Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis.

Monitoring homeostasis is an essential aspect of obtaining pathophysiological insights for treating patients. Accurate, timely assessments of homeostatic dysregulation in deep tissues typically require expensive imaging techniques or invasive biopsies. We introduce a bioresorbable shape-adaptive materials structure that enables real-time monitoring of deep-tissue homeostasis using conventional ultrasound instruments. Collections of small bioresorbable metal disks distributed within thin, pH-responsive hydrogels, deployed by surgical implantation or syringe injection, allow ultrasound-based measurements of spatiotemporal changes in pH for early assessments of anastomotic leaks after gastrointestinal surgeries, and their bioresorption after a recovery period eliminates the need for surgical extraction. Demonstrations in small and large animal models illustrate capabilities in monitoring leakage from the small intestine, the stomach, and the pancreas.

Neuromuscular consequences of spinal cord injury: New mechanistic insights and clinical considerations.

The spinal cord facilitates communication between the brain and the body, containing intrinsic systems that work with lower motor neurons (LMNs) to manage movement. Spinal cord injuries (SCIs) can lead to partial paralysis and dysfunctions in muscles below the injury. While traditionally this paralysis has been attributed to disruptions in the corticospinal tract, a growing body of work demonstrates LMN damage is a factor. Motor units, comprising the LMN and the muscle fibers with which they connect, are essential for voluntary movement. Our understanding of their changes post-SCI is still emerging, but the health of motor units is vital, especially when considering innovative SCI treatments like nerve transfer surgery. This review seeks to collate current literature on how SCI impact motor units and explore neuromuscular clinical implications and treatment avenues. SCI reduced motor unit number estimates, and surviving motor units had impaired signal transmission at the neuromuscular junction, force-generating capacity, and excitability, which have the potential to recover chronically, yet the underlaying mechanisms are unclear. Furthermore, electrodiagnostic evaluations can aid in assessing the health lower and upper motor neurons, identify suitable targets for nerve transfer surgeries, and detect patients with time sensitive injuries. Lastly, many electrodiagnostic abnormalities occur in both chronic and acute SCI, yet factors contributing to these abnormalities are unknown. Future studies are required to determine how motor units adapt following SCI and the clinical implications of these adaptations.

Segmental infralesional pathological spontaneous activity in subacute traumatic spinal cord injury.

INTRODUCTION/AIMS: There is a dearth of knowledge regarding the status of infralesional lower motor neurons (LMNs) in individuals with traumatic cervical spinal cord injury (SCI), yet there is a growing need to understand how the spinal lesion impacts LMNs caudal to the lesion epicenter, especially in the context of nerve transfer surgery to restore several key upper limb functions. Our objective was to determine the frequency of pathological spontaneous activity (PSA) at, and below, the level of spinal injury, to gain an understanding of LMN health below the spinal lesion. METHODS: Ninety-one limbs in 57 individuals (53 males, mean age = 44.4 ± 16.9 years, mean duration from injury = 3.4 ± 1.4 months, 32 with motor complete injuries), were analyzed. Analysis was stratified by injury level as (1) C4 and above, (2) C5, and (3) C6-7. Needle electromyography was performed on representative muscles innervated by the C5-6, C6-7, C7-8, and C8-T1 nerve roots. PSA was dichotomized as present or absent. Data were pooled for the most caudal infralesional segment (C8-T1). RESULTS: A high frequency of PSA was seen in all infralesional segments. The pooled frequency of PSA for all injury levels at C8-T1 was 68.7% of the limbs tested. There was also evidence of PSA at the rostral border of the neurological level of injury, with 58.3% of C5-6 muscles in those with C5-level injuries. DISCUSSION: These data support a high prevalence of infralesional LMN abnormalities following SCI, which has implications to nerve transfer candidacy, timing of the intervention, and donor nerve options.

Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity.

