Emergence of Distinct Neural Subspaces in Motor Cortical Dynamics during Volitional Adjustments of Ongoing Locomotion.

The ability to modulate ongoing walking gait with precise, voluntary adjustments is what allows animals to navigate complex terrains. However, how the nervous system generates the signals to precisely control the limbs while simultaneously maintaining locomotion is poorly understood. One potential strategy is to distribute the neural activity related to these two functions into distinct cortical activity coactivation subspaces so that both may be conducted simultaneously without disruptive interference. To investigate this hypothesis, we recorded the activity of primary motor cortex in male nonhuman primates during obstacle avoidance on a treadmill. We found that the same neural population was active during both basic unobstructed locomotion and volitional obstacle avoidance movements. We identified the neural modes spanning the subspace of the low-dimensional dynamics in primary motor cortex and found a subspace that consistently maintains the same cyclic activity throughout obstacle stepping, despite large changes in the movement itself. All of the variance corresponding to this large change in movement during the obstacle avoidance was confined to its own distinct subspace. Furthermore, neural decoders built for ongoing locomotion did not generalize to decoding obstacle avoidance during locomotion. Our findings suggest that separate underlying subspaces emerge during complex locomotion that coordinates ongoing locomotor-related neural dynamics with volitional gait adjustments. These findings may have important implications for the development of brain-machine interfaces.SIGNIFICANCE STATEMENT Locomotion and precise, goal-directed movements are two distinct movement modalities with known differing requirements of motor cortical input. Previous studies have characterized the cortical activity during obstacle avoidance while walking in rodents and felines, but, to date, no such studies have been completed in primates. Additionally, in any animal model, it is unknown how these two movements are represented in primary motor cortex (M1) low-dimensional dynamics when both activities are performed at the same time, such as during obstacle avoidance. We developed a novel obstacle avoidance paradigm in freely moving nonhuman primates and discovered that the rhythmic locomotion-related dynamics and the voluntary, gait-adjustment movement separate into distinct subspaces in M1 cortical activity. Our analysis of decoding generalization may also have important implications for the development of brain-machine interfaces.

Spatiotemporal Distribution of Electrically Evoked Spinal Compound Action Potentials During Spinal Cord Stimulation.

OBJECTIVES: Recent studies using epidural spinal cord stimulation (SCS) have demonstrated restoration of motor function in individuals previously diagnosed with chronic spinal cord injury (SCI). In parallel, the spinal evoked compound action potentials (ECAPs) induced by SCS have been used to gain insight into the mechanisms of SCS-based chronic pain therapy and to titrate closed-loop delivery of stimulation. However, the previous characterization of ECAPs recorded during SCS was performed with one-dimensional, cylindrical electrode leads. Herein, we describe the unique spatiotemporal distribution of ECAPs induced by SCS across the medial-lateral and rostral-caudal axes of the spinal cord, and their relationship to polysynaptic lower-extremity motor activation. MATERIALS AND METHODS: In each of four sheep, two 24-contact epidural SCS arrays were placed on the lumbosacral spinal cord, spanning the L3 to L6 vertebrae. Spinal ECAPs were recorded during SCS from nonstimulating contacts of the epidural arrays, which were synchronized to bilateral electromyography (EMG) recordings from six back and lower-extremity muscles. RESULTS: We observed a triphasic P1, N1, P2 peak morphology and propagation in the ECAPs during midline and lateral stimulation. Distinct regions of lateral stimulation resulted in simultaneously increased ECAP and EMG responses compared with stimulation at adjacent lateral contacts. Although EMG responses decreased during repetitive stimulation bursts, spinal ECAP amplitude did not significantly change. Both spinal ECAP responses and EMG responses demonstrated preferential ipsilateral recruitment during lateral stimulation compared with midline stimulation. Furthermore, EMG responses were correlated with stimulation that resulted in increased ECAP amplitude on the ipsilateral side of the electrode array. CONCLUSIONS: These results suggest that ECAPs can be used to investigate the effects of SCS on spinal sensorimotor networks and to inform stimulation strategies that optimize the clinical benefit of SCS in the context of managing chronic pain and the restoration of sensorimotor function after SCI.

