Accelerating neurotechnology development using an Agile methodology.

Novel bioelectronic medical devices that target neural control of visceral organs (e.g., liver, gut, spleen) or inflammatory reflex pathways are innovative class III medical devices like implantable cardiac pacemakers that are lifesaving and life-sustaining medical devices. Bringing innovative neurotechnologies early into the market and the hands of treatment providers would benefit a large population of patients inflicted with autonomic and chronic immune disorders. Medical device manufacturers and software developers widely use the Waterfall methodology to implement design controls through verification and validation. In the Waterfall methodology, after identifying user needs, a functional unit is fabricated following the verification loop (design, build, and verify) and then validated against user needs. Considerable time can lapse in building, verifying, and validating the product because this methodology has limitations for adjusting to unanticipated changes. The time lost in device development can cause significant delays in final production, increase costs, and may even result in the abandonment of the device development. Software developers have successfully implemented an Agile methodology that overcomes these limitations in developing medical software. However, Agile methodology is not routinely used to develop medical devices with implantable hardware because of the increased regulatory burden of the need to conduct animal and human studies. Here, we provide the pros and cons of the Waterfall methodology and make a case for adopting the Agile methodology in developing medical devices with physical components. We utilize a peripheral nerve interface as an example device to illustrate the use of the Agile approach to develop neurotechnologies.

Co-activation of the diaphragm and external intercostal muscles through an adaptive closed-loop respiratory pacing controller.

Introduction: Respiratory pacing is a promising alternative to traditional mechanical ventilation that has been shown to significantly increase the survival and quality of life after the neural control of the respiratory system has been compromised. However, current pacing approaches to achieve adequate ventilation tend to target only the diaphragm without pacing external intercostal muscles that are also activated during normal inspiration. Furthermore, the pacing paradigms do not allow for intermittent sighing, which carries an important physiological role. We hypothesized that simultaneous activation of the diaphragm and external intercostal muscles would improve the efficiency of respiratory pacing compared to diaphragm stimulation alone. Materials and Methods: We expanded an adaptive, closed-loop diaphragm pacing paradigm we had previously developed to include external intercostal muscle activation and sigh generation. We then investigated, using a rodent model for respiratory pacing, if simultaneous activation would delay the fatigability of the diaphragm during pacing and allow induction of appropriate sigh-like behavior in spontaneously breathing un-injured anesthetized rats (n = 8) with pacing electrodes implanted bilaterally in the diaphragm and external intercostal muscles, between 2nd and 3rd intercostal spaces. Results: With this novel pacing system, we show that fatigability of the diaphragm was lower when using combined muscle stimulation than diaphragm stimulation alone (p = 0.014) and that combined muscle stimulation was able to induce sighs with significantly higher tidal volumes compared to diaphragm stimulation alone (p = 0.014). Conclusion: Our findings demonstrate that simultaneous activation of the inspiratory muscles could be used as a suitable strategy to delay stimulation-induced diaphragmatic fatigue and to induce a sigh-like behavior that could improve respiratory health.

Engaging biological oscillators through second messenger pathways permits emergence of a robust gastric slow-wave during peristalsis.

Peristalsis, the coordinated contraction-relaxation of the muscles of the stomach is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICC) and smooth muscle (SM) cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. Understanding of the integrative role of neurotransmission and intercellular coupling in the propagation of an entrained gastric slow-wave, important for understanding motility disorders, however, remains incomplete. Using a computational framework constituted of a novel gastric motility network (GMN) model we address the hypothesis that engaging biological oscillators (i.e., ICCs) by constitutive gap junction coupling mechanisms and enteric neural innervation activated signals can confer a robust entrained gastric slow-wave. We demonstrate that while a decreasing enteric neural innervation gradient that modulates the intracellular IP3 concentration in the ICCs can guide the aboral slow-wave propagation essential for peristalsis, engaging ICCs by recruiting the exchange of second messengers (inositol trisphosphate (IP3) and Ca2+) ensures a robust entrained longitudinal slow-wave, even in the presence of biological variability in electrical coupling strengths. Our GMN with the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostrocaudal enteric neural innervation gradient allows gastric slow waves to oscillate with a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. Overall, the findings provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach, offer directions for future experiments and theoretical work, and can potentially aid in the design of new interventional pharmacological and neuromodulation device treatments for addressing gastric motility disorders.