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.NEW & NOTEWORTHY Our results showed that cancer survivors after oxaliplatin (OX) treatment exhibited stretch reflexes that were comparable with age-matched healthy individuals in the proximal upper limb. The lack of OX effect might be linked to differences between the clinical and preclinical testing paradigms. These findings refine our expectations derived from the preclinical study and guide future assessments of OX effects that may have been insensitive to our measurement techniques.

Postoperative risk of IDH-mutant glioma-associated seizures and their potential management with IDH-mutant inhibitors.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Self-powered, light-controlled, bioresorbable platforms for programmed drug delivery.

Degradable polymer matrices and porous scaffolds provide powerful mechanisms for passive, sustained release of drugs relevant to the treatment of a broad range of diseases and conditions. Growing interest is in active control of pharmacokinetics tailored to the needs of the patient via programmable engineering platforms that include power sources, delivery mechanisms, communication hardware, and associated electronics, most typically in forms that require surgical extraction after a period of use. Here we report a light-controlled, self-powered technology that bypasses key disadvantages of these systems, in an overall design that is bioresorbable. Programmability relies on the use of an external light source to illuminate an implanted, wavelength-sensitive phototransistor to trigger a short circuit in an electrochemical cell structure that includes a metal gate valve as its anode. Consequent electrochemical corrosion eliminates the gate, thereby opening an underlying reservoir to release a dose of drugs by passive diffusion into surrounding tissue. A wavelength-division multiplexing strategy allows release to be programmed from any one or any arbitrary combination of a collection of reservoirs built into an integrated device. Studies of various bioresorbable electrode materials define the key considerations and guide optimized choices in designs. In vivo demonstrations of programmed release of lidocaine adjacent the sciatic nerves in rat models illustrate the functionality in the context of pain management, an essential aspect of patient care that could benefit from the results presented here.

The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor.

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

The effects of COVID-19 on respiratory muscle performance: making the case for respiratory muscle testing and training.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in multiorgan damage primarily mediated by viral infiltration via angiotensin-converting enzyme-2 receptors on the surface of cells. A primary symptom for many patients is exertional dyspnoea which may persist even beyond recovery from the viral infection. Respiratory muscle (RM) performance was hypothesised as a contributing factor to the severity of coronavirus disease 2019 (COVID-19) symptoms, such as dyspnoea, and outcomes. This was attributed to similarities between patient populations at elevated risk for severe COVID-19 symptoms and those with a greater likelihood of baseline RM weakness and the effects of prolonged mechanical ventilation. More recent evidence suggests that SARS-CoV-2 infection itself may cause damage to the RM, and many patients who have recovered report persistent dyspnoea despite having mild cases, normal lung function or undamaged lung parenchyma. These more recent findings suggest that the role of RM in the persistent dyspnoea due to COVID-19 may be more substantial than originally hypothesised. Therefore, screening for RM weakness and providing interventions to improve RM performance appears to be important for patients with COVID-19. This article will review the impact of SARS-CoV-2 infection on RM performance and provide clinical recommendations for screening RM performance and treatment interventions.

Clinical electrodiagnostic evaluation for nerve transfer surgery in spinal cord injury: a new indication and clinical pearls.

In this review, we highlight the important role of the clinical electrodiagnostic (EDX) evaluation after cervical spinal cord injury (SCI). Our discussion focuses on the need for timely, frequent, and accurate EDX evaluations in the context of nerve transfer surgery to restore critical upper limb functions, including elbow extension, hand opening, and hand closing. The EDX evaluation is crucial to define the extent of lower motor neuron lesions and determine candidacy for surgery. We also discuss the important role of the postoperative EDX evaluation in determining prognosis and supporting rehabilitation. We propose a practical framework for EDX evaluation in this clinical setting.

Ultrasound-guided glenohumeral joint injections for shoulder pain in ALS: A case series.

