Engagement of the Rat Hindlimb Motor Cortex across Natural Locomotor Behaviors.

Contrary to cats and primates, cortical contribution to hindlimb locomotor movements is not critical in rats. However, the importance of the motor cortex to regain locomotion after neurological disorders in rats suggests that cortical engagement in hindlimb motor control may depend on the behavioral context. To investigate this possibility, we recorded whole-body kinematics, muscle synergies, and hindlimb motor cortex modulation in freely moving rats performing a range of natural locomotor procedures. We found that the activation of hindlimb motor cortex preceded gait initiation. During overground locomotion, the motor cortex exhibited consistent neuronal population responses that were synchronized with the spatiotemporal activation of hindlimb motoneurons. Behaviors requiring enhanced muscle activity or skilled paw placement correlated with substantial adjustment in neuronal population responses. In contrast, all rats exhibited a reduction of cortical activity during more automated behavior, such as stepping on a treadmill. Despite the facultative role of the motor cortex in the production of locomotion in rats, these results show that the encoding of hindlimb features in motor cortex dynamics is comparable in rats and cats. However, the extent of motor cortex modulations appears linked to the degree of volitional engagement and complexity of the task, reemphasizing the importance of goal-directed behaviors for motor control studies, rehabilitation, and neuroprosthetics. SIGNIFICANCE STATEMENT: We mapped the neuronal population responses in the hindlimb motor cortex to hindlimb kinematics and hindlimb muscle synergies across a spectrum of natural locomotion behaviors. Robust task-specific neuronal population responses revealed that the rat motor cortex displays similar modulation as other mammals during locomotion. However, the reduced motor cortex activity during more automated behaviors suggests a relationship between the degree of engagement and task complexity. This relationship emphasizes the importance of the behavioral procedure to engage the motor cortex during motor control studies, gait rehabilitation, and locomotor neuroprosthetic developments in rats.

Development, manufacturing and application of double-sided flexible implantable microelectrodes.

Many neuroprosthetic applications require the use of very small, flexible multi-channel microelectrodes (e.g. polyimide-based film-like electrodes) to fit anatomical constraints. By arranging the electrode contacts on both sides of the polyimide film, selectivity can be further increased without increasing size. In this work, two approaches to create such double-sided electrodes are described and compared: sandwich electrodes prepared by precisely gluing two single-sided structures together, and monolithic electrodes created using a new double-sided photolithography process. Both methods were successfully applied to manufacture double-sided electrodes for stimulation of the vestibular system. In a case study, the electrodes were implanted in the semicircular canals of three guinea pigs and proven to provide electrical stimulation of the vestibular nerve. For both the monolithic electrodes and the sandwich electrodes, long-term stability and functionality was observed over a period of more than 12 months. Comparing the two types of electrodes with respect to the manufacturing process, it can be concluded that monolithic electrodes are the preferred solution for very thin electrodes (<20 µm), while sandwich electrode technology is especially suitable for thicker electrodes (40-50 µm).

Pancreatic Cancer Action Network's SPARK: A Cloud-Based Patient Health Data and Analytics Platform for Pancreatic Cancer.

PURPOSE: Pancreatic cancer currently holds the position of third deadliest cancer in the United States and the 5-year survival rate is among the lowest for major cancers at just 12%. Thus, continued research efforts to better understand the clinical and molecular underpinnings of pancreatic cancer are critical to developing both early detection methodologies as well as improved therapeutic options. This study introduces Pancreatic Cancer Action Network's (PanCAN's) SPARK, a cloud-based data and analytics platform that integrates patient health data from the PanCAN's research initiatives and aims to accelerate pancreatic cancer research by making real-world patient health data and analysis tools easier to access and use. MATERIALS AND METHODS: The SPARK platform integrates clinical, molecular, multiomic, imaging, and patient-reported data generated from PanCAN's research initiatives. The platform is built on a cloud-based infrastructure powered by Velsera. Cohort exploration and browser capabilities are built using Velsera ARIA, a specialized product for leveraging clinicogenomic data to build cohorts, query variant information, and drive downstream association analyses. Data science and analytic capabilities are also built into the platform allowing researchers to perform simple to complex analysis. RESULTS: Version 1 of the SPARK platform was released to pilot users, who represented diverse end users, including molecular biologists, clinicians, and bioinformaticians. Included in the pilot release of SPARK are deidentified clinical (including treatment and outcomes data), molecular, multiomic, and whole-slide pathology images for over 600 patients enrolled in PanCAN's Know Your Tumor molecular profiling service. CONCLUSION: The pilot release of the SPARK platform introduces qualified researchers to PanCAN real-world patient health data and analytical resources in a centralized location.

Building a collaborative cloud platform to accelerate heart, lung, blood, and sleep research.

