral SCS could be used to target the lower urinary tract (LUT) and used a high-density epidural electrode array to test whether individual electrodes could selectively recruit LUT nerves.Approach. We placed a high-density epidural SCS array on the dorsal surface of the sacral spinal cord and cauda equina of anesthetized cats and recorded the stimulation-evoked activity from nerve cuffs on the pelvic, pudendal and sciatic nerves.Main results. Here we show that sacral SCS evokes responses in nerves innervating the bladder and urethra and that these nerves can be activated selectively. Sacral SCS always recruited the pelvic and pudendal nerves and selectively recruited both of these nerves in all but one animal. Individual branches of the pudendal nerve were always recruited as well. Electrodes that selectively recruited specific peripheral nerves were spatially clustered on the arrays, suggesting anatomically organized sensory pathways.Significance.This selective recruitment demonstrates a mechanism to directly modulate bladder and urethral function through known reflex pathways, which could be used to restore bladder and urethral function after injury or disease.

Closed-loop stimulation of lateral cervical spinal cord in upper-limb amputees to enable sensory discrimination: a case study.

Modern myoelectric prosthetic hands have multiple independently controllable degrees of freedom, but require constant visual attention to use effectively. Somatosensory feedback provides information not available through vision alone and is essential for fine motor control of our limbs. Similarly, stimulation of the nervous system can potentially provide artificial somatosensory feedback to reduce the reliance on visual cues to efficiently operate prosthetic devices. We have shown previously that epidural stimulation of the lateral cervical spinal cord can evoke tactile sensations perceived as emanating from the missing arm and hand in people with upper-limb amputation. In this case study, two subjects with upper-limb amputation used this somatotopically-matched tactile feedback to discriminate object size and compliance while controlling a prosthetic hand. With less than 30 min of practice each day, both subjects were able to use artificial somatosensory feedback to perform a subset of the discrimination tasks at a success level well above chance. Subject 1 was consistently more adept at determining object size (74% accuracy; chance: 33%) while Subject 2 achieved a higher accuracy level in determining object compliance (60% accuracy; chance 33%). In each subject, discrimination of the other object property was only slightly above or at chance level suggesting that the task design and stimulation encoding scheme are important determinants of which object property could be reliably identified. Our observations suggest that changes in the intensity of artificial somatosensory feedback provided via spinal cord stimulation can be readily used to infer information about object properties with minimal training.

A Computational Study of Lower Urinary Tract Nerve Recruitment with Epidural Stimulation of the Lumbosacral Spinal Cord.

Bladder dysfunction is a major health risk for people with spinal cord injury. Recently, we have demonstrated that epidural sacral spinal cord stimulation (SCS) can be used to activate lower urinary tract nerves and provide both major components of bladder control: voiding and continence. To effectively control these functions, it is necessary to selectively recruit the afferents of the pudendal nerve that evoke these distinct bladder reflexes. Translation of this innovation to clinical practice requires an understanding of optimal electrode placements and stimulation parameters to guide surgical practice and therapy design. Computational modeling is an important tool to address many of these experimentally intractable stimulation optimization questions. Here, we built a realistic MRI-based finite element computational model of the feline sacral spinal cord which included realistic axon trajectories in the dorsal and ventral roots. We coupled the model with biophysical simulations of membrane dynamics of afferent and efferent axons that project to the lower urinary tract through the pelvic and pudendal nerves. We simulated the electromagnetic fields arising from stimulation through SCS electrodes and calculated the expected recruitment of pelvic and pudendal fibers. We found that SCS can selectively recruit pudendal afferents, in agreement with our experimental data in cats. Our results suggest that SCS is a promising technology to improve bladder function after spinal cord injury, and computational modeling unlocks the potential for highly optimized, selective stimulation. Clinical Relevance - This model provides a method to non-invasively establish electrode placement and stimulation parameters for improving bladder function with epidural spinal cord stimulation.

The Bilateral Deficit Phenomenon in Elbow Flexion: Explanations for Its Inconsistent Occurrence and Detection.

The underlying mechanism(s) of the Bilateral Deficit (BLD) phenomenon is without consensus. Methodological inconsistencies across prior works may be an important source of equivocal results and interpretations. Based on repeatability problems with the BLD measure and maximal force definition, the presence or absence of the BLD phenomenon is altered, shifting conclusions of its mechanistic cause. Our purpose in this study was to examine methodological inconsistencies in applying the BLD measure to establish optimal methods for evaluating the underlying mechanism. Eleven healthy participants engaged in one familiarity and five test sessions, completing bilateral and unilateral elbow maximal voluntary isometric contractions. We defined maximal force by averaged and absolute peak and plateau values. BLD was evident if the bilateral index (BI), the ratio of the bilateral over summed unilateral forces, was statistically different from zero. We addressed interclass correlations (ICC), Chronbach's α, standard error of the mean, and minimal detectable change between and within sessions for all force measures and BI. We evaluated all combinations of sessions (i.e., 1-2, 3-5, 5-6) and maximal forces to establish the optimal number of sessions to achieve reliability. BLD was present for test sessions, but not for familiarization. All measures of maximal force were highly reliable between and within sessions (ICC(2,1) ≥ .895). BI was only considered significantly reliable in sessions 3-5 (p < .027), defined by absolute and average plateau forces, but reliability was still quantifiably poor (absolute: ICC(2,1) = .392; average: ICC(2,1) = .375). These results demonstrate that high force reliability within and between sessions does not translate to stable and reliable BI, potentially exposing the lack of any defined BLD mechanism.

Recruitment of Primary Afferents by Dorsal Root Ganglion Stimulation using the Injectrode.

Chronic pain affects millions of people in the United States and pharmacological treatments have been ineffective. Dorsal root ganglion (DRG) stimulation is a neuromodulation method that delivers electrical stimulation to the DRG to relieve pain. DRG electrodes are rigid and cylindrical. The implantation of DRG electrodes requires a technically-challenging surgery that involves steering electrodes laterally towards the DRG. The Injectrode is an injectable conductive polymer that cures in place and is capable of delivering electrical current to stimulate neural tissue. We used the Injectrode to stimulate the L6 and L7 DRG in cats, measuring neural responses evoked in the sciatic, tibial, and common peroneal nerves to measure the thresholds for activating fibers. A cylindrical stainless-steel electrode was used for comparison. Thresholds were 38% higher with the Injectrode versus stainless-steel, likely owing to its larger contact surface area with the DRG. Both Aα and Aß sensory fibers were activated using DRG stimulation. The Injectrode has the potential to offer a new and simple method for DRG stimulation that can potentially offer more complete coverage of the DRG.

Surgical placement of customized abdominal vagus nerve stimulating and gastrointestinal serosal surface recording electrodes.

Bioelectronic medical approaches to control vagus nerve-to-organ signaling have the potential to treat cardiac, respiratory, gastrointestinal (GI) and metabolic diseases, such as obesity. Unlike cervical vagus nerve stimulation (VNS), abdominal VNS could provide specific therapeutic control of the GI tract without off-target effects on thoracic organs; however, surgical approaches for abdominal VNS electrode placement are not well established. Moreover, optimal device configurations and additional placement of GI recording electrodes for closed-loop control are largely unknown. We designed VNS cuff and GI planar serosal electrodes and tested placement of these devices in laparoscopic surgery in two cadavers. We determined that electrode positioning on the ventral abdominal vagus nerve and gastric antrum was feasible but other sites, such as the duodenum and proximal stomach, were more difficult. The current investigation can guide potential placement and design of VNS cuff and GI electrodes for development of closed-loop GI therapeutic devices.