Introduction: Shoulder pain is a common secondary impairment for people living with ALS (PALS). Decreased range of motion (ROM) from weakness can lead to shoulder pathology, which can result in debilitating pain. Shoulder pain may limit PALS from participating in activities of daily living and may have a negative impact on their quality of life. This case series explores the efficacy of glenohumeral joint injections for the management of shoulder pain due to adhesive capsulitis in PALS. Methods: People living with ALS and shoulder pain were referred to sports medicine-certified physiatrists for diagnostic evaluation and management. They completed the Revised ALS Functional Rating Scale and a questionnaire asking about their pain levels and how it impacts sleep, function, and quality of life at baseline pre-injection, 1-week post-injection, 1 month post-injection, and 3 months post-injection. Results: We present five cases of PALS who were diagnosed with adhesive capsulitis and underwent glenohumeral joint injections. Though only one PALS reported complete symptom resolution, all had at least partial symptomatic improvement during the observation period. No complications were observed. Conclusions: People living with ALS require a comprehensive plan to manage shoulder pain. Glenohumeral joint injections are safe and effective for adhesive capsulitis in PALS, but alone may not completely resolve shoulder pain. Additional therapies to improve ROM and reduce pain should be considered.

Diaphragm and Phrenic Nerve Ultrasound in COVID-19 Patients and Beyond: Imaging Technique, Findings, and Clinical Applications.

The diaphragm, the principle muscle of inspiration, is an under-recognized contributor to respiratory disease. Dysfunction of the diaphragm can occur secondary to lung disease, prolonged ventilation, phrenic nerve injury, neuromuscular disease, and central nervous system pathology. In light of the global pandemic of coronavirus disease 2019 (COVID-19), there has been growing interest in the utility of ultrasound for evaluation of respiratory symptoms including lung and diaphragm sonography. Diaphragm ultrasound can be utilized to diagnose diaphragm dysfunction, assess severity of dysfunction, and monitor disease progression. This article reviews diaphragm and phrenic nerve ultrasound and describes clinical applications in the context of COVID-19.

Biofidelic dynamic compression of human cortical spheroids reproduces neurotrauma phenotypes.

Fundamental questions about patient heterogeneity and human-specific pathophysiology currently obstruct progress towards a therapy for traumatic brain injury (TBI). Human in vitro models have the potential to address these questions. Three-dimensional spheroidal cell culture protocols for human-origin neural cells have several important advantages over their two-dimensional monolayer counterparts. Three-dimensional spheroidal cultures may mature more quickly, develop more biofidelic electrophysiological activity and/or reproduce some aspects of brain architecture. Here, we present the first human in vitro model of non-penetrating TBI employing three-dimensional spheroidal cultures. We used a custom-built device to traumatize these spheroids in a quantifiable, repeatable and biofidelic manner, and correlated the heterogeneous mechanical strain field with the injury phenotype. Trauma reduced cell viability, mitochondrial membrane potential and spontaneous synchronous electrophysiological activity in the spheroids. Electrophysiological deficits emerged at lower injury severities than changes in cell viability. Also, traumatized spheroids secreted lactate dehydrogenase, a marker of cell damage, and neurofilament light chain, a promising clinical biomarker of neurotrauma. These results demonstrate that three-dimensional human in vitro models can reproduce important phenotypes of neurotrauma in vitro.

Implantation and Control of Wireless, Battery-free Systems for Peripheral Nerve Interfacing.

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

Diaphragm dysfunction in severe COVID-19 as determined by neuromuscular ultrasound.

Many survivors from severe coronavirus disease 2019 (COVID-19) suffer from persistent dyspnea and fatigue long after resolution of the active infection. In a cohort of 21 consecutive severe post-COVID-19 survivors admitted to an inpatient rehabilitation hospital, 16 (76%) of them had at least one sonographic abnormality of diaphragm muscle structure or function. This corresponded to a significant reduction in diaphragm muscle contractility as represented by thickening ratio (muscle thickness at maximal inspiration/end-expiration) for the post-COVID-19 compared to non-COVID-19 cohorts. These findings may shed new light on neuromuscular respiratory dysfunction as a contributor to prolonged functional impairments after hospitalization for post-COVID-19.