A brain-spine interface alleviating gait deficits after spinal cord injury in primates.

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.

Disparities in substance use treatment retention: An exploration of reasons for discharge from publicly funded treatment.

Although Delaware is the seventh smallest state in the country (including Washington, D.C.) in terms of population size, it has the second highest drug overdose death rate. The Delaware Division of Substance Abuse and Mental Health has increased attention in identifying disparities in treatment outcomes. We explored reasons for discharge from publicly-funded treatment in Delaware with special attention to populations at risk for health inequities, with a focus on covariates of treatment non-completion. Using secondary data collected from publicly-funded treatment providers, we analyzed data from individuals that were admitted to substance use treatment between 2015 and 2019 and had been discharged in 2019. We did this by using logistic and multinomial regression, focusing on non-completion treatment outcomes such as failure to meet requirements, loss of contact, and treatment refusal. Clients who were Black or African American, compared to white clients, were more likely to be lost contact with, administratively discharged, or marked as failing to meet treatment requirements than having a completed treatment discharge. Women were 30% less likely than men to have "failed to meet treatment requirements" compared to completing treatment. Further investigation is needed into these patterns. While treatment quality cannot be assessed using this data, the results point to a need for closer study of disparities in treatment related to race, ethnicity, gender, employment, criminal justice involvement, and type of drug used. Treatment providers should be made aware of culturally informed care, as well as client-created goals, in order to reduce disparities in exit from treatment.

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

An active electronic bidirectional interface for high resolution interrogation of the spinal cord.

Epidural electrical stimulation (EES) has shown promise as both a clinical therapeutic tool and research aid in the study of nervous system function. However, available clinical paddles are limited to using a small number of contacts due to the burden of wires necessary to connect each contact to the therapeutic device. Here, we introduce for the first time the integration of a hermetic active electronic multiplexer onto the electrode paddle array itself, removing this interconnect limitation. We evaluated the chronic implantation of an active electronic 60-contact paddle (the HD64) on the lumbosacral spinal cord of two sheep. The HD64 was implanted for 13 months and 15 months, with no device-related malfunctions or adverse events. We identified increased selectivity in EES-evoked motor responses using dense stimulating bipoles. Further, we found that dense recording bipoles decreased the spatial correlation between channels during recordings. Finally, spatial electrode encoding enabled a neural network to accurately perform EES parameter inference for unseen stimulation electrodes, reducing training data requirements. A high-density EES paddle, containing active electronics safely integrated into neural interfaces, opens new avenues for the study of nervous system function and new therapies to treat neural injury and dysfunction.

Toward a brighter constellation: multiorgan neuroimaging of neural and vascular dynamics in the spinal cord and brain.

Significance: Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). Results: We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

Development of a high-throughput laser-induced acoustic desorption probe and raster sampling for laser-induced acoustic desorption/atmospheric pressure chemical ionization.

Laser-induced acoustic desorption (LIAD) was recently coupled to atmospheric pressure chemical ionization (APCI) and shown to be of great utility for the analysis of a variety of thermally labile nonpolar analytes that are not amenable to ionization via electrospray ionization, such as nonvolatile hydrocarbons. Despite these advancements, LIAD still suffered from several limitations, including only being able to sample a small fraction of the analyte molecules deposited on a Ti foil for desorption, poor reproducibility, as well as limited laser power throughput to the backside of the foil. These limitations severely hinder the analysis of especially challenging analytes, such as asphaltenes. To address these issues, a novel high-throughput LIAD probe and an assembly for raster sampling of a LIAD foil were designed, constructed, and tested. The new probe design allows 98% of the initial laser power to be realized at the backside of the foil over the 25% achieved previously, thus improving reproducibility and allowing for the analysis of large nonvolatile analytes, including asphaltenes. The raster assembly provided a 5.7 fold increase in the surface area of a LIAD foil that could be sampled and improved reproducibility and sensitivity for LIAD experiments. The raster assembly can also improve throughput as foils containing multiple analytes can be prepared and analyzed.

