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.

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.

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.

Epidural electrical stimulation of the cervical dorsal roots restores voluntary upper limb control in paralyzed monkeys.

Regaining arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control has limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury, using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts targeting specific spinal segments produced sustained arm movements, enabling monkeys with arm paralysis to perform an unconstrained reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that residual descending inputs were necessary to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Recruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord.

Epidural electrical stimulation (EES) of lumbosacral sensorimotor circuits improves leg motor control in animals and humans with spinal cord injury (SCI). Upper-limb motor control involves similar circuits, located in the cervical spinal cord, suggesting that EES could also improve arm and hand movements after quadriplegia. However, the ability of cervical EES to selectively modulate specific upper-limb motor nuclei remains unclear. Here, we combined a computational model of the cervical spinal cord with experiments in macaque monkeys to explore the mechanisms of upper-limb motoneuron recruitment with EES and characterize the selectivity of cervical interfaces. We show that lateral electrodes produce a segmental recruitment of arm motoneurons mediated by the direct activation of sensory afferents, and that muscle responses to EES are modulated during movement. Intraoperative recordings suggested similar properties in humans at rest. These modelling and experimental results can be applied for the development of neurotechnologies designed for the improvement of arm and hand control in humans with quadriplegia.

Biophysics of Temporal Interference Stimulation.

Temporal interference (TI) is a non-invasive neurostimulation technique that utilizes high-frequency external electric fields to stimulate deep neuronal structures without affecting superficial, off-target structures. TI represents a potential breakthrough for treating conditions, such as Parkinson's disease and chronic pain. However, early clinical work on TI stimulation was met with mixed outcomes challenging its fundamental mechanisms and applications. Here, we apply established physics to study the mechanisms of TI with the goal of optimizing it for clinical use. We argue that TI stimulation cannot work via passive membrane filtering, as previously hypothesized. Instead, TI stimulation requires an ion-channel mediated signal rectification process. Unfortunately, this mechanism is also responsible for high-frequency conduction block in off-target tissues, thus challenging clinical applications of TI. In consequence, we propose a set of experimental controls that should be performed in future experiments to refine our understanding and practice of TI stimulation. A record of this paper's transparent peer review process is included in the Supplemental Information.

Spatiotemporal Maps of Proprioceptive Inputs to the Cervical Spinal Cord During Three-Dimensional Reaching and Grasping.

Proprioceptive feedback is a critical component of voluntary movement planning and execution. Neuroprosthetic technologies aiming at restoring movement must interact with it to restore accurate motor control. Optimization and design of such technologies depends on the availability of quantitative insights into the neural dynamics of proprioceptive afferents during functional movements. However, recording proprioceptive neural activity during unconstrained movements in clinically relevant animal models presents formidable challenges. In this work, we developed a computational framework to estimate the spatiotemporal patterns of proprioceptive inputs to the cervical spinal cord during three-dimensional arm movements in monkeys. We extended a biomechanical model of the monkey arm with ex-vivo measurements, and combined it with models of mammalian group-Ia, Ib and II afferent fibers. We then used experimental recordings of arm kinematics and muscle activity of two monkeys performing a reaching and grasping task to estimate muscle stretches and forces with computational biomechanics. Finally, we projected the simulated proprioceptive firing rates onto the cervical spinal roots, thus obtaining spatiotemporal maps of spinal proprioceptive inputs during voluntary movements. Estimated maps show complex and markedly distinct patterns of neural activity for each of the fiber populations spanning the spinal cord rostro-caudally. Our results indicate that reproducing the proprioceptive information flow to the cervical spinal cord requires complex spatio-temporal modulation of each spinal root. Our model can support the design of neuroprosthetic technologies as well as in-silico investigations of the primate sensorimotor system.

Soft, Implantable Bioelectronic Interfaces for Translational Research.

The convergence of materials science, electronics, and biology, namely bioelectronic interfaces, leads novel and precise communication with biological tissue, particularly with the nervous system. However, the translation of lab-based innovation toward clinical use calls for further advances in materials, manufacturing and characterization paradigms, and design rules. Herein, a translational framework engineered to accelerate the deployment of microfabricated interfaces for translational research is proposed and applied to the soft neurotechnology called electronic dura mater, e-dura. Anatomy, implant function, and surgical procedure guide the system design. A high-yield, silicone-on-silicon wafer process is developed to ensure reproducible characteristics of the electrodes. A biomimetic multimodal platform that replicates surgical insertion in an anatomy-based model applies physiological movement, emulates therapeutic use of the electrodes, and enables advanced validation and rapid optimization in vitro of the implants. Functionality of scaled e-dura is confirmed in nonhuman primates, where epidural neuromodulation of the spinal cord activates selective groups of muscles in the upper limbs with unmet precision. Performance stability is controlled over 6 weeks in vivo. The synergistic steps of design, fabrication, and biomimetic in vitro validation and in vivo evaluation in translational animal models are of general applicability and answer needs in multiple bioelectronic designs and medical technologies.

Microneurography as a tool to develop decoding algorithms for peripheral neuro-controlled hand prostheses.