The accuracy of needle electrode placement by trainees in selected forearm muscles using verification by neuromuscular ultrasound.

INTRODUCTION: Anatomic landmarks alone may not always be sufficient to accurately guide electromyography (EMG) electrode needle placement. METHODS: Senior residents and fellows (n = 11) targeted 4 forearm muscles with anatomic landmarks alone versus with audiovisual EMG feedback. Accuracy of EMG needle placement was verified using neuromuscular ultrasound imaging. RESULTS: While relatively large and superficial FCR muscle was sampled at a rate of 100% with and without audiovisual EMG feedback, accuracy of deeper and/or smaller forearm muscles (FPL, EIP, and SUP) diminished significantly without audiovisual EMG feedback. DISCUSSION: Our study suggests that in clinical scenarios in which an electrodiagnostician relies on anatomic landmarks alone to target small and deep muscles, the risk of misplacement of needle electrode is increased. Consideration for neuromuscular ultrasound to augment training and/or real time guidance in EMG practice may be appropriate.

Three-dimensional, multifunctional neural interfaces for cortical spheroids and engineered assembloids.

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms.

Musculoskeletal involvement of COVID-19: review of imaging.

The global pandemic of coronavirus disease 2019 (COVID-19) has revealed a surprising number of extra-pulmonary manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While myalgia is a common clinical feature of COVID-19, other musculoskeletal manifestations of COVID-19 were infrequently described early during the pandemic. There have been emerging reports, however, of an array of neuromuscular and rheumatologic complications related to COVID-19 infection and disease course including myositis, neuropathy, arthropathy, and soft tissue abnormalities. Multimodality imaging supports diagnosis and evaluation of musculoskeletal disorders in COVID-19 patients. This article aims to provide a first comprehensive summary of musculoskeletal manifestations of COVID-19 with review of imaging.

Advanced Materials in Wireless, Implantable Electrical Stimulators That Offer Rapid Rates of Bioresorption for Peripheral Axon Regeneration.

Injured peripheral nerves typically exhibit unsatisfactory and incomplete functional outcomes, and there are no clinically approved therapies for improving regeneration. Post-operative electrical stimulation (ES) increases axon regrowth, but practical challenges from the cost of extended operating room time to the risks and pitfalls associated with transcutaneous wire placement have prevented broad clinical adoption. This study presents a possible solution in the form of advanced bioresorbable materials for thin, flexible, wireless implant that provides precisely controlled ES of the injured nerve for a brief time in the immediate post-operative period. Afterward, rapid, complete and safe modes of bioresorption naturally and quickly eliminate all of the constituent materials in their entirety, without the need for surgical extraction. The unusually high rate of bioresorption follows from the use of a unique, bilayer enclosure that combines two distinct formulations of a biocompatible form of polyanhydride as an encapsulating structure, to accelerate the resorption of active components and confine fragments until complete resorption. Results from mouse models of tibial nerve transection with re-anastomosis indicate that this system offers levels of performance and efficacy that match those of conventional wired stimulators, but without the need to extend the operative period or to extract the device hardware.

Imaging Review of Peripheral Nerve Injuries in Patients with COVID-19.

With surging numbers of patients with coronavirus disease 2019 (COVID-19) throughout the world, neuromuscular complications and rehabilitation concerns are becoming more apparent. Peripheral nerve injury can occur in patients with COVID-19 secondary to postinfectious inflammatory neuropathy, prone positioning-related stretch and/or compression injury, systemic neuropathy, or nerve entrapment from hematoma. Imaging of peripheral nerves in patients with COVID-19 may help to characterize nerve abnormality, to identify site and severity of nerve damage, and to potentially elucidate mechanisms of injury, thereby aiding the medical diagnosis and decision-making process. This review article aims to provide a first comprehensive summary of the current knowledge of COVID-19 and peripheral nerve imaging.