On-line mass spectrometric methods for the determination of the primary products of fast pyrolysis of carbohydrates and for their gas-phase manipulation.

Mass spectrometric methodology was developed for the determination and manipulation of the primary products of fast pyrolysis of carbohydrates. To determine the true primary pyrolysis products, a very fast heating pyroprobe was coupled to a linear quadrupole ion trap mass spectrometer through a custom-built adaptor. A home-built flow tube that simulates pyrolysis reactor conditions was used to examine the secondary reactions of the primary products. Depending on the experiment, the pyrolysis products were either evaporated and quenched or allowed to react for a period of time. The quenched products were ionized in an atmospheric pressure chemical ionization (APCI) source infused with one of two ionization reagents, chloroform or ammonium hydroxide, to aid in ionization. During APCI in negative ion mode, chloroform produces chloride anions that are known to readily add to carbohydrates with little bias and little to no fragmentation. On the other hand, in positive ion mode APCI, ammonium hydroxide forms ammonium adducts with carbohydrates with little to no fragmentation. The latter method ionizes compounds that are not readily ionized upon negative ion mode APCI, such as furan derivatives. Six model compounds were studied to verify the ability of the ionization methods to ionize known pyrolysis products: glycolaldehyde, hydroxyacetone, furfural, 5-hydroxymethylfurfural, levoglucosan, and cellobiosan. The method was then used to examine fast pyrolysis of cellobiose. The primary fast pyrolysis products were determined to consist of only a handful of compounds that quickly polymerize to form anhydro-oligosaccharides when allowed to react at high temperatures for an extended period of time.

An implantable neural sensing microsystem with fiber-optic data transmission and power delivery.

We have developed a prototype cortical neural sensing microsystem for brain implantable neuroengineering applications. Its key feature is that both the transmission of broadband, multichannel neural data and power required for the embedded microelectronics are provided by optical fiber access. The fiber-optic system is aimed at enabling neural recording from rodents and primates by converting cortical signals to a digital stream of infrared light pulses. In the full microsystem whose performance is summarized in this paper, an analog-to-digital converter and a low power digital controller IC have been integrated with a low threshold, semiconductor laser to extract the digitized neural signals optically from the implantable unit. The microsystem also acquires electrical power and synchronization clocks via optical fibers from an external laser by using a highly efficient photovoltaic cell on board. The implantable unit employs a flexible polymer substrate to integrate analog and digital microelectronics and on-chip optoelectronic components, while adapting to the anatomical and physiological constraints of the environment. A low power analog CMOS chip, which includes preamplifier and multiplexing circuitry, is directly flip-chip bonded to the microelectrode array to form the cortical neurosensor device.

Demographics of the Population Experiencing Homelessness and Receiving Publicly Funded Substance Use and Mental Health Treatment Services in Delaware.

Objective: To determine the prevalence of clients experiencing homelessness in publicly funded substance use and mental health services in Delaware and uncover basic patterns in the demographics and service access of said clients. Methods: We analyzed Consumer Reporting Form data for clients admitted to publicly funded substance use and mental health treatment. All clients who were admitted to services from a publicly-funded provider and completed the CRF between 2019 and 2021 were included in this analysis (n=29,495). Results: 5,717 clients (19%) reported experiencing homelessness. 20% of men reported homelessness, compared to 18% of women, and 22% of Black clients reported homelessness, compared to 19% of White clients. 48% of admissions were to substance use treatment, 29% were to mental health treatment, and 23% were to treatment for both. Conclusions: Nearly one-fifth of clients who received publicly funded treatment between 2019 and 2021 reported experiencing homelessness, a vast overrepresentation when compared against the less than 1% of the population who was counted as homeless through the annual PIT count in Delaware. Policy Implications: Homelessness can be experienced across the lifespan and impacts individuals and families of all demographic makeups. Individuals are often unable to access primary care, insurance supported services, and chronic disease management teams resulting in a disproportionately high use of emergency services and departments for acute needs.

