An active electronic, high-density epidural paddle array for chronic spinal cord neuromodulation.

Objective: Epidural electrical stimulation (EES) has shown promise as both a clinical therapy and research tool for studying nervous system function. However, available clinical EES paddles are limited to using a small number of contacts due to the burden of wires necessary to connect each contact to the therapeutic delivery device, limiting the treatment area or density of epidural electrode arrays. We aimed to eliminate this burden using advanced on-paddle electronics. Approach: We developed a smart EES paddle with a 60-electrode programmable array, addressable using an active electronic multiplexer embedded within the electrode paddle body. The electronics are sealed in novel, ultra-low profile hermetic packaging. We conducted extensive reliability testing on the novel array, including a battery of ISO 10993-1 biocompatibility tests and determination of the hermetic package leak rate. We then evaluated the EES device in vivo, placed on the epidural surface of the ovine lumbosacral spinal cord for 15 months. Main results: The active paddle array performed nominally when implanted in sheep for over 15 months and no device-related malfunctions were observed. The onboard multiplexer enabled bespoke electrode arrangements across, and within, experimental sessions. We identified stereotyped responses to stimulation in lower extremity musculature, and examined local field potential responses to EES using high-density recording bipoles. Finally, spatial electrode encoding enabled machine learning models to accurately perform EES parameter inference for unseen stimulation electrodes, reducing the need for extensive training data in future deep models. Significance: We report the development and chronic large animal in vivo evaluation of a high-density EES paddle array containing active electronics. Our results provide a foundation for more advanced computation and processing to be integrated directly into devices implanted at the neural interface, opening new avenues for the study of nervous system function and new therapies to treat neural injury and dysfunction.

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.

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.

Intraoperative Monitoring of Spinal Cord Perfusion using Ultrasound in an Ovine Model.

Ultrasound imaging can be used to visualize the spinal cord and assess localized cord perfusion. We present in vivo data in an ovine model undergoing spinal cord stimulation and propose development of transcutaneous US imaging as a potential non-invasive imaging modality in spinal cord injury.Clinical Relevance- Ultrasound imaging can be used to aid in prognosis and diagnosis by providing qualitative and quantitative characterization of the spinal cord. This modality can be developed as a low cost, portable, and non-invasive imaging technique in spinal injury patients.

Uncovering biomarkers during therapeutic neuromodulation with PARRM: Period-based Artifact Reconstruction and Removal Method.

Advances in therapeutic neuromodulation devices have enabled concurrent stimulation and electrophysiology in the central nervous system. However, stimulation artifacts often obscure the sensed underlying neural activity. Here, we develop a method, termed Period-based Artifact Reconstruction and Removal Method (PARRM), to remove stimulation artifacts from neural recordings by leveraging the exact period of stimulation to construct and subtract a high-fidelity template of the artifact. Benchtop saline experiments, computational simulations, five unique in vivo paradigms across animal and human studies, and an obscured movement biomarker are used for validation. Performance is found to exceed that of state-of-the-art filters in recovering complex signals without introducing contamination. PARRM has several advantages: (1) it is superior in signal recovery; (2) it is easily adaptable to several neurostimulation paradigms; and (3) it has low complexity for future on-device implementation. Real-time artifact removal via PARRM will enable unbiased exploration and detection of neural biomarkers to enhance efficacy of closed-loop therapies.

Organic Electronics for Artificial Touch.

Artificial restoration of touch is an active area of research in neuroprosthetics. However, most approaches do not consider emulating the biological machinery they intend to replace. Recently, Kim et al. proposed a bioinspired artificial touch transducer that closely mimics the behavior of natural sensory afferents.

Delivering the Sense of Touch to the Human Brain.

Intracortical somatosensory interfaces have now entered the clinical domain. Darie et al. explore the implications of research published in Science Translational Medicine by Flesher et al. (2016), discuss how to design such a system given current technology, and question how to effectively communicate with users about their experience.