Research increasingly relies on interrogating large-scale data resources. The NIH National Heart, Lung, and Blood Institute developed the NHLBI BioData CatalystⓇ (BDC), a community-driven ecosystem where researchers, including bench and clinical scientists, statisticians, and algorithm developers, find, access, share, store, and compute on large-scale datasets. This ecosystem provides secure, cloud-based workspaces, user authentication and authorization, search, tools and workflows, applications, and new innovative features to address community needs, including exploratory data analysis, genomic and imaging tools, tools for reproducibility, and improved interoperability with other NIH data science platforms. BDC offers straightforward access to large-scale datasets and computational resources that support precision medicine for heart, lung, blood, and sleep conditions, leveraging separately developed and managed platforms to maximize flexibility based on researcher needs, expertise, and backgrounds. Through the NHLBI BioData Catalyst Fellows Program, BDC facilitates scientific discoveries and technological advances. BDC also facilitated accelerated research on the coronavirus disease-2019 (COVID-19) pandemic.

Alignment of angular velocity sensors for a vestibular prosthesis.

Vestibular prosthetics transmit angular velocities to the nervous system via electrical stimulation. Head-fixed gyroscopes measure angular motion, but the gyroscope coordinate system will not be coincident with the sensory organs the prosthetic replaces. Here we show a simple calibration method to align gyroscope measurements with the anatomical coordinate system. We benchmarked the method with simulated movements and obtain proof-of-concept with one healthy subject. The method was robust to misalignment, required little data, and minimal processing.

Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury.

A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.

Cancer Informatics for Cancer Centers: Scientific Drivers for Informatics, Data Science, and Care in Pediatric, Adolescent, and Young Adult Cancer.

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. This consortium has regularly held topic-focused biannual face-to-face symposiums. These meetings are a place to review cancer informatics and data science priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues that we faced at our respective institutions and cancer centers. Here, we provide meeting highlights from the latest CI4CC Symposium, which was delayed from its original April 2020 schedule because of the COVID-19 pandemic and held virtually over three days (September 24, October 1, and October 8) in the fall of 2020. In addition to the content presented, we found that holding this event virtually once a week for 6 hours was a great way to keep the kind of deep engagement that a face-to-face meeting engenders. This is the second such publication of CI4CC Symposium highlights, the first covering the meeting that took place in Napa, California, from October 14-16, 2019. We conclude with some thoughts about using data science to learn from every child with cancer, focusing on emerging activities of the National Cancer Institute's Childhood Cancer Data Initiative.

Cancer Informatics for Cancer Centers (CI4CC): Building a Community Focused on Sharing Ideas and Best Practices to Improve Cancer Care and Patient Outcomes.

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. Although each of the participating cancer centers is structured differently, and leaders' titles vary, we know firsthand there are similarities in both the issues we face and the solutions we achieve. As a consortium, we have initiated a dedicated listserv, an open-initiatives program, and targeted biannual face-to-face meetings. These meetings are a place to review our priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues we, as informatics leaders, individually face at our respective institutions and cancer centers. Here we provide a brief history of the CI4CC organization and meeting highlights from the latest CI4CC meeting that took place in Napa, California from October 14-16, 2019. The focus of this meeting was "intersections between informatics, data science, and population science." We conclude with a discussion on "hot topics" on the horizon for cancer informatics.

Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury.

The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain-spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies.

Closed-loop control of trunk posture improves locomotion through the regulation of leg proprioceptive feedback after spinal cord injury.

After spinal cord injury (SCI), sensory feedback circuits critically contribute to leg motor execution. Compelled by the importance to engage these circuits during gait rehabilitation, assistive robotics and training protocols have primarily focused on guiding leg movements to reinforce sensory feedback. Despite the importance of trunk postural dynamics on gait and balance, trunk assistance has comparatively received little attention. Typically, trunk movements are either constrained within bodyweight support systems, or manually adjusted by therapists. Here, we show that real-time control of trunk posture re-established dynamic balance amongst bilateral proprioceptive feedback circuits, and thereby restored left-right symmetry, loading and stepping consistency in rats with severe SCI. We developed a robotic system that adjusts mediolateral trunk posture during locomotion. This system uncovered robust relationships between trunk orientation and the modulation of bilateral leg kinematics and muscle activity. Computer simulations suggested that these modulations emerged from corrections in the balance between flexor- and extensor-related proprioceptive feedback. We leveraged this knowledge to engineer control policies that regulate trunk orientation and postural sway in real-time. This dynamical postural interface immediately improved stepping quality in all rats regardless of broad differences in deficits. These results emphasize the importance of trunk regulation to optimize performance during rehabilitation.

The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized-A New Paradigm in Large-Scale Computational Research.

The Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3-6. ©2017 AACR.

Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury.

Epidural electrical stimulation of lumbar segments facilitates standing and walking in animal models and humans with spinal cord injury. However, the mechanisms through which this neuromodulation therapy engages spinal circuits remain enigmatic. Using computer simulations and behavioral experiments, we provide evidence that epidural electrical stimulation interacts with muscle spindle feedback circuits to modulate muscle activity during locomotion. Hypothesis-driven strategies emerging from simulations steered the design of stimulation protocols that adjust bilateral hindlimb kinematics throughout gait execution. These stimulation strategies corrected subject-specific gait and balance deficits in rats with incomplete and complete spinal cord injury. The conservation of muscle spindle feedback circuits across mammals suggests that the same mechanisms may facilitate motor control in humans. These results provide a conceptual framework to improve stimulation protocols for clinical applications.