A Three-Dimensional Primary Cortical Culture System Compatible with Transgenic Disease Models, Virally Mediated Fluorescence, and Live Microscopy.

In vitro cell culture models can offer high-resolution and high-throughput experimentation of cellular behaviors. However, in vitro culture approaches often fail to fully recapitulate complex cell processes involving synergistic interactions between heterogeneous neural cell populations and the surrounding neural microenvironment. Here, we describe the formation of a three-dimensional primary cortical cell culture system compatible with live confocal microscopy.

Transient gamma events delineate somatosensory modality in S1.

Gamma band activity localized to the primary somatosensory cortex (S1) in humans and animals is implicated in the higher order neural processing of painful and tactile stimuli. However, it is unclear if gamma band activity differs between these distinct somatosensory modalities. Here, we coupled a novel behavioral approach with chronic extracellular electrophysiology to investigate differences in S1 gamma band activity elicited by noxious and innocuous hind paw stimulation in transgenic mice. Like prior studies, we found that trial-averaged gamma power in S1 increased following both noxious and innocuous stimuli. However, on individual trials, we noticed that evoked gamma band activity was not a continuous oscillatory signal but a series of transient spectral events. Upon further analysis we found that there was a significantly higher incidence of these gamma band events following noxious stimulation than innocuous stimulation. These findings suggest that somatosensory stimuli may be represented by specific features of gamma band activity at the single trial level, which may provide insight to mechanisms underlying acute pain.

Towards a Brighter Constellation: Multi-Organ Neuroimaging of Neural and Vascular Dynamics in the Spinal Cord and Brain.

Significance: Pain is comprised of a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: Here, we aimed to develop and validate new tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations were targeted to developing novel imaging hardware that addresses the many challenges of multi-site imaging. The second key set of innovations were targeted to enabling bioluminescent imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for bioluminescent imaging, and developed a novel modified miniscope optimized for these signals (BLmini). Results: Here, we describe novel 'universal' implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of bioluminescent signals in both foci, and a new miniscope, the 'BLmini,' which has reduced weight, cost and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a new coalition of methods for understanding spinal cord-brain interactions. This work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

Prefrontal network engagement by deep brain stimulation in limbic hubs.

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

Stereo-EEG-guided network modulation for psychiatric disorders: Surgical considerations.

BACKGROUND: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

A 3Din vitromodel of the device-tissue interface: functional and structural symptoms of innate neuroinflammation are mitigated by antioxidant ceria nanoparticles.

Objective.The recording instability of neural implants due to neuroinflammation at the device-tissue interface is a primary roadblock to broad adoption of brain-machine interfaces. While a multiphasic immune response, marked by glial scaring, oxidative stress (OS), and neurodegeneration, is well-characterized, the independent contributions of systemic and local 'innate' immune responses are not well-understood. We aimed to understand and mitigate the isolated the innate neuroinflammatory response to devices.Approach.Three-dimensional primary neural cultures provide a unique environment for studying the drivers of neuroinflammation by decoupling the innate and systemic immune systems, while conserving an endogenous extracellular matrix and structural and functional network complexity. We created a three-dimensionalin vitromodel of the device-tissue interface by seeding primary cortical cells around microwires. Live imaging of both dye and Adeno-Associated Virus (AAV) - mediated functional, structural, and lipid peroxidation fluorescence was employed to characterize the neuroinflammatory response.Main results.Live imaging of microtissues over time revealed independent innate neuroinflammation, marked by increased OS, decreased neuronal density, and increased functional connectivity. We demonstrated the use of this model for therapeutic screening by directly applying drugs to neural tissue, bypassing low bioavailability through thein vivoblood brain barrier. As there is growing interest in long-acting antioxidant therapies, we tested efficacy of 'perpetual' antioxidant ceria nanoparticles, which reduced OS, increased neuronal density, and protected functional connectivity.Significance.Our three-dimensionalin vitromodel of the device-tissue interface exhibited symptoms of OS-mediated innate neuroinflammation, indicating a significant local immune response to devices. The dysregulation of functional connectivity of microcircuits surround implants suggests the presence of an observer effect, in which the process of recording neural activity may fundamentally change the neural signal. Finally, the demonstration of antioxidant ceria nanoparticle treatment exhibited substantial promise as a neuroprotective and anti-inflammatory treatment strategy.