Autonomous control of ventilation through closed-loop adaptive respiratory pacing.

Mechanical ventilation is the standard treatment when volitional breathing is insufficient, but drawbacks include muscle atrophy, alveolar damage, and reduced mobility. Respiratory pacing is an alternative approach using electrical stimulation-induced diaphragm contraction to ventilate the lung. Oxygenation and acid-base homeostasis are maintained by matching ventilation to metabolic needs; however, current pacing technology requires manual tuning and does not respond to dynamic user-specific metabolic demand, thus requiring re-tuning of stimulation parameters as physiological changes occur. Here, we describe respiratory pacing using a closed-loop adaptive controller that can self-adjust in real-time to meet metabolic needs. The controller uses an adaptive Pattern Generator Pattern Shaper (PG/PS) architecture that autonomously generates a desired ventilatory pattern in response to dynamic changes in arterial CO2 levels and, based on a learning algorithm, modulates stimulation intensity and respiratory cycle duration to evoke this ventilatory pattern. In vivo experiments in rats with respiratory depression and in those with a paralyzed hemidiaphragm confirmed that the controller can adapt and control ventilation to ameliorate hypoventilation and restore normocapnia regardless of the cause of respiratory dysfunction. This novel closed-loop bioelectronic controller advances the state-of-art in respiratory pacing by demonstrating the ability to automatically personalize stimulation patterns and adapt to achieve adequate ventilation.

Utilizing prosthetic technology to improve quality of life: an interview with Ranu Jung and James Abbas.

In this interview, we spoke with Ranu and James at SfN Neuroscience (19-23 October 2019, Chicago, IL, USA) to discover more about their collaboration on a clinical trial aiming to improve the lives of American veterans and service members who have lost limbs. The clinical trial involves the adaptive neural systems neural-enabled prosthetic hand system [1,2].

Restoring Ventilatory Control Using an Adaptive Bioelectronic System.

Ventilatory pacing by electrical stimulation of the phrenic nerve or of the diaphragm has been shown to enhance quality of life compared to mechanical ventilation. However, commercially available ventilatory pacing devices require initial manual specification of stimulation parameters and frequent adjustment to achieve and maintain suitable ventilation over long periods of time. Here, we have developed an adaptive, closed-loop, neuromorphic, pattern-shaping controller capable of automatically determining a suitable stimulation pattern and adapting it to maintain a desired breath-volume profile on a breath-by-breath basis. The system adapts the pattern of stimulation parameters based on the error between the measured volume sampled every 40 ms and a desired breath volume profile. In vivo studies in anesthetized male Sprague-Dawley rats without and with spinal cord injury by spinal hemisection at C2 indicated that the controller was capable of automatically adapting stimulation parameters to attain a desired volume profile. Despite diaphragm hemiparesis, the controller was able to achieve a desired volume in the injured animals that did not differ from the tidal volume observed before injury (p = 0.39). Closed-loop adaptive pacing partially mitigated hypoventilation as indicated by reduction of end-tidal CO2 values during pacing. The closed-loop controller was developed and parametrized in a computational testbed before in vivo assessment. This bioelectronic technology could serve as an individualized and autonomous respiratory pacing approach for support or recovery from ventilatory deficiency.

Effects of vibrotactile feedback and grasp interface compliance on perception and control of a sensorized myoelectric hand.