BACKGROUND: The usability of dexterous hand prostheses is still hampered by the lack of natural and effective control strategies. A decoding strategy based on the processing of descending efferent neural signals recorded using peripheral neural interfaces could be a solution to such limitation. Unfortunately, this choice is still restrained by the reduced knowledge of the dynamics of human efferent signals recorded from the nerves and associated to hand movements. FINDINGS: To address this issue, in this work we acquired neural efferent activities from healthy subjects performing hand-related tasks using ultrasound-guided microneurography, a minimally invasive technique, which employs needles, inserted percutaneously, to record from nerve fibers. These signals allowed us to identify neural features correlated with force and velocity of finger movements that were used to decode motor intentions. We developed computational models, which confirmed the potential translatability of these results showing how these neural features hold in absence of feedback and when implantable intrafascicular recording, rather than microneurography, is performed. CONCLUSIONS: Our results are a proof of principle that microneurography could be used as a useful tool to assist the development of more effective hand prostheses.

Selective Recruitment of Arm Motoneurons in Nonhuman Primates Using Epidural Electrical Stimulation of the Cervical Spinal Cord.

Recovery of reaching and grasping ability is the priority for people with cervical spinal cord injury (SCI). Epidural electrical stimulation (EES) has shown promising results in improving motor control after SCI in various animal models and in humans. Notably, the application of stimulation bursts with spatiotemporal sequences that reproduce the natural activation of motoneurons restored skilled leg movements in rodent and nonhuman primate models of SCI. Here, we studied whether this conceptual framework could be transferred to the design of cervical EES protocols for the recovery of reaching and grasping in nonhuman primates. We recorded muscle activity during a reaching and grasping task in a macaque monkey and found that this task involves a stereotypical spatiotemporal map of motoneuron activation. We then characterized the specificity of a spinal implant for the delivery of EES to cervical spinal segments in the same animal. Finally, we combined these results to design a simple stimulation protocol that may reproduce natural motoneuron activation and thus facilitate upper limb movements after injury.

Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model.

Long-term biointegration of man-made neural interfaces is influenced by the mechanical properties of the implant materials. Substantial experimental work currently aims at replacing conventional hard implant materials with soft alternatives that can favour a lower immune response. Here we assess the performance of a soft electrode array implanted in the spinal epidural space of a minipig model for a period of 6 months. The electrode array includes platinum-silicone electrode contacts and elastic thin-film gold interconnects embedded in silicone. textbfIn-vivo electrode impedance and voltage transients were monitored over time. Following implantation, epidural stimulation produced muscle-specific evoked potentials and visible muscle contractions. Over time, postoperative and stimulation induced changes in electrode impedance were observed. Such trends provide a basis for future technological improvements aiming at ensuring the stability of soft implantable electrodes for neural interfacing.

ART 3.5D: an algorithm to label arteries and veins from three-dimensional angiography.

Preoperative three-dimensional (3-D) visualization of brain vasculature by digital subtraction angiography from computerized tomography (CT) in neurosurgery is gaining more and more importance, since vessels are the primary landmarks both for organs at risk and for navigation. Surgical embolization of cerebral aneurysms and arteriovenous malformations, epilepsy surgery, and stereoelectroencephalography are a few examples. Contrast-enhanced cone-beam computed tomography (CE-CBCT) represents a powerful facility, since it is capable of acquiring images in the operation room, shortly before surgery. However, standard 3-D reconstructions do not provide a direct distinction between arteries and veins, which is of utmost importance and is left to the surgeon's inference so far. Pioneering attempts by true four-dimensional (4-D) CT perfusion scans were already described, though at the expense of longer acquisition protocols, higher dosages, and sensible resolution losses. Hence, space is open to approaches attempting to recover the contrast dynamics from standard CE-CBCT, on the basis of anomalies overlooked in the standard 3-D approach. This paper aims at presenting algebraic reconstruction technique (ART) 3.5D, a method that overcomes the clinical limitations of 4-D CT, from standard 3-D CE-CBCT scans. The strategy works on the 3-D angiography, previously segmented in the standard way, and reprocesses the dynamics hidden in the raw data to recover an approximate dynamics in each segmented voxel. Next, a classification algorithm labels the angiographic voxels and artery or vein. Numerical simulations were performed on a digital phantom of a simplified 3-D vasculature with contrast transit. CE-CBCT projections were simulated and used for ART 3.5D testing. We achieved up to 90% classification accuracy in simulations, proving the feasibility of the presented approach for dynamic information recovery for arteries and veins segmentation.

Redundancy optimization strategy for hands-on robotic surgery.

During hands-on cooperative surgery, the use of a redundant robot allows to address encumbrance issues in the Operating Room (OR), which can occur due to the presence of large medical instrumentation, such as the surgical microscope. This work presents a new Null Space Optimization (NSO) strategy to constraint the position of the manipulator's elbow within predefined range of motions, according to the spatial requirements of the specific procedure, also taking into account the physical joint limits of the robotic assistant. The proposed strategy was applied to the 7 degrees of freedom (dof) lightweight robot LWR4+. The performance of the NSO was compared to two state-of-the-art null space optimization strategies, i.e. damped posture and fixed optimal posture, over a pool of three non-expert users in both strict (20deg) and negligible (100deg) angular encumbrance limitations. The NSO strategy was proved versatile in providing wide elbow mobility together with safe distance from relevant continuity null space boundaries, guaranteeing smooth guidance trajectories. Future works would be performed in order to evaluate the potential feasibility of NSO in a real surgical scenario.