A Review of Functional Restoration From Spinal Cord Stimulation in Patients With Spinal Cord Injury.

Traumatic spinal cord injury often leads to loss of sensory, motor, and autonomic function below the level of injury. Recent advancements in spinal cord electrical stimulation (SCS) for spinal cord injury have provided potential avenues for restoration of neurologic function in affected patients. This review aims to assess the efficacy of spinal cord stimulation, both epidural (eSCS) and transcutaneous (tSCS), on the return of function in individuals with chronic spinal cord injury. The current literature on human clinical eSCS and tSCS for spinal cord injury was reviewed. Seventy-one relevant studies were included for review, specifically examining changes in volitional movement, changes in muscle activity or spasticity, or return of cardiovascular pulmonary, or genitourinary autonomic function. The total participant sample comprised of 327 patients with spinal cord injury, each evaluated using different stimulation protocols, some for sensorimotor function and others for various autonomic functions. One hundred eight of 127 patients saw improvement in sensorimotor function, 51 of 70 patients saw improvement in autonomic genitourinary function, 32 of 32 patients saw improvement in autonomic pulmonary function, and 32 of 36 patients saw improvement in autonomic cardiovascular function. Although this review highlights SCS as a promising therapeutic neuromodulatory technique to improve rehabilitation in patients with SCI, further mechanistic studies and stimulus parameter optimization are necessary before clinical translation.

Fast inference of spinal neuromodulation for motor control using amortized neural networks.

Objective.Epidural electrical stimulation (EES) has emerged as an approach to restore motor function following spinal cord injury (SCI). However, identifying optimal EES parameters presents a significant challenge due to the complex and stochastic nature of muscle control and the combinatorial explosion of possible parameter configurations. Here, we describe a machine-learning approach that leverages modern deep neural networks to learn bidirectional mappings between the space of permissible EES parameters and target motor outputs.Approach.We collected data from four sheep implanted with two 24-contact EES electrode arrays on the lumbosacral spinal cord. Muscle activity was recorded from four bilateral hindlimb electromyography (EMG) sensors. We introduce a general learning framework to identify EES parameters capable of generating desired patterns of EMG activity. Specifically, we first amortize spinal sensorimotor computations in a forward neural network model that learns to predict motor outputs based on EES parameters. Then, we employ a second neural network as an inverse model, which reuses the amortized knowledge learned by the forward model to guide the selection of EES parameters.Main results.We found that neural networks can functionally approximate spinal sensorimotor computations by accurately predicting EMG outputs based on EES parameters. The generalization capability of the forward model critically benefited our inverse model. We successfully identified novel EES parameters, in under 20 min, capable of producing desired target EMG recruitment duringin vivotesting. Furthermore, we discovered potential functional redundancies within the spinal sensorimotor networks by identifying unique EES parameters that result in similar motor outcomes. Together, these results suggest that our framework is well-suited to probe spinal circuitry and control muscle recruitment in a completely data-driven manner.Significance.We successfully identify novel EES parameters within minutes, capable of producing desired EMG recruitment. Our approach is data-driven, subject-agnostic, automated, and orders of magnitude faster than manual approaches.