Neural Network Model of Vestibular Nuclei Reaction to Onset of Vestibular Prosthetic Stimulation.

The vestibular system incorporates multiple sensory pathways to provide crucial information about head and body motion. Damage to the semicircular canals, the peripheral vestibular organs that sense rotational velocities of the head, can severely degrade the ability to perform activities of daily life. Vestibular prosthetics address this problem by using stimulating electrodes that can trigger primary vestibular afferents to modulate their firing rates, thus encoding head movement. These prostheses have been demonstrated chronically in multiple animal models and acutely tested in short-duration trials within the clinic in humans. However, mainly, due to limited opportunities to fully characterize stimulation parameters, there is a lack of understanding of "optimal" stimulation configurations for humans. Here, we model possible adaptive plasticity in the vestibular pathway. Specifically, this model highlights the influence of adaptation of synaptic strengths and offsets in the vestibular nuclei to compensate for the initial activation of the prosthetic. By changing the synaptic strengths, the model is able to replicate the clinical observation that erroneous eye movements are attenuated within 30 minutes without any change to the prosthetic stimulation rate. Although our model was only built to match this time point, we further examined how it affected subsequent pulse rate modulation (PRM) and pulse amplitude modulation (PAM). PAM was more effective than PRM for nearly all stimulation configurations during these acute tests. Two non-intuitive relationships highlighted by our model explain this performance discrepancy. Specifically, the attenuation of synaptic strengths for afferents stimulated during baseline adaptation and the discontinuity between baseline and residual firing rates both disproportionally boost PAM. Comodulation of pulse rate and amplitude has been experimentally shown to induce both excitatory and inhibitory eye movements even at high baseline stimulation rates. We also modeled comodulation and found synergistic combinations of stimulation parameters to achieve equivalent output to only amplitude modulation. This may be an important strategy to reduce current spread and misalignment. The model outputs reflected observed trends in clinical testing and aspects of existing vestibular prosthetic literature. Importantly, the model provided insight to efficiently explore the stimulation parameter space, which was helpful, given limited available patient time.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury.

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

A real-time research platform to study vestibular implants with gyroscopic inputs in vestibular deficient subjects.

Researchers have succeeded in partly restoring damaged vestibular functionality in several animal models. Recently, acute interventions have also been demonstrated in human patients. Our previous work on a vestibular implant for humans used predefined stimulation patterns; here we present a research tool that facilitates motion-modulated stimulation. This requires a system that can process gyroscope measurements and send stimulation parameters to a hybrid vestibular-cochlear implant in real-time. To match natural vestibular latencies, the time from sensor input to stimulation output should not exceed 6.5 ms. We describe a system based on National Instrument's CompactRIO platform that can meet this requirement and also offers floating point precision for advanced transfer functions. It is designed for acute clinical interventions, and is sufficiently powerful and flexible to serve as a development platform for evaluating prosthetic control strategies. Amplitude and pulse frequency modulation to predetermined functions or sensor inputs have been validated. The system has been connected to human patients, who each have received a modified MED-EL cochlear implant for vestibular stimulation, and patient tests are ongoing.

Corticospinal neuroprostheses to restore locomotion after spinal cord injury.

In this conceptual review, we highlight our strategy for, and progress in the development of corticospinal neuroprostheses for restoring locomotor functions and promoting neural repair after thoracic spinal cord injury in experimental animal models. We specifically focus on recent developments in recording and stimulating neural interfaces, decoding algorithms, extraction of real-time feedback information, and closed-loop control systems. Each of these complex neurotechnologies plays a significant role for the design of corticospinal neuroprostheses. Even more challenging is the coordinated integration of such multifaceted technologies into effective and practical neuroprosthetic systems to improve movement execution, and augment neural plasticity after injury. In this review we address our progress in rodent animal models to explore the viability of a technology-intensive strategy for recovery and repair of the damaged nervous system. The technical, practical, and regulatory hurdles that lie ahead along the path toward clinical applications are enormous - and their resolution is uncertain at this stage. However, it is imperative that the discoveries and technological developments being made across the field of neuroprosthetics do not stay in the lab, but instead reach clinical fruition at the fastest pace possible.

Restoring voluntary control of locomotion after paralyzing spinal cord injury.

Half of human spinal cord injuries lead to chronic paralysis. Here, we introduce an electrochemical neuroprosthesis and a robotic postural interface designed to encourage supraspinally mediated movements in rats with paralyzing lesions. Despite the interruption of direct supraspinal pathways, the cortex regained the capacity to transform contextual information into task-specific commands to execute refined locomotion. This recovery relied on the extensive remodeling of cortical projections, including the formation of brainstem and intraspinal relays that restored qualitative control over electrochemically enabled lumbosacral circuitries. Automated treadmill-restricted training, which did not engage cortical neurons, failed to promote translesional plasticity and recovery. By encouraging active participation under functional states, our training paradigm triggered a cortex-dependent recovery that may improve function after similar injuries in humans.