Current myoelectric prosthetic limbs are limited in their ability to provide direct sensory feedback to users, which increases attentional demands and reliance on visual cues. Vibrotactile sensory substitution (VSS), which can be used to provide sensory feedback in a non-invasive manner has demonstrated some improvement in myoelectric hand control. In this work, we developed and tested two VSS configurations: one with a single burst-rate modulated actuator and another with a spatially distributed array of five coin tactors. We performed a direct comparative assessment of these two VSS configurations with able-bodied subjects to investigate sensory perception, myoelectric control of grasp force and hand aperture with a prosthesis, and the effects of interface compliance. Six subjects completed a sensory perception experiment under a stimulation only paradigm; sixteen subjects completed experiments to compare VSS performance on perception and graded myoelectric control during grasp force and hand aperture tasks; and ten subjects completed experiments to investigate the effect of mechanical compliance of the myoelectric hand on the ability to control grasp force. Results indicated that sensory perception of vibrotactile feedback was not different for the two VSS configurations in the absence of active myoelectric control, but it was better with feedback from the coin tactor array than with the single actuator during myoelectric control of grasp force. Graded myoelectric control of grasp force and hand aperture was better with feedback from the coin tactor array than with the single actuator, and myoelectric control of grasp force was improved with a compliant grasp interface. Further investigations with VSS should focus on the use of coin tactor arrays by subjects with amputation in real-world settings and on improving control of grasp force by increasing the mechanical compliance of the hand.

Bionic intrafascicular interfaces for recording and stimulating peripheral nerve fibers.

The network of peripheral nerves presents extraordinary potential for modulating and/or monitoring the functioning of internal organs or the brain. The degree to which these pathways can be used to influence or observe neural activity patterns will depend greatly on the quality and specificity of the bionic interface. The anatomical organization, which consists of multiple nerve fibers clustered into fascicles within a nerve bundle, presents opportunities and challenges that may necessitate insertion of electrodes into individual fascicles to achieve the specificity that may be required for many clinical applications. This manuscript reviews the current state-of-the-art in bionic intrafascicular interfaces, presents specific concerns for stimulation and recording, describes key implementation considerations and discusses challenges for future designs of bionic intrafascicular interfaces.

An IC-based controllable stimulator for respiratory muscle stimulation investigations.

Functional Electrical Stimulation can be used to restore motor functions loss consecutive to spinal cord injury, such as respiratory deficiency due to paralysis of ventilatory muscles. This paper presents a fully configurable IC-centered stimulator designed to investigate muscle stimulation paradigms. It provides 8 current stimulation channels with high-voltage compliance and real-time operation capabilities, to enable a wide range of FES applications. The stimulator can be used in a standalone mode, or within a closed-loop setup. Primary in vivo results show successful drive of respiratory muscles stimulation using a computer-based dedicated controller.

Use of Mueller matrix polarimetry and optical coherence tomography in the characterization of cervical collagen anisotropy.

Preterm birth (PTB) presents a serious medical health concern throughout the world. There is a high incidence of PTB in both developed and developing countries ranging from 11% to 15%, respectively. Recent research has shown that cervical collagen orientation and distribution changes during pregnancy may be useful in predicting PTB. Polarization imaging is an effective means to measure optical anisotropy in birefringent materials, such as the cervix's extracellular matrix. Noninvasive, full-field Mueller matrix polarimetry (MMP) imaging methodologies, and optical coherence tomography (OCT) imaging were used to assess cervical collagen content and structure in nonpregnant porcine cervices. We demonstrate that the highly ordered structure of the nonpregnant porcine cervix can be observed with MMP. Furthermore, when utilized ex vivo, OCT and MMP yield very similar results with a mean error of 3.46% between the two modalities.

Rehabilitation research at the National Institutes of Health moving the field forward (executive summary).

Approximately 53 million Americans live with a disability. For decades, the National Institutes of Health (NIH) has been conducting and supporting research to discover new ways to minimize disability and enhance the quality of life of people with disabilities. After the passage of the Americans With Disabilities Act, NIH established the National Center for Medical Rehabilitation Research, with the goal of developing and implementing a rehabilitation research agenda. Currently, 17 institutes and centers at NIH invest more than $500 million per year in rehabilitation research. Recently, the director of NIH, Francis Collins, appointed a Blue Ribbon Panel to evaluate the status of rehabilitation research across institutes and centers. As a follow-up to the work of that panel, NIH recently organized a conference, "Rehabilitation Research at NIH: Moving the Field Forward." This report is a summary of the discussions and proposals that will help guide rehabilitation research at NIH in the near future. (PsycINFO Database Record

Rehabilitation Research at the National Institutes of Health:: Moving the Field Forward (Executive Summary).

Approximately 53 million Americans live with a disability. For decades, the National Institutes of Health (NIH) has been conducting and supporting research to discover new ways to minimize disability and enhance the quality of life of people with disabilities. After the passage of the American With Disabilities Act, the NIH established the National Center for Medical Rehabilitation Research with the goal of developing and implementing a rehabilitation research agenda. Currently, a total of 17 institutes and centers at NIH invest more than $500 million per year in rehabilitation research. Recently, the director of NIH, Dr Francis Collins, appointed a Blue Ribbon Panel to evaluate the status of rehabilitation research across institutes and centers. As a follow-up to the work of that panel, NIH recently organized a conference under the title "Rehabilitation Research at NIH: Moving the Field Forward." This report is a summary of the discussions and proposals that will help guide rehabilitation research at NIH in the near future.This article is being published almost simultaneously in the following six journals: American Journal of Occupational Therapy, American Journal of Physical Medicine and Rehabilitation, Archives of Physical Medicine and Rehabilitation, Neurorehabilitation and Neural Repair, Physical Therapy, and Rehabilitation Psychology. Citation information is as follows: Frontera WR, Bean JF, Damiano D, et al. Am J Phys Med Rehabil. 2017;97(4):393-403.

Rehabilitation Research at the National Institutes of Health: Moving the Field Forward (Executive Summary).

Approximately 53 million Americans live with a disability. For decades, the National Institutes of Health (NIH) has been conducting and supporting research to discover new ways to minimize disability and enhance the quality of life of people with disabilities. After the passage of the Americans With Disabilities Act, NIH established the National Center for Medical Rehabilitation Research, with the goal of developing and implementing a rehabilitation research agenda. Currently, 17 institutes and centers at NIH invest more than $500 million per year in rehabilitation research. Recently, the director of NIH, Francis Collins, appointed a Blue Ribbon Panel to evaluate the status of rehabilitation research across institutes and centers. As a follow-up to the work of that panel, NIH recently organized a conference, "Rehabilitation Research at NIH: Moving the Field Forward." This report is a summary of the discussions and proposals that will help guide rehabilitation research at NIH in the near future.

Bio-Inspired Controller on an FPGA Applied to Closed-Loop Diaphragmatic Stimulation.

Cervical spinal cord injury can disrupt connections between the brain respiratory network and the respiratory muscles which can lead to partial or complete loss of ventilatory control and require ventilatory assistance. Unlike current open-loop technology, a closed-loop diaphragmatic pacing system could overcome the drawbacks of manual titration as well as respond to changing ventilation requirements. We present an original bio-inspired assistive technology for real-time ventilation assistance, implemented in a digital configurable Field Programmable Gate Array (FPGA). The bio-inspired controller, which is a spiking neural network (SNN) inspired by the medullary respiratory network, is as robust as a classic controller while having a flexible, low-power and low-cost hardware design. The system was simulated in MATLAB with FPGA-specific constraints and tested with a computational model of rat breathing; the model reproduced experimentally collected respiratory data in eupneic animals. The open-loop version of the bio-inspired controller was implemented on the FPGA. Electrical test bench characterizations confirmed the system functionality. Open and closed-loop paradigm simulations were simulated to test the FPGA system real-time behavior using the rat computational model. The closed-loop system monitors breathing and changes in respiratory demands to drive diaphragmatic stimulation. The simulated results inform future acute animal experiments and constitute the first step toward the development of a neuromorphic, adaptive, compact, low-power, implantable device. The bio-inspired hardware design optimizes the FPGA resource and time costs while harnessing the computational power of spike-based neuromorphic hardware. Its real-time feature makes it suitable for in vivo applications.

Effects of spinal cord injury-induced changes in muscle activation on foot drag in a computational rat ankle model.

Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI.